- Email: [email protected]
Role of scavenger receptors in dendritic cell function
Human Immunology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
www.ashi-hla.org
journal homepage: www.elsevier.com/locate/humimm
Review
Role of scavenger receptors in dendritic cell function Dan Wang a, Bo Sun b,⇑, Mei Feng a, Hong Feng a, Wuxian Gong b, Qiang Liu b, Shujian Ge a a b
Shandong Provincial Hospital affiliated to Shandong University, 324 Jing Wu Road, Jinan 250021, Shandong, PR China Shandong Medical Imaging Research Institute, Shandong University, 324 Jing Wu Road, Jinan 250021, Shandong, PR China
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 3 August 2014 Revised 5 February 2015 Accepted 11 March 2015 Available online xxxx
Dendritic cells (DCs), the most potent of the antigen-presenting cells, are crucial in initiating and shaping innate and adaptive immune responses. DCs discriminate unmodified self antigens from non-self and altered/modified self antigens via a large family of receptors called pattern-recognition receptors, which include Toll-like receptors and scavenger receptors (SRs). Recent findings underscore the critical role of SRs on DCs in pathogen clearance, atherosclerosis, apoptotic cell recognition, diesel exhaust particle recognition, etc. These new findings present SRs as an unexplored therapeutic target that warrants further basic and applied research, and have implications for vaccine development. This review highlights recent insights into the emerging role of these receptors in DC-mediated immune responses. Ó 2015 Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics.
Keywords: Scavenger receptors Dendritic cell Antigen-presenting cells
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . Pathogen clearance . . . . . . . . . . . . . Atherosclerosis . . . . . . . . . . . . . . . . . Apoptotic cell clearance . . . . . . . . . . Diesel exhaust particle recognition . Conclusions. . . . . . . . . . . . . . . . . . . . Competing interest. . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
1. Introduction Dendritic cells (DCs), the most potent of the antigen-presenting cells (APCs), are crucial for initiating and shaping innate and adaptive immune responses [1]. DCs play different roles in immunity, such as the activation and regulation of adaptive immune responses, restoration of the resting state, maintenance of self-
Abbreviations: DCs, dendritic cells; APCs, antigen-presenting cells; TLR, Toll like receptors; SR, scavenger receptors; SR-A, scavenger receptor; HCV, hepatitis C virus; oxLDL, oxidized LDL; mBSA, maleylated bovine serum albumin; DEP, diesel exhaust particles; LPS, lipopolysaccharide. ⇑ Corresponding author. Tel.: +86 15168866920. E-mail address: [email protected] (B. Sun).
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
00 00 00 00 00 00 00 00 00
tolerance, and anergy [2]. DCs can discriminate unmodified self antigens from non-self and altered/modified self antigens via a large family of receptors called pattern-recognition receptors, which include signaling receptors (such as Toll-like receptors [TLRs]) and endocytic receptors (such as scavenger receptors [SRs]) [3,4]. Upon stimulation of pattern-recognition receptors by non-self and altered/modified self signals, DCs undergo activation/maturation to an immunogenic phenotype, resulting in the overexpression of major histocompatibility complex (MHC), costimulatory molecules (CD80, CD86), and cytokines, and promoting the activation of naive T-cells [5]. This process ensures the transfer of molecular information collected in the periphery to other immune cell types such as neutrophil granulocytes, T-lymphocytes, B-lymphocytes, natural killer (NK), and NKT cells. DCs play
http://dx.doi.org/10.1016/j.humimm.2015.03.012 0198-8859/Ó 2015 Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics.
Please cite this article in press as: Wang D et al. Role of scavenger receptors in dendritic cell function. Hum Immunol (2015), http://dx.doi.org/10.1016/ j.humimm.2015.03.012
2
D. Wang et al. / Human Immunology xxx (2015) xxx–xxx
a pivotal role in inflammatory diseases, autoimmune diseases, and cancer as well as in the designing of new types of vaccines based on DC biology. Investigating the underlying mechanisms of DC–pathogen interactions may help us to better comprehend the immune response in physiological and pathological events and to identify new targets for therapeutic intervention. SRs were first defined by Goldstein and Brown, and were originally identified by their ability to recognize and remove modified lipoproteins involved in cholesterol and lipoprotein metabolism [6]. However, several reports have showed that some SRs can also recognize unmodified lipoproteins, and studies have supported the role of SR-mediated endocytosis of modified low-density lipoprotein (LDL) in foam cell formation and atherosclerosis [7]. Recent studies have demonstrated the critical role of SRs (CD36 and SR type B, class I [SR-BI]) in platelet hyperreactivity in dyslipidemia and atherosclerosis progression [8]. SR-BI deficiency in mice results in enhanced lymphocyte proliferation and altered cytokine production [9]. SRs carry out a striking and broad range of functions, such as pathogen clearance, apoptotic cell clearance, lipid transport, cellular adhesion, intracellular cargo transport, and even taste perception [8,10–15]. Currently, SRs are recognized to be a large family of structurally diverse, transmembrane and cell-surface glycoproteins restricted to macrophages, DCs, endothelial cells, and a few other cell types [16]. DCs are unique APCs that have the ability to stimulate naive T-cells [17]. The priming and expansion of naive T-cells depend on efficient antigen presentation by the surface receptors on DCs. A recent study reported that cell-surface SR-BI expression is very low or undetectable on human monocytes, T-cells, and B-cells, but high on human DCs and primary human hepatocytes [18]. SR-BI expression is induced during the differentiation of monocytes into DCs [18,19]. These findings indicate that SRs might play a specific role in DC function. Therefore, in this review, we highlight recent insights into the emerging roles of SRs on DCs in the initiation and shaping of innate and adaptive immune responses, notably, in pathogen clearance and atherosclerosis formation.
2. Pathogen clearance DCs are pivotal in the initiation of immune responses to control and eliminate viral and microbial infections. SRs have been reported to play crucial physiological roles in innate immune defense by recognizing several different microbial structures and microbial-surface proteins [12,20,21]. SRs act as phagocytic receptors mediating direct, non-opsonic phagocytosis of pathogenic microbes by macrophages and DCs, and some SRs (such as CD36) have been shown to act as coreceptors for TLRs in responses to microbial diacylglycerides [8,22]. The class A macrophage SR (SR-A) on DCs may dampen the proinflammatory response or products to pathogenic microbes. Becker et al. showed that the expression of murine SR-A is restricted to specific subpopulations of CD11b+DEC-205+MHCII+ bone marrowderived DCs (BM-DCs) and CD11b+CD4-B220 CD80intCD86hi splenic DCs [23]. They demonstrated that the receptor significantly limited DC maturation in response to endotoxin; SR-A /dyslipidemia BM-DCs display enhanced expression of the costimulatory molecule CD40 and increased production of the pro-inflammatory cytokine tumor necrosis factor-a (TNF-a) upon lipopolysaccharide (LPS)-driven maturation. In another study, phagocytosis and uptake of Neisseria meningitidis by human DCs via SR-A were shown to increase the release of TNF-a, interleukin (IL)-1b, and IL-6; the enhanced secretion of IL-8 after recognition was not dependent on phagocytosis [24]. Malaria is a devastating disease that inflicts enormous morbidity and mortality, and is caused by the protozoan parasites,
Plasmodium species [25]. Although several Plasmodium species cause malaria, Plasmodium falciparum accounts for the majority of malarial deaths in humans [26]. Studies have demonstrated that CD36 mediates the binding of P. falciparum-infected red blood cells (iRBCs) to human monocyte-derived DCs and reduces the production of TNF-a and IL-12 [27]. Gowda et al. recently determined the levels of CD36-adherent iRBCs internalized by and the levels of pro-inflammatory cytokines produced by human DCs treated with anti-CD36 antibody and by CD36-deficient murine DCs [28]. Their results confirmed that CD36 contributes significantly to the uptake of iRBCs and the production of pro-inflammatory cytokines by DCs; moreover, DCs with internalized iRBCs could activate NK and T-cells to produce interferon (IFN)-c. Furthermore, they implied that the effect of CD36 on the anti-malarial immunity conferred by DCs is imprinted early during infection when the parasite load is low [28]. Among the blood-borne viruses, hepatitis C virus (HCV) is a major cause of chronic liver inflammation worldwide. Over 75% cases of HCV infection develop into persistent disease that can ultimately progress to cirrhosis and hepatocellular carcinoma [29,30]. DCs play crucial roles in the initiation of antiviral immunity. Although the role of DCs in HCV infection has been extensively studied, the molecular mechanisms of HCV antigen uptake and processing by blood DCs are poorly understood. Some groups have proposed that SRs play a role in HCV-related adaptive immune responses by DCs [31,32]. SR-BI has been demonstrated to play a prominent role in HCV binding and uptake by human monocyte-derived DCs [18]. SR-BI expression was found to continuously increase during the differentiation of monocytes into DCs, and correlate with the initiation of the binding of HCV-like particles (HCV-LPs). These findings indicate that SR-BI may target HCV antigens in the cytosol, where the antigens gain access to the MHC class I presentation pathway; this is followed by efficient cross-presentation to HCV-specific CD8+ T-cells. This novel function of SR-BI is further supported by the observation that high-density lipoprotein (HDL) enhances and anti-SR-BI markedly inhibits the binding of HCV-LPs to DCs. Finally, very low expression of SR-BI was observed on both the myeloid and plasmacytoid subsets of DCs, compared to the expression on in vitro-generated monocyte-derived DCs [18]. In addition, the same group reported in a later work that the acquisition of HCV in cell culture by ex vivo, isolated human myeloid DCs was not markedly altered in the presence of SR-BI antibody [33]. These findings were supported by Marukian et al. who reported that the level of SR-BI RNA expression in human blood DC subsets was >3-log lower than the expression level in in vitro-generated monocyte-derived DCs [34]. Beauvillain et al. [35] demonstrated that maleylated-bovine serum albumin, a ligand of most SRs, inhibited HCV nonstructural protein 3 (NS3) binding to human DCs. Furthermore, by using SR-expressing Chinese hamster ovary (CHO) cells, they observed that NS3 bound to SR-A1- and SR expressed on endothelial cells-I (SREC-I)-transfected CHO cells but not to CHO cells expressing other SRs. Moreover, both SRs and TLR2 contributed to NS3-induced myeloid cell activation [35]. In addition, SR-A and SREC-I participated in the cross presentation of NS3 by DCs, via a mechanism involving the endocytosis of exogenous antigens from infected dying or dead cells by peripheral or intrahepatic DCs, antigen processing in the cytosol/ endosomal compartment, and ‘‘cross routing’’ to the MHC I pathway [36,37]. These data are very relevant to increase our knowledge of the mechanisms involved in HCV infection and facilitate the development of effective vaccines against HCV infection [38]. Furthermore, it has been shown that antigens complexed to heat shock protein 90 (Hsp90) can be specifically bound by SREC-I, endocytosed, and MHC-I cross-presented by murine BM-DCs [39]. It has also been observed that SREC-I can bind and
Please cite this article in press as: Wang D et al. Role of scavenger receptors in dendritic cell function. Hum Immunol (2015), http://dx.doi.org/10.1016/ j.humimm.2015.03.012
D. Wang et al. / Human Immunology xxx (2015) xxx–xxx
3
Fig. 1. Schematic diagram for SRs involved in DCs function in pathogen clearance.
internalize proteins that act as chaperones and enable the uptake of bacterial proteins or peptides via SREC-I into human peripheral blood monocyte-derived DCs, such as the urinary glycoprotein Tamm–Horsfall protein [40] and the pancreatic zymogen granule membrane protein 2 [41]. In addition, SREC-I appears to cooperate with TLR2 to trigger the activation of DCs by Klebsiella pneumonia (Fig. 1). 3. Atherosclerosis Atherosclerosis is regarded as a chronic inflammatory vessel disease characterized by early endothelial dysfunction in response to the endothelial activation of monocytes and T-cells mediating the progression of atherosclerosis [42]. Recent studies have demonstrated the impact of DCs on the initiation and progression of atherosclerosis [43]. DCs in the subendothelial space in the aorta can efficiently accumulate lipids and differentiate into foam cells [44]. DCs located in the vessel wall recognize foreign and autoantigens (oxidized LDL [oxLDL], bacterial and viral antigens, HSP 60/ 65) [45,46]. The uptake of oxLDL by DCs might promote the transition of differentiating monocytes into mature DCs, and result in the enhanced presentation of lipid and peptide antigens to NKT and T-cells, further stimulating vascular inflammation and monocyte adhesion in atherosclerotic plaques [47,48]. SRs are the major receptors of oxLDL. The stimulation of DCs by oxLDL through its binding to SRs (LOX-1, CD36, and CD205) leads to DC activation and can be accompanied by enhanced cytokine production, which is triggered, at least in part, via the activation of the nuclear factor (NF)-kB pathway [49]. These results demonstrate that vascular inflammation may be aggravated by oxLDL-induced DC activation through binding to SRs (CD36 and SR-A) [50]. High glucose levels can induce the upregulation of SRs (SR-A, CD36, and LOX-1) and promote the maturation of DCs in a dose-dependent manner [51]. The blockage of SR-A and CD36 significantly reduce the oxLDL-uptake capacity of DCs, suggesting some contribution of CD36 and SR-A to atherosclerosis formation by human DCs under diabetic conditions. However, the blockage of LOX-1 did not significantly inhibit the endocytosis of DiI-oxLDL by high glucose-treated DCs [51]. The beneficial effect of reconstituted HDL (rHDL) on atherosclerotic plaques has been demonstrated in models of atherosclerosis, myocardial infarction, and stroke [52,53]. One study showed that rHDL inhibited the TLR-induced maturation of DCs. Treatment of DCs with rHDL prevented the upregulation of the cell-surface molecules CD80, CD83, and CD86 and inhibited the TLR-driven activation of the inflammatory transcription factor NF-kB [54]. SR-BI binds to HDL with high affinity, and plays diverse roles in the modulation of global cholesterol homeostasis, vascular cell function, and the potential implications of these processes in
atherosclerosis [55]. Whether or not this receptor participates in the abovementioned inhibitory effect on DCs and the underlying mechanism if it does, require further evaluation. 4. Apoptotic cell clearance Upon stimulation with ‘‘danger signals,’’ DCs transmit three signals, including MHC-Ag, costimulatory molecules (such as CD80 and CD86), and pro-inflammatory cytokines (such as IL-12) to induce immunity. Evidence suggests that DCs must transmit all three signals to effectively activate T-cells. T-cells are tolerized after a cognate interaction with the antigens presented by an APC in the absence of costimulatory molecules. Apoptotic cells have been proposed to suppress DC immunogenicity by ligating specific receptors on the DC surface [56]. CD36 on the DC surface participates in the clearance of apoptotic cells by recognizing the anionic phospholipid phosphatidylserine in the outer leaflets of apoptotic-cell membranes [57]. This SR can also bind apoptotic cells and contribute to their peripheral tolerance, and prevents autoimmunity by impairing DC maturation [58]. One study provided evidence that human peripheral blood plasmacytoid DCs constitutively express CD36 and CD61, which are known to be essential for apoptotic cell-mediated tolerance induction, and constitutively produce IL-10 [59]. A recent study has demonstrated that agonists of monoclonal antibodies to CR3, but not CD36, suppressed DC activity by suppressing inflammatory cytokine release [60]. The mechanism by which CD36 modulates DC activity remains unclear, and further research on this topic may be of therapeutic importance in both transplantation and autoimmunity. The maturation-inducing agents LPS and TNF-a induce monocytederived DC maturation, and might lead to the considerably diminished protein and RNA expression of CD36 [61]. The reduction in CD36 expression during DC maturation might prevent maturing DCs from receiving maturation-inhibitory signals from the binding and uptake of apoptotic cells. The engagement of cell-surface CD36 on mononuclear phagocytes by antibodies or specific ligands (e.g., phosphatidylserine, P. falciparum-infected erythrocytes, and thrombospondin-1) enhances IL-10 secretion, reduces TNF-a and IL-1 secretion [58], and negatively regulates human DC functional maturation [27,61,62]. 5. Diesel exhaust particle recognition Exposure to diesel exhaust particles (DEPs) is associated with an increased incidence of asthma, chronic obstructive pulmonary disease, and allergic rhinitis [63]. DCs have been shown to play a key role in controlling the lung immune response to DEPs, which also modulate DC function [64]. Taront et al. demonstrated that DEPs modulate the effects of TLR2 and TLR4 ligands on the
Please cite this article in press as: Wang D et al. Role of scavenger receptors in dendritic cell function. Hum Immunol (2015), http://dx.doi.org/10.1016/ j.humimm.2015.03.012
4
D. Wang et al. / Human Immunology xxx (2015) xxx–xxx
Table 1 SRs involved in DCs function in atherosclerosis, apoptotic cells clearance and DEP recognition. SR
Ligand
Role in DCs function
DC
References
LOX-1, CD36 and CD205 SR-A, CD36 and LOX-1 CD36 CD36 and CD61 CR3 LOX-1 and SR-B1
oxLDL oxLDL Apoptotic cells Apoptotic cells Abs to CR3 DEP
Mediate oxLDL uptake by DCs Increase the oxLDL uptake capacity of DCs by high glucose Participates in the clearance of apoptotic cells, impaire DC maturation Involve in uptake of apoptotic cells and in induction of tolerance Provides a ‘‘nondanger’’ signal that suppresses the stimulatory capacity of DCs Regulate DC maturation
Human MDDCs Human MDDCs Human MDDCs Human PDCs Mice BMDCs Human MDDCs
[47,48] [49] [55,56] [57] [58–60] [62]
Notes: PBMC-derived DCs (MDDC); Bone marrow-derived DCs (BMDCs); Plasmacytoid dendritic cells (PDC); Diesel exhaust particles (DEP).
expression of the SRs LOX-1 and SR-B1 on monocyte-derived DCs [64]. Pretreatment with the SR ligand maleylated ovalbumin inhibited the endocytosis of DEPs by monocyte-derived DCs [65]. Moreover, a low dose (1 lg/ml) of this SR ligand blocked the effects of DEPs on the LPS-activated DC phenotype (decrease in CD86 and HLA-DR expression) and on the secretion of CXCL10, IL-12, and TNF-a [64]. These results show that interfering with the expression and function of SRs might be one way to limit the impact of DEPs on the lung immune response [64]. Furthermore, RUNX3 regulates the activity of the CD36 promoter and negatively regulates CD36 expression in myeloid cell lines through RUNX-binding elements at positions 33 and 98 [66]. The class G SR (SR-PSOX) was originally identified as a transmembrane-type chemokine designated CXCL16 and is also expressed in DCs [16] (Table 1). 6. Conclusions A growing body of evidence demonstrates that several SRs play important roles in DC function by acting as pattern-recognition receptors or coreceptors of TLRs. In addition, the molecular basis of the recognition and signaling pathways for many SRs on DCs are poorly understood, as these receptors have rather broad ligand-binding specificity. Recent findings also underscore a critical role of SRs in immune responses. It will be especially interesting to assess the impact of naturally occurring SRs involved in many critical cellular processes on DC immune responses, and this have implications for vaccine development. Competing interest The authors declare that they have no competing interests. Acknowledgments This study was supported by the National Natural Science Foundation of China (Nos. 81202307, 81201144, 31100836, and 81201865) and Shandong Provincial Science and Technology Development Plan (No. 2014GSF118137). References [1] Szabo A, Rajnavolgyi E. Collaboration of Toll-like and RIG-I-like receptors in human dendritic cells: tRIGgering antiviral innate immune responses. Am. J. Clin. Exp. Immunol. 2013;2:195–207. [2] Steinman RM. Decisions about dendritic cells: past, present, and future. Annu. Rev. Immunol. 2012;30:1–22. [3] Peiser L, Mukhopadhyay S, Gordon S. Scavenger receptors in innate immunity. Curr. Opin. Immunol. 2002;14:123–8. [4] Steinman RM, Hemmi H. Dendritic cells: translating innate to adaptive immunity. Curr. Top. Microbiol. Immunol. 2006;311:17–58. [5] Jenkins MK, Schwartz RH. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J. Exp. Med. 1987;165:302–19. [6] Goldstein JL, Ho YK, Basu SK, Brown MS. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc. Natl. Acad. Sci. USA 1979;76:333–7.
[7] Tsou CY, Chen CY, Zhao JF, Su KH, Lee HT, Lin SJ, et al. Activation of soluble guanylyl cyclase prevents foam cell formation and atherosclerosis. Acta. Physiol. 2014;210:799–810. [8] Areschoug T, Gordon S. Scavenger receptors: role in innate immunity and microbial pathogenesis. Cell. Microbiol. 2009;11:1160–9. [9] Feng H, Guo L, Wang D, Gao H, Hou G, Zheng Z, et al. Deficiency of scavenger receptor BI leads to impaired lymphocyte homeostasis and autoimmune disorders in mice. Arterioscler. Thromb. Vasc. Biol. 2011;31:2543–51. [10] Pluddemann A, Neyen C, Gordon S. Macrophage scavenger receptors and hostderived ligands. Methods 2007;43:207–17. [11] Canton J, Neculai D, Grinstein S. Scavenger receptors in homeostasis and immunity. Nat. Rev. Immunol. 2013;13:621–34. [12] Mukhopadhyay S, Gordon S. The role of scavenger receptors in pathogen recognition and innate immunity. Immunobiology 2004;209:39–49. [13] Sun M, Finnemann SC, Febbraio M, Shan L, Annangudi SP, Podrez EA, et al. Light-induced oxidation of photoreceptor outer segment phospholipids generates ligands for CD36-mediated phagocytosis by retinal pigment epithelium: a potential mechanism for modulating outer segment phagocytosis under oxidant stress conditions. J. Biol. Chem. 2006;281:4222–30. [14] Herrmann M, Schafer C, Heiss A, Graber S, Kinkeldey A, Buscher A, et al. Clearance of fetuin-A-containing calciprotein particles is mediated by scavenger receptor-A. Circ. Res. 2012;111:575–84. [15] Taylor PR, Martinez-Pomares L, Stacey M, Lin HH, Brown GD, Gordon S. Macrophage receptors and immune recognition. Annu. Rev. Immunol. 2005;23:901–44. [16] Murphy JE, Tedbury PR, Homer-Vanniasinkam S, Walker JH, Ponnambalam S. Biochemistry and cell biology of mammalian scavenger receptors. Atherosclerosis 2005;182:1–15. [17] Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245–52. [18] Barth H, Schnober EK, Neumann-Haefelin C, Thumann C, Zeisel MB, Diepolder HM, et al. Scavenger receptor class B is required for hepatitis C virus uptake and cross-presentation by human dendritic cells. J. Virol. 2008;82:3466–79. [19] Buechler C, Ritter M, Quoc CD, Agildere A, Schmitz G. Lipopolysaccharide inhibits the expression of the scavenger receptor Cla-1 in human monocytes and macrophages. Biochem. Biophys. Res. Commun. 1999;262:251–4. [20] Areschoug T, Gordon S. Pattern recognition receptors and their role in innate immunity: focus on microbial protein ligands. Contrib. Microbiol. 2008;15:45–60. [21] Pluddemann A, Hoe JC, Makepeace K, Moxon ER, Gordon S. The macrophage scavenger receptor A is host-protective in experimental meningococcal septicaemia. PLoS Pathog. 2009;5:e1000297. [22] Hoebe K, Georgel P, Rutschmann S, Du X, Mudd S, Crozat K, et al. CD36 is a sensor of diacylglycerides. Nature 2005;433:523–7. [23] Becker M, Cotena A, Gordon S, Platt N. Expression of the class A macrophage scavenger receptor on specific subpopulations of murine dendritic cells limits their endotoxin response. Eur. J. Immunol. 2006;36:950–60. [24] Villwock A, Schmitt C, Schielke S, Frosch M, Kurzai O. Recognition via the class A scavenger receptor modulates cytokine secretion by human dendritic cells after contact with Neisseria meningitidis. Microbes Infect. 2008;10:1158–65. [25] Gething PW, Patil AP, Smith DL, Guerra CA, Elyazar IR, Johnston GL, et al. A new world malaria map: Plasmodium falciparum endemicity in 2010. Malar. J. 2011;10:378. [26] Guerra CA, Gikandi PW, Tatem AJ, Noor AM, Smith DL, Hay SI, et al. The limits and intensity of Plasmodium falciparum transmission: implications for malaria control and elimination worldwide. PLoS Med. 2008;5:e38. [27] Urban BC, Willcox N, Roberts DJ. A role for CD36 in the regulation of dendritic cell function. Proc. Natl. Acad. Sci. USA 2001;98:8750–5. [28] Gowda NM, Wu X, Kumar S, Febbraio M, Gowda DC. CD36 contributes to malaria parasite-induced pro-inflammatory cytokine production and NK and T cell activation by dendritic cells. PLoS One 2013;8:e77604. [29] Hoofnagle JH. Course and outcome of hepatitis C. Hepatology 2002;36:S21–9. [30] Webster DP, Klenerman P, Collier J, Jeffery KJ. Development of novel treatments for hepatitis C. Lancet Infect. Dis. 2009;9:108–17. [31] Scarselli E, Ansuini H, Cerino R, Roccasecca RM, Acali S, Filocamo G, et al. The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO J. 2002;21:5017–25. [32] Bartosch B, Vitelli A, Granier C, Goujon C, Dubuisson J, Pascale S, et al. Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor. J. Biol. Chem. 2003;278: 41624–30.
Please cite this article in press as: Wang D et al. Role of scavenger receptors in dendritic cell function. Hum Immunol (2015), http://dx.doi.org/10.1016/ j.humimm.2015.03.012
D. Wang et al. / Human Immunology xxx (2015) xxx–xxx [33] Lambotin M, Baumert TF, Barth H. Distinct intracellular trafficking of hepatitis C virus in myeloid and plasmacytoid dendritic cells. J. Virol. 2010;84:8964–9. [34] Marukian S, Jones CT, Andrus L, Evans MJ, Ritola KD, Charles ED, et al. Cell culture-produced hepatitis C virus does not infect peripheral blood mononuclear cells. Hepatology 2008;48:1843–50. [35] Beauvillain C, Meloni F, Sirard JC, Blanchard S, Jarry U, Scotet M, et al. The scavenger receptors SRA-1 and SREC-I cooperate with TLR2 in the recognition of the hepatitis C virus non-structural protein 3 by dendritic cells. J. Hepatol. 2010;52:644–51. [36] Accapezzato D, Visco V, Francavilla V, Molette C, Donato T, Paroli M, et al. Chloroquine enhances human CD8+ T cell responses against soluble antigens in vivo. J. Exp. Med. 2005;202:817–28. [37] Spadaro F, Lapenta C, Donati S, Abalsamo L, Barnaba V, Belardelli F, et al. IFNalpha enhances cross-presentation in human dendritic cells by modulating antigen survival, endocytic routing, and processing. Blood 2012;119:1407–17. [38] Armengol C, Bartoli R, Sanjurjo L, Serra I, Amezaga N, Sala M, et al. Role of scavenger receptors in the pathophysiology of chronic liver diseases. Crit. Rev. Immunol. 2013;33:57–96. [39] Murshid A, Gong J, Calderwood SK. Heat shock protein 90 mediates efficient antigen cross presentation through the scavenger receptor expressed by endothelial cells-I. J. Immunol. 2010;185:2903–17. [40] Pfistershammer K, Klauser C, Leitner J, Stockl J, Majdic O, Weichhart T, et al. Identification of the scavenger receptors SREC-I, Cla-1 (SR-BI), and SR-AI as cellular receptors for Tamm–Horsfall protein. J. Leukoc. Biol. 2008;83: 131–8. [41] Holzl MA, Hofer J, Kovarik JJ, Roggenbuck D, Reinhold D, Goihl A, et al. The zymogen granule protein 2 (GP2) binds to scavenger receptor expressed on endothelial cells I (SREC-I). Cell. Immunol. 2011;267:88–93. [42] Busch M, Westhofen TC, Koch M, Lutz MB, Zernecke A. Dendritic cell subset distributions in the aorta in healthy and atherosclerotic mice. PLoS One 2014;9:e88452. [43] Perrins CJ, Bobryshev YV. Current advances in understanding of immunopathology of atherosclerosis. Virchows Arch. 2011;458:117–23. [44] Paulson KE, Zhu SN, Chen M, Nurmohamed S, Jongstra-Bilen J, Cybulsky MI. Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis. Circ. Res. 2010;106:383–90. [45] Bobryshev YV. Dendritic cells in atherosclerosis: current status of the problem and clinical relevance. Eur. Heart J. 2005;26:1700–4. [46] Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 2005;352:1685–95. [47] Alderman CJ, Bunyard PR, Chain BM, Foreman JC, Leake DS, Katz DR. Effects of oxidised low density lipoprotein on dendritic cells: a possible immunoregulatory component of the atherogenic micro-environment? Cardiovasc. Res. 2002;55:806–19. [48] Coutant F, Perrin-Cocon L, Agaugue S, Delair T, Andre P, Lotteau V. Mature dendritic cell generation promoted by lysophosphatidylcholine. J. Immunol. 2002;169:1688–95. [49] Nickel T, Schmauss D, Hanssen H, Sicic Z, Krebs B, Jankl S, et al. OxLDL uptake by dendritic cells induces upregulation of scavenger-receptors, maturation and differentiation. Atherosclerosis 2009;205:442–50.
5
[50] Miller YI, Choi SH, Wiesner P, Fang L, Harkewicz R, Hartvigsen K, et al. Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ. Res. 2011;108:235–48. [51] Lu H, Yao K, Huang D, Sun A, Zou Y, Qian J, et al. High glucose induces upregulation of scavenger receptors and promotes maturation of dendritic cells. Cardiovasc. Diabetol. 2013;12:80. [52] Tardif JC, Gregoire J, L’Allier PL, Ibrahim R, Lesperance J, Heinonen TM, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 2007;297:1675–82. [53] Shaw JA, Bobik A, Murphy A, Kanellakis P, Blombery P, Mukhamedova N, et al. Infusion of reconstituted high-density lipoprotein leads to acute changes in human atherosclerotic plaque. Circ. Res. 2008;103:1084–91. [54] Spirig R, Schaub A, Kropf A, Miescher S, Spycher MO, Rieben R. Reconstituted high-density lipoprotein modulates activation of human leukocytes. PLoS One 2013;8:e71235. [55] Mineo C, Shaul PW. Functions of scavenger receptor class B, type I in atherosclerosis. Curr. Opin. Lipidol. 2012;23:487–93. [56] Ip WK, Lau YL. Distinct maturation of, but not migration between, human monocyte-derived dendritic cells upon ingestion of apoptotic cells of early or late phases. J. Immunol. 2004;173:189–96. [57] Albert ML, Pearce SF, Francisco LM, Sauter B, Roy P, Silverstein RL, et al. Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J. Exp. Med. 1998;188:1359–68. [58] Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I. Immunosuppressive effects of apoptotic cells. Nature 1997;390:350–1. [59] Parcina M, Schiller M, Gierschke A, Heeg K, Bekeredjian-Ding I. PDC expressing CD36, CD61 and IL-10 may contribute to propagation of immune tolerance. Autoimmunity 2009;42:353–5. [60] Behrens EM, Sriram U, Shivers DK, Gallucci M, Ma Z, Finkel TH, et al. Complement receptor 3 ligation of dendritic cells suppresses their stimulatory capacity. J. Immunol. 2007;178:6268–79. [61] Chen X, Doffek K, Sugg SL, Shilyansky J. Phosphatidylserine regulates the maturation of human dendritic cells. J. Immunol. 2004;173:2985–94. [62] Doyen V, Rubio M, Braun D, Nakajima T, Abe J, Saito H, et al. Thrombospondin 1 is an autocrine negative regulator of human dendritic cell activation. J. Exp. Med. 2003;198:1277–83. [63] Porter M, Karp M, Killedar S, Bauer SM, Guo J, Williams D, et al. Diesel-enriched particulate matter functionally activates human dendritic cells. Am. J. Respir. Cell. Mol. Biol. 2007;37:706–19. [64] Taront S, Dieudonne A, Blanchard S, Jeannin P, Lassalle P, Delneste Y, et al. Implication of scavenger receptors in the interactions between diesel exhaust particles and immature or mature dendritic cells. Part. Fibre Toxicol. 2009;6:9. [65] Abraham R, Singh N, Mukhopadhyay A, Basu SK, Bal V, Rath S. Modulation of immunogenicity and antigenicity of proteins by maleylation to target scavenger receptors on macrophages. J. Immunol. 1995;154(1):1–8. [66] Puig-Kroger A, Dominguez-Soto A, Martinez-Munoz L, Serrano-Gomez D, Lopez-Bravo M, Sierra-Filardi E, et al. RUNX3 negatively regulates CD36 expression in myeloid cell lines. J. Immunol. 2006;177:2107–14.
Please cite this article in press as: Wang D et al. Role of scavenger receptors in dendritic cell function. Hum Immunol (2015), http://dx.doi.org/10.1016/ j.humimm.2015.03.012
Contents lists available at ScienceDirect
www.ashi-hla.org
journal homepage: www.elsevier.com/locate/humimm
Review
Role of scavenger receptors in dendritic cell function Dan Wang a, Bo Sun b,⇑, Mei Feng a, Hong Feng a, Wuxian Gong b, Qiang Liu b, Shujian Ge a a b
Shandong Provincial Hospital affiliated to Shandong University, 324 Jing Wu Road, Jinan 250021, Shandong, PR China Shandong Medical Imaging Research Institute, Shandong University, 324 Jing Wu Road, Jinan 250021, Shandong, PR China
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 3 August 2014 Revised 5 February 2015 Accepted 11 March 2015 Available online xxxx
Dendritic cells (DCs), the most potent of the antigen-presenting cells, are crucial in initiating and shaping innate and adaptive immune responses. DCs discriminate unmodified self antigens from non-self and altered/modified self antigens via a large family of receptors called pattern-recognition receptors, which include Toll-like receptors and scavenger receptors (SRs). Recent findings underscore the critical role of SRs on DCs in pathogen clearance, atherosclerosis, apoptotic cell recognition, diesel exhaust particle recognition, etc. These new findings present SRs as an unexplored therapeutic target that warrants further basic and applied research, and have implications for vaccine development. This review highlights recent insights into the emerging role of these receptors in DC-mediated immune responses. Ó 2015 Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics.
Keywords: Scavenger receptors Dendritic cell Antigen-presenting cells
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . Pathogen clearance . . . . . . . . . . . . . Atherosclerosis . . . . . . . . . . . . . . . . . Apoptotic cell clearance . . . . . . . . . . Diesel exhaust particle recognition . Conclusions. . . . . . . . . . . . . . . . . . . . Competing interest. . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
1. Introduction Dendritic cells (DCs), the most potent of the antigen-presenting cells (APCs), are crucial for initiating and shaping innate and adaptive immune responses [1]. DCs play different roles in immunity, such as the activation and regulation of adaptive immune responses, restoration of the resting state, maintenance of self-
Abbreviations: DCs, dendritic cells; APCs, antigen-presenting cells; TLR, Toll like receptors; SR, scavenger receptors; SR-A, scavenger receptor; HCV, hepatitis C virus; oxLDL, oxidized LDL; mBSA, maleylated bovine serum albumin; DEP, diesel exhaust particles; LPS, lipopolysaccharide. ⇑ Corresponding author. Tel.: +86 15168866920. E-mail address: [email protected] (B. Sun).
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
. . . . . . . . .
00 00 00 00 00 00 00 00 00
tolerance, and anergy [2]. DCs can discriminate unmodified self antigens from non-self and altered/modified self antigens via a large family of receptors called pattern-recognition receptors, which include signaling receptors (such as Toll-like receptors [TLRs]) and endocytic receptors (such as scavenger receptors [SRs]) [3,4]. Upon stimulation of pattern-recognition receptors by non-self and altered/modified self signals, DCs undergo activation/maturation to an immunogenic phenotype, resulting in the overexpression of major histocompatibility complex (MHC), costimulatory molecules (CD80, CD86), and cytokines, and promoting the activation of naive T-cells [5]. This process ensures the transfer of molecular information collected in the periphery to other immune cell types such as neutrophil granulocytes, T-lymphocytes, B-lymphocytes, natural killer (NK), and NKT cells. DCs play
http://dx.doi.org/10.1016/j.humimm.2015.03.012 0198-8859/Ó 2015 Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics.
Please cite this article in press as: Wang D et al. Role of scavenger receptors in dendritic cell function. Hum Immunol (2015), http://dx.doi.org/10.1016/ j.humimm.2015.03.012
2
D. Wang et al. / Human Immunology xxx (2015) xxx–xxx
a pivotal role in inflammatory diseases, autoimmune diseases, and cancer as well as in the designing of new types of vaccines based on DC biology. Investigating the underlying mechanisms of DC–pathogen interactions may help us to better comprehend the immune response in physiological and pathological events and to identify new targets for therapeutic intervention. SRs were first defined by Goldstein and Brown, and were originally identified by their ability to recognize and remove modified lipoproteins involved in cholesterol and lipoprotein metabolism [6]. However, several reports have showed that some SRs can also recognize unmodified lipoproteins, and studies have supported the role of SR-mediated endocytosis of modified low-density lipoprotein (LDL) in foam cell formation and atherosclerosis [7]. Recent studies have demonstrated the critical role of SRs (CD36 and SR type B, class I [SR-BI]) in platelet hyperreactivity in dyslipidemia and atherosclerosis progression [8]. SR-BI deficiency in mice results in enhanced lymphocyte proliferation and altered cytokine production [9]. SRs carry out a striking and broad range of functions, such as pathogen clearance, apoptotic cell clearance, lipid transport, cellular adhesion, intracellular cargo transport, and even taste perception [8,10–15]. Currently, SRs are recognized to be a large family of structurally diverse, transmembrane and cell-surface glycoproteins restricted to macrophages, DCs, endothelial cells, and a few other cell types [16]. DCs are unique APCs that have the ability to stimulate naive T-cells [17]. The priming and expansion of naive T-cells depend on efficient antigen presentation by the surface receptors on DCs. A recent study reported that cell-surface SR-BI expression is very low or undetectable on human monocytes, T-cells, and B-cells, but high on human DCs and primary human hepatocytes [18]. SR-BI expression is induced during the differentiation of monocytes into DCs [18,19]. These findings indicate that SRs might play a specific role in DC function. Therefore, in this review, we highlight recent insights into the emerging roles of SRs on DCs in the initiation and shaping of innate and adaptive immune responses, notably, in pathogen clearance and atherosclerosis formation.
2. Pathogen clearance DCs are pivotal in the initiation of immune responses to control and eliminate viral and microbial infections. SRs have been reported to play crucial physiological roles in innate immune defense by recognizing several different microbial structures and microbial-surface proteins [12,20,21]. SRs act as phagocytic receptors mediating direct, non-opsonic phagocytosis of pathogenic microbes by macrophages and DCs, and some SRs (such as CD36) have been shown to act as coreceptors for TLRs in responses to microbial diacylglycerides [8,22]. The class A macrophage SR (SR-A) on DCs may dampen the proinflammatory response or products to pathogenic microbes. Becker et al. showed that the expression of murine SR-A is restricted to specific subpopulations of CD11b+DEC-205+MHCII+ bone marrowderived DCs (BM-DCs) and CD11b+CD4-B220 CD80intCD86hi splenic DCs [23]. They demonstrated that the receptor significantly limited DC maturation in response to endotoxin; SR-A /dyslipidemia BM-DCs display enhanced expression of the costimulatory molecule CD40 and increased production of the pro-inflammatory cytokine tumor necrosis factor-a (TNF-a) upon lipopolysaccharide (LPS)-driven maturation. In another study, phagocytosis and uptake of Neisseria meningitidis by human DCs via SR-A were shown to increase the release of TNF-a, interleukin (IL)-1b, and IL-6; the enhanced secretion of IL-8 after recognition was not dependent on phagocytosis [24]. Malaria is a devastating disease that inflicts enormous morbidity and mortality, and is caused by the protozoan parasites,
Plasmodium species [25]. Although several Plasmodium species cause malaria, Plasmodium falciparum accounts for the majority of malarial deaths in humans [26]. Studies have demonstrated that CD36 mediates the binding of P. falciparum-infected red blood cells (iRBCs) to human monocyte-derived DCs and reduces the production of TNF-a and IL-12 [27]. Gowda et al. recently determined the levels of CD36-adherent iRBCs internalized by and the levels of pro-inflammatory cytokines produced by human DCs treated with anti-CD36 antibody and by CD36-deficient murine DCs [28]. Their results confirmed that CD36 contributes significantly to the uptake of iRBCs and the production of pro-inflammatory cytokines by DCs; moreover, DCs with internalized iRBCs could activate NK and T-cells to produce interferon (IFN)-c. Furthermore, they implied that the effect of CD36 on the anti-malarial immunity conferred by DCs is imprinted early during infection when the parasite load is low [28]. Among the blood-borne viruses, hepatitis C virus (HCV) is a major cause of chronic liver inflammation worldwide. Over 75% cases of HCV infection develop into persistent disease that can ultimately progress to cirrhosis and hepatocellular carcinoma [29,30]. DCs play crucial roles in the initiation of antiviral immunity. Although the role of DCs in HCV infection has been extensively studied, the molecular mechanisms of HCV antigen uptake and processing by blood DCs are poorly understood. Some groups have proposed that SRs play a role in HCV-related adaptive immune responses by DCs [31,32]. SR-BI has been demonstrated to play a prominent role in HCV binding and uptake by human monocyte-derived DCs [18]. SR-BI expression was found to continuously increase during the differentiation of monocytes into DCs, and correlate with the initiation of the binding of HCV-like particles (HCV-LPs). These findings indicate that SR-BI may target HCV antigens in the cytosol, where the antigens gain access to the MHC class I presentation pathway; this is followed by efficient cross-presentation to HCV-specific CD8+ T-cells. This novel function of SR-BI is further supported by the observation that high-density lipoprotein (HDL) enhances and anti-SR-BI markedly inhibits the binding of HCV-LPs to DCs. Finally, very low expression of SR-BI was observed on both the myeloid and plasmacytoid subsets of DCs, compared to the expression on in vitro-generated monocyte-derived DCs [18]. In addition, the same group reported in a later work that the acquisition of HCV in cell culture by ex vivo, isolated human myeloid DCs was not markedly altered in the presence of SR-BI antibody [33]. These findings were supported by Marukian et al. who reported that the level of SR-BI RNA expression in human blood DC subsets was >3-log lower than the expression level in in vitro-generated monocyte-derived DCs [34]. Beauvillain et al. [35] demonstrated that maleylated-bovine serum albumin, a ligand of most SRs, inhibited HCV nonstructural protein 3 (NS3) binding to human DCs. Furthermore, by using SR-expressing Chinese hamster ovary (CHO) cells, they observed that NS3 bound to SR-A1- and SR expressed on endothelial cells-I (SREC-I)-transfected CHO cells but not to CHO cells expressing other SRs. Moreover, both SRs and TLR2 contributed to NS3-induced myeloid cell activation [35]. In addition, SR-A and SREC-I participated in the cross presentation of NS3 by DCs, via a mechanism involving the endocytosis of exogenous antigens from infected dying or dead cells by peripheral or intrahepatic DCs, antigen processing in the cytosol/ endosomal compartment, and ‘‘cross routing’’ to the MHC I pathway [36,37]. These data are very relevant to increase our knowledge of the mechanisms involved in HCV infection and facilitate the development of effective vaccines against HCV infection [38]. Furthermore, it has been shown that antigens complexed to heat shock protein 90 (Hsp90) can be specifically bound by SREC-I, endocytosed, and MHC-I cross-presented by murine BM-DCs [39]. It has also been observed that SREC-I can bind and
Please cite this article in press as: Wang D et al. Role of scavenger receptors in dendritic cell function. Hum Immunol (2015), http://dx.doi.org/10.1016/ j.humimm.2015.03.012
D. Wang et al. / Human Immunology xxx (2015) xxx–xxx
3
Fig. 1. Schematic diagram for SRs involved in DCs function in pathogen clearance.
internalize proteins that act as chaperones and enable the uptake of bacterial proteins or peptides via SREC-I into human peripheral blood monocyte-derived DCs, such as the urinary glycoprotein Tamm–Horsfall protein [40] and the pancreatic zymogen granule membrane protein 2 [41]. In addition, SREC-I appears to cooperate with TLR2 to trigger the activation of DCs by Klebsiella pneumonia (Fig. 1). 3. Atherosclerosis Atherosclerosis is regarded as a chronic inflammatory vessel disease characterized by early endothelial dysfunction in response to the endothelial activation of monocytes and T-cells mediating the progression of atherosclerosis [42]. Recent studies have demonstrated the impact of DCs on the initiation and progression of atherosclerosis [43]. DCs in the subendothelial space in the aorta can efficiently accumulate lipids and differentiate into foam cells [44]. DCs located in the vessel wall recognize foreign and autoantigens (oxidized LDL [oxLDL], bacterial and viral antigens, HSP 60/ 65) [45,46]. The uptake of oxLDL by DCs might promote the transition of differentiating monocytes into mature DCs, and result in the enhanced presentation of lipid and peptide antigens to NKT and T-cells, further stimulating vascular inflammation and monocyte adhesion in atherosclerotic plaques [47,48]. SRs are the major receptors of oxLDL. The stimulation of DCs by oxLDL through its binding to SRs (LOX-1, CD36, and CD205) leads to DC activation and can be accompanied by enhanced cytokine production, which is triggered, at least in part, via the activation of the nuclear factor (NF)-kB pathway [49]. These results demonstrate that vascular inflammation may be aggravated by oxLDL-induced DC activation through binding to SRs (CD36 and SR-A) [50]. High glucose levels can induce the upregulation of SRs (SR-A, CD36, and LOX-1) and promote the maturation of DCs in a dose-dependent manner [51]. The blockage of SR-A and CD36 significantly reduce the oxLDL-uptake capacity of DCs, suggesting some contribution of CD36 and SR-A to atherosclerosis formation by human DCs under diabetic conditions. However, the blockage of LOX-1 did not significantly inhibit the endocytosis of DiI-oxLDL by high glucose-treated DCs [51]. The beneficial effect of reconstituted HDL (rHDL) on atherosclerotic plaques has been demonstrated in models of atherosclerosis, myocardial infarction, and stroke [52,53]. One study showed that rHDL inhibited the TLR-induced maturation of DCs. Treatment of DCs with rHDL prevented the upregulation of the cell-surface molecules CD80, CD83, and CD86 and inhibited the TLR-driven activation of the inflammatory transcription factor NF-kB [54]. SR-BI binds to HDL with high affinity, and plays diverse roles in the modulation of global cholesterol homeostasis, vascular cell function, and the potential implications of these processes in
atherosclerosis [55]. Whether or not this receptor participates in the abovementioned inhibitory effect on DCs and the underlying mechanism if it does, require further evaluation. 4. Apoptotic cell clearance Upon stimulation with ‘‘danger signals,’’ DCs transmit three signals, including MHC-Ag, costimulatory molecules (such as CD80 and CD86), and pro-inflammatory cytokines (such as IL-12) to induce immunity. Evidence suggests that DCs must transmit all three signals to effectively activate T-cells. T-cells are tolerized after a cognate interaction with the antigens presented by an APC in the absence of costimulatory molecules. Apoptotic cells have been proposed to suppress DC immunogenicity by ligating specific receptors on the DC surface [56]. CD36 on the DC surface participates in the clearance of apoptotic cells by recognizing the anionic phospholipid phosphatidylserine in the outer leaflets of apoptotic-cell membranes [57]. This SR can also bind apoptotic cells and contribute to their peripheral tolerance, and prevents autoimmunity by impairing DC maturation [58]. One study provided evidence that human peripheral blood plasmacytoid DCs constitutively express CD36 and CD61, which are known to be essential for apoptotic cell-mediated tolerance induction, and constitutively produce IL-10 [59]. A recent study has demonstrated that agonists of monoclonal antibodies to CR3, but not CD36, suppressed DC activity by suppressing inflammatory cytokine release [60]. The mechanism by which CD36 modulates DC activity remains unclear, and further research on this topic may be of therapeutic importance in both transplantation and autoimmunity. The maturation-inducing agents LPS and TNF-a induce monocytederived DC maturation, and might lead to the considerably diminished protein and RNA expression of CD36 [61]. The reduction in CD36 expression during DC maturation might prevent maturing DCs from receiving maturation-inhibitory signals from the binding and uptake of apoptotic cells. The engagement of cell-surface CD36 on mononuclear phagocytes by antibodies or specific ligands (e.g., phosphatidylserine, P. falciparum-infected erythrocytes, and thrombospondin-1) enhances IL-10 secretion, reduces TNF-a and IL-1 secretion [58], and negatively regulates human DC functional maturation [27,61,62]. 5. Diesel exhaust particle recognition Exposure to diesel exhaust particles (DEPs) is associated with an increased incidence of asthma, chronic obstructive pulmonary disease, and allergic rhinitis [63]. DCs have been shown to play a key role in controlling the lung immune response to DEPs, which also modulate DC function [64]. Taront et al. demonstrated that DEPs modulate the effects of TLR2 and TLR4 ligands on the
Please cite this article in press as: Wang D et al. Role of scavenger receptors in dendritic cell function. Hum Immunol (2015), http://dx.doi.org/10.1016/ j.humimm.2015.03.012
4
D. Wang et al. / Human Immunology xxx (2015) xxx–xxx
Table 1 SRs involved in DCs function in atherosclerosis, apoptotic cells clearance and DEP recognition. SR
Ligand
Role in DCs function
DC
References
LOX-1, CD36 and CD205 SR-A, CD36 and LOX-1 CD36 CD36 and CD61 CR3 LOX-1 and SR-B1
oxLDL oxLDL Apoptotic cells Apoptotic cells Abs to CR3 DEP
Mediate oxLDL uptake by DCs Increase the oxLDL uptake capacity of DCs by high glucose Participates in the clearance of apoptotic cells, impaire DC maturation Involve in uptake of apoptotic cells and in induction of tolerance Provides a ‘‘nondanger’’ signal that suppresses the stimulatory capacity of DCs Regulate DC maturation
Human MDDCs Human MDDCs Human MDDCs Human PDCs Mice BMDCs Human MDDCs
[47,48] [49] [55,56] [57] [58–60] [62]
Notes: PBMC-derived DCs (MDDC); Bone marrow-derived DCs (BMDCs); Plasmacytoid dendritic cells (PDC); Diesel exhaust particles (DEP).
expression of the SRs LOX-1 and SR-B1 on monocyte-derived DCs [64]. Pretreatment with the SR ligand maleylated ovalbumin inhibited the endocytosis of DEPs by monocyte-derived DCs [65]. Moreover, a low dose (1 lg/ml) of this SR ligand blocked the effects of DEPs on the LPS-activated DC phenotype (decrease in CD86 and HLA-DR expression) and on the secretion of CXCL10, IL-12, and TNF-a [64]. These results show that interfering with the expression and function of SRs might be one way to limit the impact of DEPs on the lung immune response [64]. Furthermore, RUNX3 regulates the activity of the CD36 promoter and negatively regulates CD36 expression in myeloid cell lines through RUNX-binding elements at positions 33 and 98 [66]. The class G SR (SR-PSOX) was originally identified as a transmembrane-type chemokine designated CXCL16 and is also expressed in DCs [16] (Table 1). 6. Conclusions A growing body of evidence demonstrates that several SRs play important roles in DC function by acting as pattern-recognition receptors or coreceptors of TLRs. In addition, the molecular basis of the recognition and signaling pathways for many SRs on DCs are poorly understood, as these receptors have rather broad ligand-binding specificity. Recent findings also underscore a critical role of SRs in immune responses. It will be especially interesting to assess the impact of naturally occurring SRs involved in many critical cellular processes on DC immune responses, and this have implications for vaccine development. Competing interest The authors declare that they have no competing interests. Acknowledgments This study was supported by the National Natural Science Foundation of China (Nos. 81202307, 81201144, 31100836, and 81201865) and Shandong Provincial Science and Technology Development Plan (No. 2014GSF118137). References [1] Szabo A, Rajnavolgyi E. Collaboration of Toll-like and RIG-I-like receptors in human dendritic cells: tRIGgering antiviral innate immune responses. Am. J. Clin. Exp. Immunol. 2013;2:195–207. [2] Steinman RM. Decisions about dendritic cells: past, present, and future. Annu. Rev. Immunol. 2012;30:1–22. [3] Peiser L, Mukhopadhyay S, Gordon S. Scavenger receptors in innate immunity. Curr. Opin. Immunol. 2002;14:123–8. [4] Steinman RM, Hemmi H. Dendritic cells: translating innate to adaptive immunity. Curr. Top. Microbiol. Immunol. 2006;311:17–58. [5] Jenkins MK, Schwartz RH. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J. Exp. Med. 1987;165:302–19. [6] Goldstein JL, Ho YK, Basu SK, Brown MS. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc. Natl. Acad. Sci. USA 1979;76:333–7.
[7] Tsou CY, Chen CY, Zhao JF, Su KH, Lee HT, Lin SJ, et al. Activation of soluble guanylyl cyclase prevents foam cell formation and atherosclerosis. Acta. Physiol. 2014;210:799–810. [8] Areschoug T, Gordon S. Scavenger receptors: role in innate immunity and microbial pathogenesis. Cell. Microbiol. 2009;11:1160–9. [9] Feng H, Guo L, Wang D, Gao H, Hou G, Zheng Z, et al. Deficiency of scavenger receptor BI leads to impaired lymphocyte homeostasis and autoimmune disorders in mice. Arterioscler. Thromb. Vasc. Biol. 2011;31:2543–51. [10] Pluddemann A, Neyen C, Gordon S. Macrophage scavenger receptors and hostderived ligands. Methods 2007;43:207–17. [11] Canton J, Neculai D, Grinstein S. Scavenger receptors in homeostasis and immunity. Nat. Rev. Immunol. 2013;13:621–34. [12] Mukhopadhyay S, Gordon S. The role of scavenger receptors in pathogen recognition and innate immunity. Immunobiology 2004;209:39–49. [13] Sun M, Finnemann SC, Febbraio M, Shan L, Annangudi SP, Podrez EA, et al. Light-induced oxidation of photoreceptor outer segment phospholipids generates ligands for CD36-mediated phagocytosis by retinal pigment epithelium: a potential mechanism for modulating outer segment phagocytosis under oxidant stress conditions. J. Biol. Chem. 2006;281:4222–30. [14] Herrmann M, Schafer C, Heiss A, Graber S, Kinkeldey A, Buscher A, et al. Clearance of fetuin-A-containing calciprotein particles is mediated by scavenger receptor-A. Circ. Res. 2012;111:575–84. [15] Taylor PR, Martinez-Pomares L, Stacey M, Lin HH, Brown GD, Gordon S. Macrophage receptors and immune recognition. Annu. Rev. Immunol. 2005;23:901–44. [16] Murphy JE, Tedbury PR, Homer-Vanniasinkam S, Walker JH, Ponnambalam S. Biochemistry and cell biology of mammalian scavenger receptors. Atherosclerosis 2005;182:1–15. [17] Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245–52. [18] Barth H, Schnober EK, Neumann-Haefelin C, Thumann C, Zeisel MB, Diepolder HM, et al. Scavenger receptor class B is required for hepatitis C virus uptake and cross-presentation by human dendritic cells. J. Virol. 2008;82:3466–79. [19] Buechler C, Ritter M, Quoc CD, Agildere A, Schmitz G. Lipopolysaccharide inhibits the expression of the scavenger receptor Cla-1 in human monocytes and macrophages. Biochem. Biophys. Res. Commun. 1999;262:251–4. [20] Areschoug T, Gordon S. Pattern recognition receptors and their role in innate immunity: focus on microbial protein ligands. Contrib. Microbiol. 2008;15:45–60. [21] Pluddemann A, Hoe JC, Makepeace K, Moxon ER, Gordon S. The macrophage scavenger receptor A is host-protective in experimental meningococcal septicaemia. PLoS Pathog. 2009;5:e1000297. [22] Hoebe K, Georgel P, Rutschmann S, Du X, Mudd S, Crozat K, et al. CD36 is a sensor of diacylglycerides. Nature 2005;433:523–7. [23] Becker M, Cotena A, Gordon S, Platt N. Expression of the class A macrophage scavenger receptor on specific subpopulations of murine dendritic cells limits their endotoxin response. Eur. J. Immunol. 2006;36:950–60. [24] Villwock A, Schmitt C, Schielke S, Frosch M, Kurzai O. Recognition via the class A scavenger receptor modulates cytokine secretion by human dendritic cells after contact with Neisseria meningitidis. Microbes Infect. 2008;10:1158–65. [25] Gething PW, Patil AP, Smith DL, Guerra CA, Elyazar IR, Johnston GL, et al. A new world malaria map: Plasmodium falciparum endemicity in 2010. Malar. J. 2011;10:378. [26] Guerra CA, Gikandi PW, Tatem AJ, Noor AM, Smith DL, Hay SI, et al. The limits and intensity of Plasmodium falciparum transmission: implications for malaria control and elimination worldwide. PLoS Med. 2008;5:e38. [27] Urban BC, Willcox N, Roberts DJ. A role for CD36 in the regulation of dendritic cell function. Proc. Natl. Acad. Sci. USA 2001;98:8750–5. [28] Gowda NM, Wu X, Kumar S, Febbraio M, Gowda DC. CD36 contributes to malaria parasite-induced pro-inflammatory cytokine production and NK and T cell activation by dendritic cells. PLoS One 2013;8:e77604. [29] Hoofnagle JH. Course and outcome of hepatitis C. Hepatology 2002;36:S21–9. [30] Webster DP, Klenerman P, Collier J, Jeffery KJ. Development of novel treatments for hepatitis C. Lancet Infect. Dis. 2009;9:108–17. [31] Scarselli E, Ansuini H, Cerino R, Roccasecca RM, Acali S, Filocamo G, et al. The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO J. 2002;21:5017–25. [32] Bartosch B, Vitelli A, Granier C, Goujon C, Dubuisson J, Pascale S, et al. Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor. J. Biol. Chem. 2003;278: 41624–30.
Please cite this article in press as: Wang D et al. Role of scavenger receptors in dendritic cell function. Hum Immunol (2015), http://dx.doi.org/10.1016/ j.humimm.2015.03.012
D. Wang et al. / Human Immunology xxx (2015) xxx–xxx [33] Lambotin M, Baumert TF, Barth H. Distinct intracellular trafficking of hepatitis C virus in myeloid and plasmacytoid dendritic cells. J. Virol. 2010;84:8964–9. [34] Marukian S, Jones CT, Andrus L, Evans MJ, Ritola KD, Charles ED, et al. Cell culture-produced hepatitis C virus does not infect peripheral blood mononuclear cells. Hepatology 2008;48:1843–50. [35] Beauvillain C, Meloni F, Sirard JC, Blanchard S, Jarry U, Scotet M, et al. The scavenger receptors SRA-1 and SREC-I cooperate with TLR2 in the recognition of the hepatitis C virus non-structural protein 3 by dendritic cells. J. Hepatol. 2010;52:644–51. [36] Accapezzato D, Visco V, Francavilla V, Molette C, Donato T, Paroli M, et al. Chloroquine enhances human CD8+ T cell responses against soluble antigens in vivo. J. Exp. Med. 2005;202:817–28. [37] Spadaro F, Lapenta C, Donati S, Abalsamo L, Barnaba V, Belardelli F, et al. IFNalpha enhances cross-presentation in human dendritic cells by modulating antigen survival, endocytic routing, and processing. Blood 2012;119:1407–17. [38] Armengol C, Bartoli R, Sanjurjo L, Serra I, Amezaga N, Sala M, et al. Role of scavenger receptors in the pathophysiology of chronic liver diseases. Crit. Rev. Immunol. 2013;33:57–96. [39] Murshid A, Gong J, Calderwood SK. Heat shock protein 90 mediates efficient antigen cross presentation through the scavenger receptor expressed by endothelial cells-I. J. Immunol. 2010;185:2903–17. [40] Pfistershammer K, Klauser C, Leitner J, Stockl J, Majdic O, Weichhart T, et al. Identification of the scavenger receptors SREC-I, Cla-1 (SR-BI), and SR-AI as cellular receptors for Tamm–Horsfall protein. J. Leukoc. Biol. 2008;83: 131–8. [41] Holzl MA, Hofer J, Kovarik JJ, Roggenbuck D, Reinhold D, Goihl A, et al. The zymogen granule protein 2 (GP2) binds to scavenger receptor expressed on endothelial cells I (SREC-I). Cell. Immunol. 2011;267:88–93. [42] Busch M, Westhofen TC, Koch M, Lutz MB, Zernecke A. Dendritic cell subset distributions in the aorta in healthy and atherosclerotic mice. PLoS One 2014;9:e88452. [43] Perrins CJ, Bobryshev YV. Current advances in understanding of immunopathology of atherosclerosis. Virchows Arch. 2011;458:117–23. [44] Paulson KE, Zhu SN, Chen M, Nurmohamed S, Jongstra-Bilen J, Cybulsky MI. Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis. Circ. Res. 2010;106:383–90. [45] Bobryshev YV. Dendritic cells in atherosclerosis: current status of the problem and clinical relevance. Eur. Heart J. 2005;26:1700–4. [46] Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 2005;352:1685–95. [47] Alderman CJ, Bunyard PR, Chain BM, Foreman JC, Leake DS, Katz DR. Effects of oxidised low density lipoprotein on dendritic cells: a possible immunoregulatory component of the atherogenic micro-environment? Cardiovasc. Res. 2002;55:806–19. [48] Coutant F, Perrin-Cocon L, Agaugue S, Delair T, Andre P, Lotteau V. Mature dendritic cell generation promoted by lysophosphatidylcholine. J. Immunol. 2002;169:1688–95. [49] Nickel T, Schmauss D, Hanssen H, Sicic Z, Krebs B, Jankl S, et al. OxLDL uptake by dendritic cells induces upregulation of scavenger-receptors, maturation and differentiation. Atherosclerosis 2009;205:442–50.
5
[50] Miller YI, Choi SH, Wiesner P, Fang L, Harkewicz R, Hartvigsen K, et al. Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ. Res. 2011;108:235–48. [51] Lu H, Yao K, Huang D, Sun A, Zou Y, Qian J, et al. High glucose induces upregulation of scavenger receptors and promotes maturation of dendritic cells. Cardiovasc. Diabetol. 2013;12:80. [52] Tardif JC, Gregoire J, L’Allier PL, Ibrahim R, Lesperance J, Heinonen TM, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 2007;297:1675–82. [53] Shaw JA, Bobik A, Murphy A, Kanellakis P, Blombery P, Mukhamedova N, et al. Infusion of reconstituted high-density lipoprotein leads to acute changes in human atherosclerotic plaque. Circ. Res. 2008;103:1084–91. [54] Spirig R, Schaub A, Kropf A, Miescher S, Spycher MO, Rieben R. Reconstituted high-density lipoprotein modulates activation of human leukocytes. PLoS One 2013;8:e71235. [55] Mineo C, Shaul PW. Functions of scavenger receptor class B, type I in atherosclerosis. Curr. Opin. Lipidol. 2012;23:487–93. [56] Ip WK, Lau YL. Distinct maturation of, but not migration between, human monocyte-derived dendritic cells upon ingestion of apoptotic cells of early or late phases. J. Immunol. 2004;173:189–96. [57] Albert ML, Pearce SF, Francisco LM, Sauter B, Roy P, Silverstein RL, et al. Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J. Exp. Med. 1998;188:1359–68. [58] Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I. Immunosuppressive effects of apoptotic cells. Nature 1997;390:350–1. [59] Parcina M, Schiller M, Gierschke A, Heeg K, Bekeredjian-Ding I. PDC expressing CD36, CD61 and IL-10 may contribute to propagation of immune tolerance. Autoimmunity 2009;42:353–5. [60] Behrens EM, Sriram U, Shivers DK, Gallucci M, Ma Z, Finkel TH, et al. Complement receptor 3 ligation of dendritic cells suppresses their stimulatory capacity. J. Immunol. 2007;178:6268–79. [61] Chen X, Doffek K, Sugg SL, Shilyansky J. Phosphatidylserine regulates the maturation of human dendritic cells. J. Immunol. 2004;173:2985–94. [62] Doyen V, Rubio M, Braun D, Nakajima T, Abe J, Saito H, et al. Thrombospondin 1 is an autocrine negative regulator of human dendritic cell activation. J. Exp. Med. 2003;198:1277–83. [63] Porter M, Karp M, Killedar S, Bauer SM, Guo J, Williams D, et al. Diesel-enriched particulate matter functionally activates human dendritic cells. Am. J. Respir. Cell. Mol. Biol. 2007;37:706–19. [64] Taront S, Dieudonne A, Blanchard S, Jeannin P, Lassalle P, Delneste Y, et al. Implication of scavenger receptors in the interactions between diesel exhaust particles and immature or mature dendritic cells. Part. Fibre Toxicol. 2009;6:9. [65] Abraham R, Singh N, Mukhopadhyay A, Basu SK, Bal V, Rath S. Modulation of immunogenicity and antigenicity of proteins by maleylation to target scavenger receptors on macrophages. J. Immunol. 1995;154(1):1–8. [66] Puig-Kroger A, Dominguez-Soto A, Martinez-Munoz L, Serrano-Gomez D, Lopez-Bravo M, Sierra-Filardi E, et al. RUNX3 negatively regulates CD36 expression in myeloid cell lines. J. Immunol. 2006;177:2107–14.
Please cite this article in press as: Wang D et al. Role of scavenger receptors in dendritic cell function. Hum Immunol (2015), http://dx.doi.org/10.1016/ j.humimm.2015.03.012