- Email: [email protected]
Renal Function: Guardian of Immune Homeostasis
Immunity
Previews Renal Function: Guardian of Immune Homeostasis € ckner1,2,3,* Katja Bru
1Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA 2Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA 3Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA *Correspondence: [email protected] https://doi.org/10.1016/j.immuni.2019.09.017
Microbial cell components from the intestinal microbiota spread systemically in a healthy host, posing the threat of inappropriate immune activation. In this issue of Immunity, Troha et al. identify a key role for renal function in the clearance of circulating Lys-type peptidoglycan, revealing a mechanism that keeps these inflammatory triggers in check to maintain systemic immune homeostasis. Microbial cell wall components and their soluble fragments can act as pathogenassociated molecular patterns (PAMPs), triggering innate immune responses across the animal kingdom. PAMPS are detected by multiple classes of transmembrane and intracellular patternrecognition receptors (PRRs), including Toll-like receptors (TLRs) and peptidoglycan recognition proteins (PGRPs), which trigger downstream NFkB pathways (Buchon et al., 2014; Irazoki et al., 2019; Kieser and Kagan, 2017). This activation and the resulting humoral and cellular responses are key to the defense against pathogens. On the other hand, tight control is needed to avoid undue activation and inflammation by components of the gut microbiota, which are known to spread from the intestine at low levels and circulate freely in blood and other body fluids (Buchon et al., 2014; Irazoki et al., 2019). In this issue of Immunity, Troha et al. (2019) examine the mechanisms preventing Toll activation by Lys-type peptidoglycan (PGN), a cell wall component of Gram-positive bacteria, using the fruit fly Drosophila melanogaster as a genetic model. Their findings reveal a role for renal function in the maintenance of systemic immune homeostasis and offer a clue on the exacerbated systemic inflammatory state associated with chronic kidney disease in humans. Drosophila renal function is carried out by pericardial and garland nephrocytes (Figure 1) that specialize in filtration and share structural, molecular, and functional similarities with vertebrate podocytes of the kidney glomeruli, including a filtration diaphragm (Denholm and Skaer,
2009). Drosophila nephrocytes store and degrade filtered material, whereas secretory function in Drosophila is carried out by a separate organ, the Malpighian tubules (Denholm and Skaer, 2009). Studying a Drosophila mutant that lacks nephrocytes (Klf15NN), Troha et al. (2019) found systemic overactivation of Toll signaling, as evidenced by increased expression of Toll transcriptional targets and increased survival following bacterial infection. Without infection, Klf15NN flies showed reduced lifespan relative to wildtype (WT) flies. In a series of elegant experiments using germ-free conditions, gut inoculation with specific bacterial strains, and genetic epistasis with signaling components of the Toll, Imd, and unrelated damage-associated molecular pattern (DAMP) pathways, Troha et al. (2019) demonstrated that exacerbated Toll signaling in nephrocyte-deficient flies is linked to the microbiota, particularly to Lys-type PGN of Grampositive bacteria. The authors detected elevated amounts of PGN in the hemolymph (body fluid) of nephrocyte-deficient Klf15NN mutants, and subsequently investigated the ability of nephrocytes to remove PGN from circulation. Indeed, PGN immunostaining and functional genetic testing of endocytic and lysosomal components revealed that PGN is subject to nephrocyte filtration, enriched through endocytosis, and ultimately degraded in the lysosomal compartment (Figure 1). The discovery by Troha et al. (2019) on the key role of renal function in the removal of PGN and maintenance of immune homeostasis is of fundamental interest for vertebrate biology and disease. It raises many questions: analogous to Drosophila
596 Immunity 51, October 15, 2019 ª 2019 Elsevier Inc.
nephrocytes, do the glomeruli of vertebrate kidneys remove microbial PAMPs from circulation in the blood, thereby reducing a core trigger of immune signaling? If this function exists, how is it affected by acute or chronic kidney disease, particularly glomerulonephritis? Should elevated circulating levels of microbial PAMPs arise from kidney disease, they may promote systemic inflammation that in turn could further deteriorate kidney function and affect overall health. There is evidence in support of this hypothesis: chronic kidney disease is strongly associated with exacerbated systemic inflammation (Kurts et al., 2013; Su et al., 2017). A candidate mediator linking elevated circulating PGN with systemic inflammation may be the pleiotropic interleukin 6 (IL-6), which is inducible by Gram-positive PGN, among other stimuli (Chiu et al., 2009; Su et al., 2017). This suggests a roadmap for the exploration of vertebrate renal function in the immune homeostasis of PGN and may offer clues for future therapeutic approaches. The systemic spread of products from the microbiota not only plays roles in the regulation of innate immunity, but also has wide-reaching effects on animal development, tissue homeostasis, organismal and drug metabolism, behavior, and a variety of pathologies including cancer and neurodegenerative and cardiovascular diseases (Knight et al., 2017). Some of these effects are mediated by PGN fragments from the microbiota that act as signaling molecules, for example governing the lifespan of blood cells, modulating brain development and behavior, and promoting somnogenic activity (Irazoki et al., 2019). Accordingly, to avoid adverse
Immunity
Previews
Figure 1. Drosophila Renal Function Maintains Lys-Type PGN Immune Homeostasis
Left: Drosophila nephrocyte function promotes immune homeostasis. Top: the microbiota of the gut produce PGN (dark blue) in the form of both PGN mesh of bacterial cell walls and soluble PGN fragments (PAMPs). Middle: soluble PGN fragments from the gut enter the hemolymph, spreading systemically in the animal (medium blue). Bottom: systemic PGN, particularly Lys-type PGN from Gram-positive bacteria, is removed from the hemolymph by nephrocytes (dark blue). Pericardial nephrocytes are located in rows lining the tubular heart in the abdomen; garland nephrocytes are located in a cluster surrounding the proventriculus in the thorax. PGN clearance involves filtration through the nephrocyte diaphragm into lacunae (invaginations), endocytosis (small blue vesicles), and degradation in the lysosome (large blue vesicles). As a consequence, systemic levels of PGN in the hemolymph are reduced (light blue), thereby preventing activation of Toll signaling. Human analogies for the Drosophila counterparts are schematized alongside. Right: lack of nephrocytes in Drosophila Klf15NN mutants causes systemic inflammation. As in wild-type flies, the microbiota of the gut (dark blue) produce PGN, and soluble PGN fragments from the gut enter the hemolymph, spreading in the animal systemically (medium blue). However, since Klf15NN mutants are devoid of nephrocytes, they lack renal clearance of Lys-type PGN from the hemolymph. Consequently, levels of PGN in the hemolymph remain high (medium blue), triggering Toll signaling and systemic inflammation.
effects from overreaching the inflammatory response and other biological effects, PGN concentrations in circulation and in specific tissues must be tightly controlled, likely at multiple levels of regulation. The study by Troha et al. (2019) reveals an important contribution of renal function to the clearance and regulation of PAMPs and provides insight into a mechanism that checks systemic Toll activation by regulating circulating Lys-type PGN. This complements previous reports on mechanisms that dampen activation of the Drosophila Imd pathway by Gram-negative DAP-type PGN through its degradation by the amidase domain of PGRPs (e.g., PGRP-LB and PGRP-SC), sequestration of PGRPs (e.g., Pirk sequestering PGRP-LC), and negative regulation of the Imd pathway at the transcriptional level (e.g., Caudal) (Buchon et al., 2014). The fact that cells possess various mechanisms to deactivate DAP-type PGN and dampen associated Imd signaling may be at the core of why renal clearance is crucial
for Lys-type PGN, for which fewer alternative mechanisms may exist. Accordingly, Klf15NN mutants lacking nephrocytes show only Lys-type PGN-dependent Toll activation and not DAP-type PGN-dependent activation of Imd signaling, which can be deactivated by other means. Do other cell types and organs take part in the systemic clearance of PGN, particularly of Gram-positive Lys-type PGN? Interestingly, genetic ablation of hemocytes in Drosophila results in systemic Toll activation, similar to what is seen in the absence of nephrocytes (Arefin et al., 2015). Likewise, in hemocytedeficient flies, the inflammatory phenotype appears to be linked to the microbiota, as antibiotic treatment eliminates the systemic Toll overactivation phenotype (Arefin et al., 2015). In that system, Arefin et al. (2015) proposed a role for nitric oxide in the developmental consequences of this systemic inflammatory response, but the findings by Troha et al. (2019) now warrant a closer look at
the involvement of microbiota-derived Lys-type PGN and potential routes of PGN degradation by hemocytes. PGN removal by hemocytes may be based on phagocytosis or other forms of transmembrane transport. As a side note, Klf15NN mutants show reduced labeling of hemocytes by fluorescent bacteria, which may point to reduced hemocyte numbers, although Troha et al. (2019) showed that phagocytic saturation of hemocytes per se did not eliminate the difference between controls and the Klf15NN-associated Toll activation phenotype. By analogy, it will be interesting to investigate a spectrum of other cell types in vertebrates besides glomerular renal cells for putative roles in the elimination of soluble PGN and other PAMPs from circulation. Possible candidates may be cells of hematopoietic origin and scavenger endothelial cells that clear macromolecules, a cell type proposed to be analogous to Drosophila pericardial nephrocytes (Troha et al. 2019). No matter whether additional cell populations may contribute to systemic PGN elimination, the study by Troha et al. (2019) sets a milestone for renal function in the organismal regulation of immune homeostasis. These findings in Drosophila now set the stage to investigate vertebrate systems for conserved principles in immune homeostasis and microbiota-linked disease.
ACKNOWLEDGMENTS K.B. is supported by National Institutes of Health grants 1R01GM112083 and 1R01GM131094.
REFERENCES Arefin, B., Kucerova, L., Krautz, R., Kranenburg, H., Parvin, F., and Theopold, U. (2015). Apoptosis in Hemocytes Induces a Shift in Effector Mechanisms in the Drosophila Immune System and Leads to a Pro-Inflammatory State. PLoS ONE 10, e0136593. Buchon, N., Silverman, N., and Cherry, S. (2014). Immunity in Drosophila melanogaster–from microbial recognition to whole-organism physiology. Nat. Rev. Immunol. 14, 796–810. Chiu, Y.C., Lin, C.Y., Chen, C.P., Huang, K.C., Tong, K.M., Tzeng, C.Y., Lee, T.S., Hsu, H.C., and Tang, C.H. (2009). Peptidoglycan enhances IL-6 production in human synovial fibroblasts via TLR2 receptor, focal adhesion kinase, Akt, and AP-1- dependent pathway. J. Immunol. 183, 2785–2792.
Immunity 51, October 15, 2019 597
Immunity
Previews Denholm, B., and Skaer, H. (2009). Bringing together components of the fly renal system. Curr. Opin. Genet. Dev. 19, 526–532. Irazoki, O., Hernandez, S.B., and Cava, F. (2019). Peptidoglycan Muropeptides: Release, Perception, and Functions as Signaling Molecules. Front. Microbiol. 10, 500. Kieser, K.J., and Kagan, J.C. (2017). Multi-receptor detection of individual bacterial products by the
innate immune system. Nat. Rev. Immunol. 17, 376–390. Knight, R., Callewaert, C., Marotz, C., Hyde, E.R., Debelius, J.W., McDonald, D., and Sogin, M.L. (2017). The Microbiome and Human Biology. Annu. Rev. Genomics Hum. Genet. 18, 65–86. Kurts, C., Panzer, U., Anders, H.J., and Rees, A.J. (2013). The immune system and kidney disease: basic concepts and clinical implications. Nat. Rev. Immunol. 13, 738–753.
Su, H., Lei, C.T., and Zhang, C. (2017). Interleukin-6 Signaling Pathway and Its Role in Kidney Disease: An Update. Front. Immunol. 8, 405. Troha, K., Nagy, P., Pivovar, A., Lazzaro, B.P., Hartley, P.S., and Buchon, N. (2019). Nephrocytes Remove Microbiota-Derived Peptidoglycan from Systemic Circulation to Maintain Immune Homeostasis. Immunity 51, this issue, 625–637.
The Neuropeptide CGRP Induces Bipolar Syndrome in Group 2 Innate Lymphoid Cells Yasutaka Motomura,1 Tetsuro Kobayashi,2 and Kazuyo Moro1,2,3,* 1Laboratory for Innate Immune Systems, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka Suita-shi, Osaka 565-0871, Japan 2Laboratory for Innate Immune Systems, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan 3Laboratory for Innate Immune Systems, Immunology Frontier Research Center (iFReC), Osaka University, 3-1, Yamadaoka Suita-shi, Osaka 565-0871, Japan *Correspondence: [email protected] https://doi.org/10.1016/j.immuni.2019.09.015
In this issue of Immunity, Nagashima et al., Wallrapp et al., and Xu et al. demonstrate that the neuropeptide calcitonin gene-related peptide (CGRP) fine tunes type 2 innate immune response via suppressing group 2 innate lymphoid cells (ILC2s).
The immune system involves dynamic interplays between numerous cell types via various immune factors. It is crucial to direct each immune cell to the right location in a spatially and temporally controlled manner. Innate lymphoid cells (ILCs) are localized in the mucosal tissue and act as the first line of immunological defense by constantly monitoring pathogens invading from the outside. When pathogens invade, ILCs rapidly respond to the signals produced by the destruction of the epithelial barrier, initiate the innate immune machinery, and further amplify the acquired immune response (Sonnenberg and Hepworth, 2019). The epithelial-derived alarmin, interleukin (IL)-33, potently activates ILC2s, which produce IL-5 and IL-13 and induce type 2 immune response. Furthermore, ILC2s contribute to homeostasis of the body, in part through regulation of tissue repair via amphiregulin (Areg). In contrast, uncontrolled activation of ILC2s leads to a pathogenic
state, such as allergic inflammation and fibrosis. Therefore, it is crucial to understand the molecular mechanisms by which ILC2 activation occurs. Various factors that positively and negatively regulate the function of ILC2 have been identified (Kabata et al., 2018). In addition to classical cytokinemediated regulatory networks, neuronal signals have emerged as critical regulators of ILC2 function (Klose and Artis, 2019). Vasoactive intestinal peptide (VIP), which is involved in nutrient intake and central circadian rhythm, induces IL-5 production from ILC2s and maintains eosinophil homeostasis. The neuropeptide neuromedin U (NMU) induces a rapid and potent production of type 2 inflammatory and tissue-protective cytokines from ILC2s. Engagement of b-adrenergic receptor signaling on ILC2s dampens type 2 responses. These findings have provoked a paradigm shift in our understanding of neuro-immune communication
598 Immunity 51, October 15, 2019 ª 2019 Elsevier Inc.
involved in orchestrating tissue homeostasis and integrity. In this issue of Immunity, Nagashima et al. (2019), Wallrapp et al. (2019), and Xu et al., (2019) show that neuropeptide CGRP acts as another negative regulator of ILC2s, providing additional insights into the neuro-immune crosstalk that fine tunes type 2 immune responses. Transient receptor potential vanilloid 1 expressing neurons secrete CGRP, which then acts on various immune cells, such as T and B cells, dendritic cells, mast cells, and macrophages (Assas et al., 2014). Recently, pulmonary neuroendocrine cells (PNECs), specialized epithelial cells that sense hypoxia and produce neurotransmitters, have been reported to amplify allergic responses via CGRP and g-aminobutyric acid secretion, which leads to IL-5 production from ILC2s (Sui et al., 2018). The three papers in this issue further investigate the
Previews Renal Function: Guardian of Immune Homeostasis € ckner1,2,3,* Katja Bru
1Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA 2Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA 3Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA *Correspondence: [email protected] https://doi.org/10.1016/j.immuni.2019.09.017
Microbial cell components from the intestinal microbiota spread systemically in a healthy host, posing the threat of inappropriate immune activation. In this issue of Immunity, Troha et al. identify a key role for renal function in the clearance of circulating Lys-type peptidoglycan, revealing a mechanism that keeps these inflammatory triggers in check to maintain systemic immune homeostasis. Microbial cell wall components and their soluble fragments can act as pathogenassociated molecular patterns (PAMPs), triggering innate immune responses across the animal kingdom. PAMPS are detected by multiple classes of transmembrane and intracellular patternrecognition receptors (PRRs), including Toll-like receptors (TLRs) and peptidoglycan recognition proteins (PGRPs), which trigger downstream NFkB pathways (Buchon et al., 2014; Irazoki et al., 2019; Kieser and Kagan, 2017). This activation and the resulting humoral and cellular responses are key to the defense against pathogens. On the other hand, tight control is needed to avoid undue activation and inflammation by components of the gut microbiota, which are known to spread from the intestine at low levels and circulate freely in blood and other body fluids (Buchon et al., 2014; Irazoki et al., 2019). In this issue of Immunity, Troha et al. (2019) examine the mechanisms preventing Toll activation by Lys-type peptidoglycan (PGN), a cell wall component of Gram-positive bacteria, using the fruit fly Drosophila melanogaster as a genetic model. Their findings reveal a role for renal function in the maintenance of systemic immune homeostasis and offer a clue on the exacerbated systemic inflammatory state associated with chronic kidney disease in humans. Drosophila renal function is carried out by pericardial and garland nephrocytes (Figure 1) that specialize in filtration and share structural, molecular, and functional similarities with vertebrate podocytes of the kidney glomeruli, including a filtration diaphragm (Denholm and Skaer,
2009). Drosophila nephrocytes store and degrade filtered material, whereas secretory function in Drosophila is carried out by a separate organ, the Malpighian tubules (Denholm and Skaer, 2009). Studying a Drosophila mutant that lacks nephrocytes (Klf15NN), Troha et al. (2019) found systemic overactivation of Toll signaling, as evidenced by increased expression of Toll transcriptional targets and increased survival following bacterial infection. Without infection, Klf15NN flies showed reduced lifespan relative to wildtype (WT) flies. In a series of elegant experiments using germ-free conditions, gut inoculation with specific bacterial strains, and genetic epistasis with signaling components of the Toll, Imd, and unrelated damage-associated molecular pattern (DAMP) pathways, Troha et al. (2019) demonstrated that exacerbated Toll signaling in nephrocyte-deficient flies is linked to the microbiota, particularly to Lys-type PGN of Grampositive bacteria. The authors detected elevated amounts of PGN in the hemolymph (body fluid) of nephrocyte-deficient Klf15NN mutants, and subsequently investigated the ability of nephrocytes to remove PGN from circulation. Indeed, PGN immunostaining and functional genetic testing of endocytic and lysosomal components revealed that PGN is subject to nephrocyte filtration, enriched through endocytosis, and ultimately degraded in the lysosomal compartment (Figure 1). The discovery by Troha et al. (2019) on the key role of renal function in the removal of PGN and maintenance of immune homeostasis is of fundamental interest for vertebrate biology and disease. It raises many questions: analogous to Drosophila
596 Immunity 51, October 15, 2019 ª 2019 Elsevier Inc.
nephrocytes, do the glomeruli of vertebrate kidneys remove microbial PAMPs from circulation in the blood, thereby reducing a core trigger of immune signaling? If this function exists, how is it affected by acute or chronic kidney disease, particularly glomerulonephritis? Should elevated circulating levels of microbial PAMPs arise from kidney disease, they may promote systemic inflammation that in turn could further deteriorate kidney function and affect overall health. There is evidence in support of this hypothesis: chronic kidney disease is strongly associated with exacerbated systemic inflammation (Kurts et al., 2013; Su et al., 2017). A candidate mediator linking elevated circulating PGN with systemic inflammation may be the pleiotropic interleukin 6 (IL-6), which is inducible by Gram-positive PGN, among other stimuli (Chiu et al., 2009; Su et al., 2017). This suggests a roadmap for the exploration of vertebrate renal function in the immune homeostasis of PGN and may offer clues for future therapeutic approaches. The systemic spread of products from the microbiota not only plays roles in the regulation of innate immunity, but also has wide-reaching effects on animal development, tissue homeostasis, organismal and drug metabolism, behavior, and a variety of pathologies including cancer and neurodegenerative and cardiovascular diseases (Knight et al., 2017). Some of these effects are mediated by PGN fragments from the microbiota that act as signaling molecules, for example governing the lifespan of blood cells, modulating brain development and behavior, and promoting somnogenic activity (Irazoki et al., 2019). Accordingly, to avoid adverse
Immunity
Previews
Figure 1. Drosophila Renal Function Maintains Lys-Type PGN Immune Homeostasis
Left: Drosophila nephrocyte function promotes immune homeostasis. Top: the microbiota of the gut produce PGN (dark blue) in the form of both PGN mesh of bacterial cell walls and soluble PGN fragments (PAMPs). Middle: soluble PGN fragments from the gut enter the hemolymph, spreading systemically in the animal (medium blue). Bottom: systemic PGN, particularly Lys-type PGN from Gram-positive bacteria, is removed from the hemolymph by nephrocytes (dark blue). Pericardial nephrocytes are located in rows lining the tubular heart in the abdomen; garland nephrocytes are located in a cluster surrounding the proventriculus in the thorax. PGN clearance involves filtration through the nephrocyte diaphragm into lacunae (invaginations), endocytosis (small blue vesicles), and degradation in the lysosome (large blue vesicles). As a consequence, systemic levels of PGN in the hemolymph are reduced (light blue), thereby preventing activation of Toll signaling. Human analogies for the Drosophila counterparts are schematized alongside. Right: lack of nephrocytes in Drosophila Klf15NN mutants causes systemic inflammation. As in wild-type flies, the microbiota of the gut (dark blue) produce PGN, and soluble PGN fragments from the gut enter the hemolymph, spreading in the animal systemically (medium blue). However, since Klf15NN mutants are devoid of nephrocytes, they lack renal clearance of Lys-type PGN from the hemolymph. Consequently, levels of PGN in the hemolymph remain high (medium blue), triggering Toll signaling and systemic inflammation.
effects from overreaching the inflammatory response and other biological effects, PGN concentrations in circulation and in specific tissues must be tightly controlled, likely at multiple levels of regulation. The study by Troha et al. (2019) reveals an important contribution of renal function to the clearance and regulation of PAMPs and provides insight into a mechanism that checks systemic Toll activation by regulating circulating Lys-type PGN. This complements previous reports on mechanisms that dampen activation of the Drosophila Imd pathway by Gram-negative DAP-type PGN through its degradation by the amidase domain of PGRPs (e.g., PGRP-LB and PGRP-SC), sequestration of PGRPs (e.g., Pirk sequestering PGRP-LC), and negative regulation of the Imd pathway at the transcriptional level (e.g., Caudal) (Buchon et al., 2014). The fact that cells possess various mechanisms to deactivate DAP-type PGN and dampen associated Imd signaling may be at the core of why renal clearance is crucial
for Lys-type PGN, for which fewer alternative mechanisms may exist. Accordingly, Klf15NN mutants lacking nephrocytes show only Lys-type PGN-dependent Toll activation and not DAP-type PGN-dependent activation of Imd signaling, which can be deactivated by other means. Do other cell types and organs take part in the systemic clearance of PGN, particularly of Gram-positive Lys-type PGN? Interestingly, genetic ablation of hemocytes in Drosophila results in systemic Toll activation, similar to what is seen in the absence of nephrocytes (Arefin et al., 2015). Likewise, in hemocytedeficient flies, the inflammatory phenotype appears to be linked to the microbiota, as antibiotic treatment eliminates the systemic Toll overactivation phenotype (Arefin et al., 2015). In that system, Arefin et al. (2015) proposed a role for nitric oxide in the developmental consequences of this systemic inflammatory response, but the findings by Troha et al. (2019) now warrant a closer look at
the involvement of microbiota-derived Lys-type PGN and potential routes of PGN degradation by hemocytes. PGN removal by hemocytes may be based on phagocytosis or other forms of transmembrane transport. As a side note, Klf15NN mutants show reduced labeling of hemocytes by fluorescent bacteria, which may point to reduced hemocyte numbers, although Troha et al. (2019) showed that phagocytic saturation of hemocytes per se did not eliminate the difference between controls and the Klf15NN-associated Toll activation phenotype. By analogy, it will be interesting to investigate a spectrum of other cell types in vertebrates besides glomerular renal cells for putative roles in the elimination of soluble PGN and other PAMPs from circulation. Possible candidates may be cells of hematopoietic origin and scavenger endothelial cells that clear macromolecules, a cell type proposed to be analogous to Drosophila pericardial nephrocytes (Troha et al. 2019). No matter whether additional cell populations may contribute to systemic PGN elimination, the study by Troha et al. (2019) sets a milestone for renal function in the organismal regulation of immune homeostasis. These findings in Drosophila now set the stage to investigate vertebrate systems for conserved principles in immune homeostasis and microbiota-linked disease.
ACKNOWLEDGMENTS K.B. is supported by National Institutes of Health grants 1R01GM112083 and 1R01GM131094.
REFERENCES Arefin, B., Kucerova, L., Krautz, R., Kranenburg, H., Parvin, F., and Theopold, U. (2015). Apoptosis in Hemocytes Induces a Shift in Effector Mechanisms in the Drosophila Immune System and Leads to a Pro-Inflammatory State. PLoS ONE 10, e0136593. Buchon, N., Silverman, N., and Cherry, S. (2014). Immunity in Drosophila melanogaster–from microbial recognition to whole-organism physiology. Nat. Rev. Immunol. 14, 796–810. Chiu, Y.C., Lin, C.Y., Chen, C.P., Huang, K.C., Tong, K.M., Tzeng, C.Y., Lee, T.S., Hsu, H.C., and Tang, C.H. (2009). Peptidoglycan enhances IL-6 production in human synovial fibroblasts via TLR2 receptor, focal adhesion kinase, Akt, and AP-1- dependent pathway. J. Immunol. 183, 2785–2792.
Immunity 51, October 15, 2019 597
Immunity
Previews Denholm, B., and Skaer, H. (2009). Bringing together components of the fly renal system. Curr. Opin. Genet. Dev. 19, 526–532. Irazoki, O., Hernandez, S.B., and Cava, F. (2019). Peptidoglycan Muropeptides: Release, Perception, and Functions as Signaling Molecules. Front. Microbiol. 10, 500. Kieser, K.J., and Kagan, J.C. (2017). Multi-receptor detection of individual bacterial products by the
innate immune system. Nat. Rev. Immunol. 17, 376–390. Knight, R., Callewaert, C., Marotz, C., Hyde, E.R., Debelius, J.W., McDonald, D., and Sogin, M.L. (2017). The Microbiome and Human Biology. Annu. Rev. Genomics Hum. Genet. 18, 65–86. Kurts, C., Panzer, U., Anders, H.J., and Rees, A.J. (2013). The immune system and kidney disease: basic concepts and clinical implications. Nat. Rev. Immunol. 13, 738–753.
Su, H., Lei, C.T., and Zhang, C. (2017). Interleukin-6 Signaling Pathway and Its Role in Kidney Disease: An Update. Front. Immunol. 8, 405. Troha, K., Nagy, P., Pivovar, A., Lazzaro, B.P., Hartley, P.S., and Buchon, N. (2019). Nephrocytes Remove Microbiota-Derived Peptidoglycan from Systemic Circulation to Maintain Immune Homeostasis. Immunity 51, this issue, 625–637.
The Neuropeptide CGRP Induces Bipolar Syndrome in Group 2 Innate Lymphoid Cells Yasutaka Motomura,1 Tetsuro Kobayashi,2 and Kazuyo Moro1,2,3,* 1Laboratory for Innate Immune Systems, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka Suita-shi, Osaka 565-0871, Japan 2Laboratory for Innate Immune Systems, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan 3Laboratory for Innate Immune Systems, Immunology Frontier Research Center (iFReC), Osaka University, 3-1, Yamadaoka Suita-shi, Osaka 565-0871, Japan *Correspondence: [email protected] https://doi.org/10.1016/j.immuni.2019.09.015
In this issue of Immunity, Nagashima et al., Wallrapp et al., and Xu et al. demonstrate that the neuropeptide calcitonin gene-related peptide (CGRP) fine tunes type 2 innate immune response via suppressing group 2 innate lymphoid cells (ILC2s).
The immune system involves dynamic interplays between numerous cell types via various immune factors. It is crucial to direct each immune cell to the right location in a spatially and temporally controlled manner. Innate lymphoid cells (ILCs) are localized in the mucosal tissue and act as the first line of immunological defense by constantly monitoring pathogens invading from the outside. When pathogens invade, ILCs rapidly respond to the signals produced by the destruction of the epithelial barrier, initiate the innate immune machinery, and further amplify the acquired immune response (Sonnenberg and Hepworth, 2019). The epithelial-derived alarmin, interleukin (IL)-33, potently activates ILC2s, which produce IL-5 and IL-13 and induce type 2 immune response. Furthermore, ILC2s contribute to homeostasis of the body, in part through regulation of tissue repair via amphiregulin (Areg). In contrast, uncontrolled activation of ILC2s leads to a pathogenic
state, such as allergic inflammation and fibrosis. Therefore, it is crucial to understand the molecular mechanisms by which ILC2 activation occurs. Various factors that positively and negatively regulate the function of ILC2 have been identified (Kabata et al., 2018). In addition to classical cytokinemediated regulatory networks, neuronal signals have emerged as critical regulators of ILC2 function (Klose and Artis, 2019). Vasoactive intestinal peptide (VIP), which is involved in nutrient intake and central circadian rhythm, induces IL-5 production from ILC2s and maintains eosinophil homeostasis. The neuropeptide neuromedin U (NMU) induces a rapid and potent production of type 2 inflammatory and tissue-protective cytokines from ILC2s. Engagement of b-adrenergic receptor signaling on ILC2s dampens type 2 responses. These findings have provoked a paradigm shift in our understanding of neuro-immune communication
598 Immunity 51, October 15, 2019 ª 2019 Elsevier Inc.
involved in orchestrating tissue homeostasis and integrity. In this issue of Immunity, Nagashima et al. (2019), Wallrapp et al. (2019), and Xu et al., (2019) show that neuropeptide CGRP acts as another negative regulator of ILC2s, providing additional insights into the neuro-immune crosstalk that fine tunes type 2 immune responses. Transient receptor potential vanilloid 1 expressing neurons secrete CGRP, which then acts on various immune cells, such as T and B cells, dendritic cells, mast cells, and macrophages (Assas et al., 2014). Recently, pulmonary neuroendocrine cells (PNECs), specialized epithelial cells that sense hypoxia and produce neurotransmitters, have been reported to amplify allergic responses via CGRP and g-aminobutyric acid secretion, which leads to IL-5 production from ILC2s (Sui et al., 2018). The three papers in this issue further investigate the