Autophagy and proinflammatory cytokines: Interactions and clinical implications

Autophagy and proinflammatory cytokines: Interactions and clinical implications

Cytokine and Growth Factor Reviews xxx (xxxx) xxx–xxx Contents lists available at ScienceDirect Cytokine and Growth Factor Reviews journal homepage:...

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Cytokine and Growth Factor Reviews xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

Cytokine and Growth Factor Reviews journal homepage: www.elsevier.com/locate/cytogfr

Autophagy and proinflammatory cytokines: Interactions and clinical implications Yun Gea, Man Huanga, Yong-ming Yaob, a b



Department of General Intensive Care Unit, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China Trauma Research Center, First Hospital Affiliated to the Chinese PLA General Hospital, No.51 Fu-Cheng Road, Beijing 100048, China

A R T I C LE I N FO

A B S T R A C T

Keywords: Autophagy Proinflammatory cytokines Innate immune response Adaptive immune response Diseases

Autophagy is a ubiquitous cellular process that regulates cell growth, survival, development and death. Its process is closely associated with diverse conditions, such as liver diseases, neurodegenerative diseases, myopathy, heart diseases, cancer, immunization, and inflammatory diseases. Thus, understanding the modulation of autophagy may provide novel insight into potential therapeutic targets. Autophagy is closely intertwined with inflammatory and immune responses, and cytokines may help mediate this interaction. Autophagy has been shown to regulate, and be regulated by, a wide range of proinflammatory cytokines. This review aims to summarize recent progress in elucidating the interplay between autophagy and proinflammatory cytokines, including IFN-γ, TNF-α, IL-17, and cytokines of the IL-1 family (e.g., IL-1α, IL-1β, IL-33, and IL-36).

1. Introduction In the late 1950s, autophagy was first described as a cellular response to nutrient deprivation that allows removal of damaged organelles [1]. Autophagy is now appreciated as being crucial for cell homeostasis and survival. Generally, the autophagic cascade occurs constitutively at a basal level in various cells and is initiated under stress conditions, such as endoplasmic reticulum stress (ERS), growth factor withdrawal, nutrient deprivation, mitochondrial damage, and inflammation [2–4]. Various subcategories of autophagy have been defined: chaperone-mediated autophagy (CMA), microautophagy, and macroautophagy. During CMA, cytosolic target substrate incorporate the chaperone protein which contains a Lys-Phe-Glu-Arg-Gln (KFERQ)like pentapetide motif via the recognition of heat shock cognate 70 kDa protein (HSC70). Next, HSC70 triggers the delivery of the cargo into the lysosomal lumenin a lysosomal-associated membrane protein 2A (LAMP2A) receptor-dependent manner [1]. Microautophagy refers to the translocation of substrate into lysosome for degradation via either direct protrusion, invagination, or septation of lysosomal. In

macroautophagy, the formation of autophagosomes, the double membrane-bound vesicles, which engulf organelles, cytoplasmic proteins, or other materials. The autophagosomes are transported to lysosomes for the form of autolysosomes [3]. In all three types, the target cargos are ultimately degraded by hydrolases. This review focuses on macroautophagy, which is herein termed simply autophagy. Proinflammatory cytokines have crucial influences on systemic immune and inflammatory responses. These evolutionarily conserved cytokines are generated by innate and adaptive immune cells and regulate their function and survival. The interplay between autophagy and cytokines may be a fundamental mechanism coordinating the activity of the innate and adaptive immune systems [5,6]. Different cytokines can regulate autophagy levels. For example, the proinflammatory cytokine interferon (IFN)-γ triggers autophagy to eliminate invading pathogens, such as Mycobacteria and Chlamydia [7,8]. Autophagy is also induced by interleukin (IL)-1, tumor necrosis factor (TNF)-α, IL-17, and IL-6, whereas the process is blocked by IL-13, IL-33, IL-10, and IL-4. At the same time, autophagy can modulate cytokine production and secretion. Because proinflammatory cytokines and

Abbreviations: ATG, autophagy-related proteins; CMA, chaperone-mediated autophagy; ULK1, Unc-51-like kinase 1; PI3K, phosphatidylinositol 3-kinase; mTOR, mammalian target of rapamycin; PE, phosphatidylethanolamine; IFN-γ, interferon-γ; IL-1, interleukin-1; IL-17, interleukin-17; IL-33, interleukin-33; IL-36, interleukin-36; PRR, pattern recognition receptor; TLR, toll-like receptor; TNF-α, tumor necrosis factor-α; TGF-β, transforming growth factor-β; NLR, NOD-like receptor; RLR, (RIG-1)-I-like receptor; PAMPs, pathogen-associated molecular patterns; ROS, reactive oxygen species; LPS, lipopolysaccharide; APC, antigen presenting cell; MHC, major histocompatibility complex; STAT, signal transducer and activation of transcription; MAPK, mitogen-activated protein kinase; DC, dendritic cell; PBMC, peripheral blood mononuclear cells; JNK, c-Jun amino-terminal kinase; ERK, extracellular signal-regulated kinase; 3-MA, 3-methyladenine; ER, endoplasmic reticulum; ERS, endoplasmic reticulum stress ⁎ Corresponding author. E-mail address: c_ff@sina.com (Y.-m. Yao). https://doi.org/10.1016/j.cytogfr.2018.07.001 Received 21 June 2018; Received in revised form 10 July 2018; Accepted 11 July 2018 1359-6101/ © 2018 Elsevier Ltd. All rights reserved.

Please cite this article as: Ge, Y., Cytokine and Growth Factor Reviews (2018), https://doi.org/10.1016/j.cytogfr.2018.07.001

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Fig. 1. Autophagic pathways in eukaryotic cells and their roles in cellular survival (e.g., homeostasis, metabolism, and the immune system) and cell death. Generally, autophagy is classified into three types: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Inmacroautophagy, cytoplasmic material is sequestered into a pre-autophagosomal membrane structure called the phagophore, in the presence of an autophagic inducer (e.g., cytoplasmic material, cytokines). The phagophore membrane then expands and encloses its cargo to form a double-membrane vesicle, the autophagosome. The autophagosome fuses with a lysosome (or, in yeast, a vacuole) to form an autolysosome. In microautophagy, cytoplasmic materials are trafficked to lysosome via direct protrusion or invagination at the lysosomal membrane. In CMA, the cytosolic target substrate binds to Lys-Phe-Glu-Arg-Gln (KFERQ)like pentapetide motif dependent on the recognition of heat shock cognate 70 kDa protein (HSC70) and then was delivered into lysosomes via lysosomal-associated membrane protein 2A (LAMP2A) receptor. In all three forms of autophagy, their cargos are degraded by acid hydrolases in the end. After the resulting macromolecules are transported back into the cytosol through membrane permeases, they can either be used to synthesize proteins or oxidized by the mitochondria to generate ATP for cell survival. However, when autophagy occurs at excessive levels or under certain physiological conditions, it can lead to type II programmed cell death (PCD). See the text for additional details.

[18]. Currently, autophagy is believed to be important for clearing pathogens via autolysosome-dependent degradation and for modulating innate as well as adaptive immunity. Adaptive immunity depends on the recognition of extra- or intracellular peptide epitopes presented by major histocompatibility complex (MHC) class I and II molecules, which are identified by CD4+ and CD8+ T cells [19–22]. As a result of this recognition, autophagy promotes the trafficking of extracellular antigens (e.g., microbial antigens) to endosomes, where they are loaded onto MHC class II molecules and subsequently transported to the plasma membrane, and presented as antigens to CD4+ T cells [23]. Meanwhile, autophagy accelerates antigen loading onto MHC class I molecules, which prime antigenspecific CD8+ T cells. This promotes antigen "cross-presentation", which is crucial for activating T cell response [24,25]. In this way, autophagy can regulate lymphocyte development and functional diversification. In fact, autophagy plays multiple roles in the immune system, and activation of autophagy can facilitate pathogen clearance.

autophagy play key roles in the pathophysiology of disease, crosstalk between them has become a key research topic and an area of substantial progress. 2. Overview of the autophagic pathway In autophagy, lysosomal proteolysis disposes of aged or aberrant organelles and proteins. Double-membrane vesicles, called autophagosomes or autophagic vacuoles, target and engulf denatured proteins or damaged organelles [9–11] via a multi-step process involving initiation, vesicle nucleation, vesicle expansion and completion, which have been extensively studied (Fig. 1). At least 30 autophagy-related genes (Atgs) have been identified in yeast, and mammalian orthologs of various Atgs have been shown to modulate autophagy [12,13]. In the initial stages of autophagy, the Atg1 complex is activated. In yeast, the Atg1 complex is composed of the Atg17-Atg31-Atg29 subcomplex, Atg1, and Atg13. In mammals, this complex, also known as the Unc-51-like kinase (ULK) complex, refers to the mammalian Atg1 homolog ULK1 or ULK2, mammalian autophagy -related13 homolog (Atg13, a putative counterpart of yeast Atg17), RB1-inducible coiledcoil 1 (RB1CC1), and Atg101 [14,15]. During the vesicle nucleation stage, a phosphatidylinositol 3-kinase (PI3K) complex composed of vacuolar protein sorting 34 (Vps34), Beclin-1, and Atg14 must be activated. The primary function of this complex is to recruit Atg proteins to the phagophore assembly site (PAS). For vesicle expansion and completion, the isolation membrane elongates as the PAS expands via the actions of two ubiquitin-like (UbI) conjugation systems: the conjugate of Atg12-Atg5-Atg16L1, and the conjugate of phosphatidylethanolamine (PE)-microtubule-associated protein 1 light chain 3 (LC3, also known as Atg8). In the final stages of autophagy, the mature autophagosome fuses with the lysosome to form the autolysosome, in which the cargo is degraded by hydrolases. The end products are released back into the cytosol [16,17].

3.2. Autophagy and inflammation Autophagy and inflammation are two crucial biological processes associated with physiological and pathophysiological states. Notably, autophagy is essential for regulating the inflammatory response [26,27]. Sufficient pathogen recognition can drive the inflammatory response, leading to recruitment of immune cells. Production of chemoand cytokines recruits other immune cells and simultaneously activates dendritic cells (DCs) involved in the adaptive immune response [28,29]. Pathogen-associated molecular patterns (PAMPs) may improve autophagic activation by triggering signaling pathways involving the mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK). Toll-like receptors (TLRs) trigger pathways that induce autophagy in macrophages as well as other cell types [30]. For example, TLR4 activation leads to the ubiquitination of TNF receptor-associated factor 6 (TRAF6)/BECN1/Beclin-1. TRAF6 also activates the upstream autophagic activator ULK1. In addition to TLRs, nucleotide-binding oligomerization domain2 (NOD2) can induce autophagy in DCs and target Atg16 L1 to the plasma membrane at the site of bacterial entry [31,32]. Autophagy is critical for a well-balanced inflammatory response,

3. Interactions of autophagy with immunity and inflammation 3.1. Autophagy and immunity Autophagy may be a primordial form of eukaryotic innate immunity 2

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also involved JAK1/2, p38 MAPK, and PI3K signaling [43]. Macrophages infected with the avirulent H37Ra strain of M. tuberculosis trigger autophagy, while mycobacteria-containing phagosomes are typically negative for LC3. IFN-γ-activated macrophages before infection increased the co-localization of bacilli Calmette-Guerin (BCG) with LC3. Murine macrophages lacking Beclin-1 completely abolished the effect of IFN-γ on the maturation of BCG-containing phagosomes, indicating that the action of IFN-γ depended completely on autophagy [44,45]. Likely, the deletion of S100A10 inhibited IFN-γtriggered increases in LC3II in human lung epithelial cells, and S100A10 enhanced IFN-γ-driven autophagy via ULK1 [46]. The ULK1 complex then translocated to endoplasmic reticulum -mitochondria upon autophagosome formation. IFN-γ can accelerate the elimination of other pathogens (C. trachomatis and B.cenocepacia) by autophagic activation. Knocking down Irga6 in mouse embryonic fibroblasts (MEFs) prevented them from capturing C. trachomatis in autolysosomes, creating resistance to IFN-γstimulated killing and promoting pathogen growth. Thus, Irga6 is essential for IFN-γ-primed autophagy [47]. In the case of B. cenocepacia infection, IFN-γ promoted clearance of the pathogen from human cystic fibrosis macrophages by enhancing autophagosome formation and lysosomal trafficking [48]. In addition to helping eradicate pathogens, autophagy may regulate cellular metabolism under normal conditions and in numerous diseases [49]. For example, IFN-γ-mediated autophagy might modulate tryptophan metabolism in human kidney epithelial cells. In this process, induction of tryptophan metabolism promoted the general control nonderepressible-2 (GCN2) kinase, which phosphorylated the autophagy activator eukaryotic translation initiation factor 2a (eIF2a) [50]. This recently described ability of autophagy to promote biosynthesis and metabolic homeostasis might clarify interactions between IFN-γ and autophagy.

Fig. 2. The interplay between proinflammatory cytokines and autophagy. Cytokines including TNF-α, IL-1α, and IL-1β can induce autophagy, while autophagy regulates cytokine production in a context-dependent manner. IFN-γ markedly activates autophagy, and autophagy enhances IFN-γ production. IL17 has dual effects on the autophagic flux, whereas autophagy inhibits IL-17 release. Additionally, IL-33 inhibits autophagy. Nevertheless, the effects of IL36 on autophagy are unknown.

and thus promotes homeostasis in this manner. However, autophagy plays opposing roles in certain conditions, and excessive autophagy may lead to cell death, which is known as autophagic cell death or type II programmed cell death. 4. Reciprocal regulation between proinflammatory cytokines and autophagy

4.1.2. Autophagy facilitates IFN-γ production Autophagy, in turn, can induce IFN-γ production and facilitate the inflammatory response [51]. For instance, conditional knockdown of Atg5 markedly impaired IFN-γ-induced LC3 conversion and autophagosome formation, leading to a decrease in IFN-γ secretion in CD4+ T cells. Autophagy obviously promoted IFN-γ-inducible inflammatory responses [52]. Similarly, MEFs deficient in Atg5 and Atg7 were resistant to the IFN-γ-induced JAK2-STAT1 pathway, suggesting that autophagy was involved in the IFN-γ-dependent cascade [46]. Regulators of negative contextual factors in the IFN-γ signaling pathway have been associated with SHP2, SOCS1, and SOCS3 [53]. Suppression of SHP2 expression significantly enhanced IFN-γ-dependent STAT1 phosphorylation, implicating SHP2 in the suppression of the IFN-γ pathway in Atg5−/− MEFs [46]. Moreover, the excessive generation of reactive oxygen species (ROS) resulting from the absence of autophagy up-regulated SHP2 expression, which inhibited STAT1; at the same time, the abundant ROS facilitated SHP2 activation by inhibiting IFN-γinduced JAK2-STAT1 signaling [54,55].

4.1. IFN-γ and autophagic activity IFN-γ is a central proinflammatory cytokine produced primarily by natural killer cells as well as by activated CD4+ or CD8+ T cells. IFN-γ plays a crucial role in innate and adaptive immunity [33,34] by activating multiple immunomodulatory molecules, and participates in various inflammatory and autoimmune disorders [35]. Emerging evidence suggests that IFN-γ augments autophagy, which then promotes antigen presentation, cellular proliferation, and viral and bacterial clearance. This activation of autophagy then stimulates IFN-γ release in a positive feedback loop [32,36] (Figs. 2 and 3a, Table 1). 4.1.1. IFN-γ can induce autophagy IFN-γ can drive autophagy to help eliminate invading pathogens or trigger cell death. IFN-γ has been shown to promote a major helper T cell (Th)1-type response that helps protect the host from M. tuberculosis together with IFN-γ-dependent GTPases [37,38]. IFN-γ acts on macrophages to enhance the innate defensive processes of receptor-mediated phagocytosis and microbial killing, and promotes autophagy to eradicate intracellular pathogens [39–41]. Although how IFN-γ induces autophagy is not completely clear, IFN-γ may activate macrophages via a pathway involving the family M member 1 GTPase Irgm1/IRGM1, leading to maturation of mycobacteria-containing phagosomes. IFN-γ reportedly elevated concanavalinA (Con A)-induced autophagic flux in hepatoma cell lines, resulting in cell death. Silencing Irgm1 suppressed IFN-γ/Con A-mediated lysosomal membrane permeabilization and hepatocyte death [42]. In Irgm1−/− primary macrophages, IFN-γ induced autophagy via a pathway independent of signal transducer and activator of transcription (STAT)1 but dependent on mitogen-activated protein kinase (MAPK) 14. IFN-γ-mediated autophagy in macrophages

4.2. TNF-α and autophagic activation TNF-α is a pleiotropic cytokine and modulates proinflammatory responses, cell proliferation, differentiation, and death. Increasing evidence supports the concept that TNF-α and autophagy interfere with one another [56] (Figs. 2 and 3b, Table 2). 4.2.1. TNF-α promotes autophagy In numerous diseases associated with inflammatory responses, endotoxins trigger TNF-α production to accelerate disease progression. TNF-α primes autophagy in various cells, including osteoclasts, epithelial cells, T lymphoblastic leukemic cells, skeletal muscle cells, and vascular smooth muscle cells [56–61]. How TNF-α induces autophagy in different cell types is poorly understood. In human atherosclerotic 3

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Fig. 3. Mechanisms underlying the interplay between proinflammatory cytokines and autophagy. (a) IFN-γ leads to autophagic activation via multiple mechanisms, including regulation of the JAK1/2, Irgm1/IRGM, p38 MAPK, S100A10/ULK1, and PI3K pathways. Autophagy, in turn, enhances IFN-γ formation via the ROS/JAK2/STAT1 and SHP2/STAT1 signaling pathways. (b) TNF-α positively regulates autophagy through the ERK1/2, JNK, p38 MAPK-NF-κB, and ROS signaling pathways. Autophagy modulates TNF-α induction in a context-dependent manner. (c) IL-17 activates the ERK1/2-Beclin-1-p62 pathway leading to autophagy. On the other hand, IL-17 inhibits autophagy via the BCL2Beclin-1 and PI3K-GSK3β pathways. Autophagy, in turn, down-regulates IL-17 production via p38 MAPK signaling. (d) IL-α and IL-1β activate endoplasmic reticulum stress (ERS) with subsequent autophagy, while autophagy enhances the formation of IL-α, IL-1β, and IL-18 in an NLRP3 inflammasome-dependent manner. (e) IL-33 has potential negative effects on autophagy.

4.2.2. Autophagy regulates TNF-α formation Regulation of TNF-α production is a potential strategy for controlling inflammatory diseases. Autophagy appears to up- or down-regulate TNF-α formation depending on the cellular context. On the one hand, autophagy induction can suppress TNF-α release and thereby mitigate inflammatory responses. On the other hand, autophagy may trigger the secretion of proinflammatory cytokines including TNF-α, IL-8 and IL-6, as well as activate the inflammasome. In macrophages treated with lipopolysaccharide (LPS), autophagy decreased TNF-α expression; in primary macrophages, suppression of autophagy using the inhibitor Bafilomycin A1 or deletion of the LC3B gene restored the inhibition of TNF-α expression [67]. Conversely, treatment with the autophagy inhibitor 3-methyladenine (3-MA) in human or murine cells substantially reduced the TLR-dependent secretion of IL-6 and TNF-α. In human peripheral blood mononuclear cells (PBMCs) stimulated with LPS or

vascular smooth muscle cells, TNF-α up-regulated the expression of the autophagy-related genes LC3 and Beclin-1 through the c-Jun aminoterminal kinase (JNK) pathway, while it suppressed Akt activity [62]. Treating MCF-7 human breast cancer cells with TNF-α augmented autophagy through a pathway involving extracellular signal-regulated kinase (ERK) 1/2, while stimulating NF-κB in Ewing sarcoma cells down-regulated TNF-α-mediated autophagy, leading to the generation of abundant ROS [63,64]. In rat intestinal epithelial cells, TNF-α reduced oxygen consumption, increased the generation of mitochondrial ROS, and decreased mitochondrial membrane potential, thereby enhancing autophagy in the mitochondria and causing mitochondrial dysfunction [65]. In murine fibrosarcoma L929 cells, TNF-α-induced autophagy inhibited necroptosis by blocking the p38 MAPK-NF-κB pathway [66].

Table 1 Interactions between IFN-γ and autophagy. Interaction

Authors

Year

Cell types studied

Refs.

IFN-γ induces autophagy

Lienard et al. Chen et al. Assani et al. Ohshima et al. Matsuzawa et al. Dutta et al. Fougeray et al. Chang et al. Tu et al. Sharma et al. Feng et al. Chang et al. Liu et al.

2016 2017 2014 2014 2012 2012 2012 2011 2011 2014 2009 2010 2015

mouse bone marrow-derived macrophages human bronchial epithelium cell lines human monocyte-derived macrophages mouse embryonic fibroblasts RAW 264.7 murine macrophages human promonocytic cell lines human kidney epithelial cells murine hepatoma cell lines human gastric cancer cell lines human monocyte-derived macrophages mouse CD4+ T lymphocytes mouse macrophage RAW264.7 cells and mouse embryonic fibroblasts mouse bone marrow-derived dendritic cells

[37] [46] [48] [41] [43] [44] [50] [42] [36] [45] [39] [51] [52]

Autophagy promotes IFN-γ production

4

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Table 2 Interactions between TNF-α and autophagy. Interaction

Authors

Year

Cell types studied

Refs.

TNF-α induces autophagy

Wang et al. Rodríguez et al. Lin et al. Ye et al. Keller et al. Jia et al. Baregamian et al. Prokesch et al. Lin et al. Liu et al. Pun et al.

2015 2012 2013 2011 2011 2006 2009 2017 2013 2016 2015

differentiated rat pheochromocytoma (PC12) cells human omental adipocytes human osteoclasts murine fibrosarcoma L929 cells primary human skeletal muscle cells human atherosclerotic vascular smooth cells mouse intestinal epithelial cells human trophoblast cell lines SGHPL-4 mouse bone marrow-derived osteoclasts mouse peritoneal macrophages mouse peritoneal macrophages and RAW 264.7 macrophage cell lines

[58] [61] [56] [66] [57] [62] [63] [60] [59] [69] [67]

Autophagy induces TNF-α production Autophagy inhibits TNF-α release

induction of autophagy might inhibit apoptosis to promote FLS survival. In pulmonary fibrosis, conversely, blockade of IL-17A drove autophagy and resolved inflammation, thereby attenuating the progression of disease. Other studies have provided clues about how IL-17A modulates autophagy. In lung epithelial cells, IL-17A stimulated PI3Kglycogen synthase kinase 3 β (GSK3β) signaling to suppress the phosphorylation of B cell CLL/lymphoma 2 (BCL2), which decreased BCL2 ubiquitination and therefore reduced its degradation. The resulting interaction between BCL2 and BECN1 inhibited autophagy. Thus, a signaling cascade involving IL17A-PI3K-GSK3B-BCL2 appears to downregulate the autophagy process [76,77].

PAM3Cys, 3-MA decreased the transcription of TNF-α while up-regulating the transcription of IL-1β [68]. Similarly, 3-MA pretreatment significantly attenuated TiAl6V4 particle-induced TNF-α expression in macrophages and animal models [69,70]. Collectively, autophagy upor down-regulates TNF-α secretion depending on the cellular context. 4.3. Dual effects of IL-17 on autophagic flux IL-17, which is primarily secreted by IL-17-producing Th17 cells, mediates the inflammatory response and helps establish the tumor microenvironment. The IL-17 family of cytokines consists of six members, including IL-17A to IL-17F. IL-17A and IL-17F drive T cell priming, antibody synthesis, cytokine formation, and provoking inflammation [71] (Figs. 2 and 3c, Table 3).

4.3.2. Autophagy inhibits IL-17 release In several inflammatory disorders, such as Crohn's disease, autophagy regulates the Th1/Th17 balance. For example, treatment with the autophagy/lysosomal inhibitor chloroquine in human monocyte-derived Langerhans-like cells obviously increased the IL-17A release by CD4+ T cells while reducing IFN-γ secretion. Chloroquine regulated the production of IL-17 in a p38 MAPK-dependent manner, possibly by triggering Th17 immunity. Autophagosome-modulated IL-1 release, along with release of transforming growth factor (TGF)-β and IL-6, drives the differentiation of Th17 cells, implying autophagic regulation of the Th1/Th17 balance [78,79].

4.3.1. The impact of IL-17 on autophagy IL-17A was shown to induce autophagy in B cells in vitro [72], which increased the activity of the ubiquitin-proteasome system and triggered ERK1/2 phosphorylation, which up-regulated p62 and Beclin1 expression, and protected B cells from apoptosis. 3-MA markedly inhibited these changes induced by IL-17A. Both IL-17A and IL-17F increased LC3-II accumulation, regulated the intracellular redistribution of LC3, promoted autophagic flux, and facilitated the formation of autophagosomes as well as acidic vesicular organelles. It has been indicated that IL-17F is more efficient than IL-17A at provoking the autophagic cascade. IL-17A and IL-17F can trigger the autophagic process to clear M. terrae from macrophages [72–74]. In addition to regulating host defenses, IL-17 plays an important role in the pathogenesis of rheumatoid arthritis (RA). In fibroblast-like synoviocytes (FLSs), the major cells invading cartilage and bone in RA, IL-17 induced mitochondrial dysfunction, which enhanced autophagy [75]. Initially, IL-17-mediated inflammation impaired mitochondrial respiration and drove infiltration by Th17 cells. The subsequent

4.4. Proinflammatory cytokines of the IL-1 family and autophagy Proinflammatory cytokines of the IL-1 family (IL-1α, IL-1β, IL-18, IL-33, and IL-36) orchestrate inflammatory and immune processes. These cytokines are released during the early stages of inflammation and have been named “alarmins” because they alert the host to induce an inflammatory reaction. IL-1α and IL-1β can drive the autophagic process, which modulates the secretion and degradation of IL-1α, IL-1β, and IL-18 [80] (Figs. 2 and 3d–e, Table 4).

Table 3 Interactions between IL-17 and autophagy. Interaction

Authors

Year

Cell types studied

Refs.

IL-17 induces autophagy

Wu et al.

2017

[74]

Orosz et al. Kim et al. Yuan et al. Zhou et al.

2016 2017 2014 2016

Liu et al.

2013

Reed et al.

2015

Said et al.

2014

human SMMC-7721, L02 and HepG2 cell lines RAW 264.7 macrophages synoviocytes mouse B cells human hepatocellular carcinoma cell lines mouse type II alveolar epithelial cells mouse bone marrow-derived dendritic cells human monocyte-derived Langerhans-like cells and dendritic cells

IL-17 inhibits autophagy

Autophagy reduces IL-17 induction

4.4.1. The effect of IL-α and IL-1β on autophagy IL-1β, the master proinflammatory cytokine, is typically produced by macrophages and monocytes. IL-1α and IL-1β bind to IL-1 receptor 1 and initiate inflammatory cascades. IL-1β can also stimulate the production of IL-1α and IL-23, making this cytokine very important for mediating the inflammatory response. IL-1β acts as a natural adjuvant to stimulate antigen-specific immune responses. Recently, IL-1α and IL1β was demonstrated to trigger autophagosome formation, and they may induce autophagy as part of a negative feedback loop to limit the inflammatory response, and promote cytokine-mediated anti-microbial defense [81]. In murine pancreatic acinar cells, IL-1β activated ERS, which triggered Ca2+ release into the cytosol and ultimately induced autophagy [82]. Meanwhile, autophagic flux was impaired, leading to trypsin activation and pancreatic injury. In addition, IL-1β stimulated autophagy via mitochondrial signaling, which exerted protective effects [83].

[73] [75] [72] [77] [76] [79] [78]

5

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Table 4 Interactions of IL-1β and IL-33 with autophagy. Interaction

Authors

Year

Cell types studied

Refs.

IL-1β activates autophagy

Shen et al. Xu et al. Zhang et al. Dupont et al. IIyas et al. Brickle et al. Symington et al. Shi et al. Luca et al. Castro et al. Lee et al. Saitoh et al. Gao et al. Gao et al.

2017 2014 2015 2011 2016 2015 2015 2012 2014 2012 2012 2008 2017 2017

human degenerative nucleus pulposus cells rat pancreatic acinar cell lines AR42J HEK293T and U2OS cells primary murine bone marrow-derived macrophages mouse hepatic macrophages human laboring fetal membranes mouse bone marrow-derived macrophages mouse bone marrow-derived macrophages human and mouse peripheral blood mononuclear cells murine bone marrow-derived dendritic cells and macrophages mouse embryonic fibroblasts murine macrophages brain tissue brain tissue

[83] [82] [81] [90] [87] [89] [86] [93] [94] [92] [91] [85] [95] [96]

Autophagy facilitates IL-1β secrection Autophagy limits IL-1β secrection

IL-33 inhibits autophagy

IL-36 cytokines comprise IL-36α (IL-1F6), IL-36β (IL-1F8), and IL36γ (IL-1F9). All three cytokines signal via the same heterodimeric receptor to regulate the same signaling cascade and activate MAPKs and NF-κB [97]. IL-36 can prime immune cells and trigger the release of cyto- and chemokines, resulting in the recruitment and activation of DCs and CD4+ T cells in the adaptive immune response. Studies have not yet addressed whether autophagy regulates IL-36 induction during the immune response.

4.4.2. Autophagy regulates the production of IL-1β, IL-18, and IL-1α IL-1β is present in the lumen and intermembrane space of autophagosomes, suggesting that its secretion and degradation may depend on autophagy. Indeed, autophagy strongly modulates IL-1β production, which requires caspase-1 activation followed by inflammasome formation. The delivery of IL-1β to autophagosomes depends on two lysosome-targeting KFERQ sequences and the chaperone protein Hsp90 [81]. Autophagy also contributes to IL-1β release through an unconventional mechanism involving the AIM2 inflammasome. In an epithelioid cell line, AIM2 inflammasome aggregation was associated with end-binding protein 1 (EB1) [84]. Further details regarding inflammasome involvement remain to be elucidated. Autophagy specifically targets pro-IL-1β for lysosomal degradation and therefore indirectly reduces IL-1β secretion. The genetic knockdown of Atg16L1 in macrophages increased IL-1β release in response to LPS stimulation in mice [85]. Likely, treatment with 3-MA or deletion of Atg7 or Beclin-1 obviously caused DCs and macrophages to produce IL-1β in response to TLR3 or TLR4 agonists. Treating macrophages with TLR agonists resulted in IL-1β localization in autophagosomes [86]. Furthermore, knockdown of Atg5 in mouse macrophages significantly elevated the serum levels of IL-1β by promoting the cleavage of pro-IL1β into its active form in the liver [87]. In murine intestinal epithelial cells in which Atg7 was inhibited, LPS markedly up-regulated IL-1β mRNA expression, while knocking out LC3B resulted in the release of IL-18 and IL-1β in response to sepsis in mice challenged by LPS [88–91]. In addition, down-regulation of autophagy enhanced the production of IL-18, which was processed by caspase-1 in an inflammasome-dependent manner. Treatment with 3-MA further increased the LPS-stimulated formation of IL-1α via a mechanism independent of NLRP3 [92–94].

5. Potential regulation of autophagy and proinflammatory cytokines in diseases Autophagy is a promising target in therapy against various infectious, inflammatory, and autoimmune diseases [2,10]. Because autophagy promotes cellular homeostasis by orchestrating inflammatory and immune responses, enhancing autophagy and host immunity may help to eradicate pathogens such as bacteria, fungi, viruses, and protozoa [7,18,28,41,47]. Proinflammatory cytokines play key roles in modulation of autophagy and immunity. For example, TNF-α, IL-1β, and IFN-γ induced autophagy to enhance the elimination of M. tuberculosis from the host (Table 5) [38,40]. In this case, autophagy activated T cells, promoted antigen presentation and triggered the fusion of lysosomes with autophagosomes containing the pathogen. Concomitantly, such autophagy reduced IL-1β production and increased TNF-α secretion, implying that these cytokines might play different roles in host immunity against M. tuberculosis. IFN-γ-driven autophagy can help clear other invading microorganisms, including C. trachomatis, B. cenocepacia, and Toxoplasma gondii [41,47,48]. IFN-γ primes monocytes and improves their phagocytic ability and antigen presentation. IFN-γ-driven autophagy is closely associated with restoration of immune functions. In trauma patients, INF-γ inhalation significantly enhanced HLA-DR expression in alveolar macrophages and reduced the risk of ventilator-associated pneumonia [98]. In fact, IFN-γ therapy was used in severely infected patients [99], and one septic patient with mucormycosis responded rapidly to combination therapy of IFN-γ and the anti-PD1 antibody nivolumab [100]. These results suggested that IFN-γ could be used as an immune-adjuvant therapy for restoring immune functions and eliminating invading pathogens from patients who were immunosuppressed, such as patients affected by sepsis, trauma, and invasive fungal infection. Despite these promising studies, we are unaware of randomized controlled trials investigating the efficacy of IFN-γ therapy. Despite the apparent therapeutic benefits of autophagy, dysregulated or uncontrolled autophagy may be related to the development of various diseases. It was noted that IL-1β impaired autophagic flux and activated trypsinogen, contributing to the pathogenesis of acute pancreatitis [82]. Therefore, modulating IL-1β-driven autophagy would be a therapeutic target against this disease. Additionally, TNF-α-

4.4.3. IL-33 and IL-36 IL-33 and IL-36, the most recently identified members of the IL-1 family of proinflammatory cytokines, are expressed in various tissues and specific immune cells. Both cytokines stimulate the production of cyto- and chemokines by natural killer cells and natural killer T cells of the innate immune system. The resulting release of cyto- and chemokines regulates innate immune responses against pathogens. During the adaptive immune response, IL-33 and IL-36 amplify the induction of cytokines by Th1 cells. The outcomes of IL-33 and IL-36 activity depend on the overall immune state of the host [80]. Until now, little has been known concerning the interactions of these molecules with autophagy. A recent study showed that IL-33 appeared to down-regulate the autophagic activation of apoptosis and the inflammatory response, thereby protecting mice against injury from collagenase-induced intracerebral hemorrhage [95]. Similarly, IL-33 inhibited autophagic activity and apoptosis in neonatal rats, protecting neurons from the effects of recurrent seizure [96]. 6

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Table 5 Autophagy-mediated effects of proinflammatory cytokines in diseases. Disease

Effects

Refs.

Cystic fibrosis Toxoplasma gondii infection Mycobacterium tuberculosis infection

IFN-γ promotes the autophagy-mediated clearance of B. cenocepacia from human cystic fibrosis macrophages IFN-γ inhibits proliferation of T.gondii by inducing autophagy IFN-γ eliminates intracellular M. tuberculosis by activating autop+ hagy IFN-γ mediates host resistance against Chlamydia by inducing autophagy IFN-γ impairs autophagic flux and results in α-synuclein accumulation by compromising lysosomal acidification in dopaminergic cells TNF-α induces inflammatory bone loss via autophagy IL-17 induces mitochondrial dysfunction and autophagosome formation in fibroblast-like synoviocytes IL17 A inhibits autophagic activity via PI3K-GSK3B-BCL2 signaling in lung epithelial cells IL-1β triggers impaired autophagic flux and then activates trypsinogen IL-33 provides neuroprotection by suppressing inflammation, apoptosis, and autophagic activation IL-33 provides potential neuroprotection by suppressing apoptosis and autophagy as well as NF-κB-mediated inflammatory pathways

[48] [41] [38] [40,44,45]

Chlamydia infection Parkinson's disease Rheumatoid arthritis Rheumatoid arthritis Pulmonary fibrosis Acute pancreatitis Intracerebral hemorrhage Recurrent neonatal seizure

[47] [58] [56,59] [75] [76] [82] [95] [96]

instructed the writing of the manuscript.

dependent autophagy was involved in osteoclast-oriented bone resorption and erosion in patients with RA. Inactivating autophagy using chloroquine and hydroxy-chloroquine obviously prevented the bone loss, suggesting a novel therapeutic approach against RA [59]. Moreover, IL-17 caused mitochondrial dysfunction in FLSs in RA, and enhanced the formation of autophagosomes that showed anti-apoptotic properties and promoted FLS survival [75]. Taken together, the regulation of TNF-α and IL-17 appears to be potential therapeutic strategies in the treatment of RA. Recently, the novel cytokine IL-33 was found to protect neurons from the effects of recurrent neonatal seizure and intracerebral hemorrhage; it exerted these effects by inhibiting autophagy, apoptosis, and inflammation [95,96]. Further studies should explore whether IL-33 can exert therapeutic effects in various diseases in the setting of clinical application setting.

Conflict of interest statement The authors have declared that no competing interests exist. Acknowledgments This work was supported by grants from the National Natural Science Foundation (81730057, 81501664) and the National Key Research and Development Program of China (2017YFC1103302). References [1] P. Boya, F. Reggiori, P. Codogno, Emerging regulation and functions of autophagy, Nat. Cell Biol. 15 (2013) 713–720. [2] N. Mizushima, B. Levine, A.M. Cuervo, D.J. Klionsky, Autophagy fights disease through cellular self-digestion, Nature 451 (2008) 1069–1075. [3] P. Codogno, M. Mehrpour, T. Proikas-Cezanne, Canonical and non-canonical autophagy: variations on a common theme of self-eating? Nat. Rev. Mol. Cell Biol. 13 (2012) 7–12. [4] R. Singh, A.M. Cuervo, Autophagy in the cellular energetic balance, Cell Metab. 13 (2011) 495–504. [5] D.J. Klionsky, Autophagy: from phenomenology to molecular understanding in less than a decade, Nat. Rev. Mol. Cell Biol. 8 (2007) 931–937. [6] S.B. Singh, W. Ornatowski, I. Vergne, J. Naylor, M. Delgado, E. Roberts, et al., Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria, Nat. Cell Biol. 12 (2010) 1154–1165. [7] M.A. Al-Zeer, H.M. Al-Younes, P.R. Braun, J. Zerrahn, T.F. Meyer, IFN-gamma-inducible Irga6 mediates host resistance against Chlamydia trachomatis via autophagy, PLoS One 4 (2009) e4588. [8] Y.P. Chang, C.C. Tsai, W.C. Huang, C.Y. Wang, C.L. Chen, Y.S. Lin, et al., Autophagy facilitates IFN-gamma-induced Jak2-STAT1 activation and cellular inflammation, J. Biol. Chem. 285 (2010) 28715–28722. [9] N. Mizushima, M. Komatsu, Autophagy: renovation of cells and tissues, Cell 147 (2011) 728–741. [10] J.D. Rabinowitz, E. White, Autophagy and metabolism, Science 330 (2010) 1344–1348. [11] J. Fullgrabe, D.J. Klionsky, B. Joseph, The return of the nucleus: transcriptional and epigenetic control of autophagy, Nat. Rev. Mol. Cell Biol. 15 (2014) 65–74. [12] Y. Ohsumi, Historical landmarks of autophagy research, Cell Res. 24 (2014) 9–23. [13] D. Papinski, M. Schuschnig, W. Reiter, L. Wilhelm, C.A. Barnes, A. Maiolica, et al., Early steps in autophagy depend on direct phosphorylation of Atg9 by the Atg1 kinase, Mol. Cell 53 (2014) 471–483. [14] M. Walczak, S. Martens, Dissecting the role of the Atg12-Atg5-Atg16 complex during autophagosome formation, Autophagy 9 (2013) 424–425. [15] R.C. Russell, ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase, Nat. Cell Biol. 15 (2013) 741–750. [16] G. Bjorkoy, T. Lamark, A. Brech, H. Outzen, M. Perander, A. Overvatn, et al., p62/ SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death, J. Cell Biol. 171 (2015) 603–614. [17] Y. Takahashi, D. Coppola, N. Matsushita, H.D. Cualing, M. Sun, Y. Sato, et al., Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis, Nat. Cell Biol. 9 (2007) 1142–1151. [18] T. Saitoh, N. Fujita, T. Yoshimori, S. Akira, Autophagy and innate immunity, Tanpakushitsu Kakusan Koso 53 (Suppl. 16) (2008) 2279–2285. [19] Z. Yin, C. Pascual, D.J. Klionsky, Autophagy: machinery and regulation, Microb. Cell 3 (2016) 588–596. [20] S.T. Shibutani, T. Saitoh, H. Nowag, C. Münz, T. Yoshimori, Autophagy and

6. Summary and perspectives Autophagic processes can orchestrate the transcription, processing, and production of proinflammatory cytokines, serving as a negative feedback loop for the modulation of inflammatory as well as immune responses. Autophagy-dependent pathogen eradication may lead to host defenses and activation of adaptive immunity in infectious diseases. Therefore, autophagy is a promising target for developing novel therapeutic strategies against inflammatory and infectious diseases, including sepsis, respiratory infections, and Crohn's disease. Most investigations of autophagy have been performed in cellular and animal studies, with little progress being made in the clinical setting. Future work is needed to elucidate the complex roles of autophagy in immune settings, especially since these impacts are likely to vary with specific signaling microenvironments. For instance, the outcomes of crosstalk between autophagy and proinflammatory cytokines, which are essential players in the innate and adaptive immune systems, are likely dependent on the cellular context. TNF-α, IL-1β, and IFN-γ promote autophagy and prevent pathogen invasion; IFN-γ, in addition, can promote the generation of immunity in diseases involving immunosuppression. On the other hand, TNF-α, IL-1β, or IL-17 can trigger excessive autophagy, which contributes to the pathophysiology of several diseases. Therefore, the modulation of autophagy as a therapeutic target is a double-edged sword. Further research is critically needed to understand the full complexities of the balance between autophagic processes and proinflammatory cytokines as well as the underlying molecular machinery. Studies are also warranted to precisely assess the function of autophagy and immune responses in different diseases. Author contributions statement YG conducted the literature review and drafted the manuscript. MH provided critical writing in the revised manuscript. Y-mY designed and 7

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Yun Ge M.S. received his master degree from Wenzhou Medical University in 2012. He is an ICU doctor in the Second Affiliated Hospital of Zhejiang University School of Medicine in Hangzhou, China. His main research interests include host immune dysfunction and its potential regulation pathway in sepsis, shock, trauma, and multiple organ dysfunction syndrome, etc. Currently, he is investigating molecular mechanisms of cytokines mediated regulation of autophagy in septic patients and animals. Animal studies were performed to understand the effects of proinflammatory cytokines intervention in sepsis mice.

Man Huang M.D. Professor, Director of department of general intensive care unit at the Second Affiliated Hospital of Zhejiang University School of Medicine. She received the doctoral degree from Zhejiang University. Her main research interests were focused on sepsis, shock, acute kidney injury, and multiple organ dysfunction syndrome, etc. Currently, she works on the biochemical and molecular aspects of critical diseases. Her research project has been supported by the National Natural Science Foundation.

Yong-ming Yao M.D., Ph.D., Professor of Surgery, Director of Trauma Research Center, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, China. He graduated from the Third Military Medical University in 1990, and finished post-doctor certification in Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in Vienna, Austria. He is the President Elect of International Federation of Shock Societies (IFSS), the Chairman of Chinese Shock and Sepsis Society, the President of China DAMP and Inflammation Association, the Chairman of Chinese Microbiological Toxins Society, and the Vice-Chairman of Chinese Society for Emergency & Resuscitation, etc. He is the associate editors or members of editorial board for 37 journals, including Shock, Mil Med Res, etc. Altogether 549 scientific articles have been published in national and international journals. His research project has been supported in parts by the National Basic Research Program of China, National Natural Science Outstanding Youth Foundation of China, and Key Project of National Natural Science Foundation of China. He has won numerous international and national prizes for his achievements in the past 30 years. His research specialization was focused on host immune dysfunction and its potential regulation pathway in shock, sepsis, and multiple organ dysfunction syndrome after major trauma and burns.

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