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Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion

Complement synthesis in cells of origin is strongly linked to the pathogenesis and progression of renal disease. Multiple studies have examined local C3 synthesis in renal disease and elucidated the contribution of local cellular sources, but the contribution of infiltrating inflammatory cells remai...

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Autores principales: Liu, Yanyan, Wang, Kun, Liang, Xinjun, Li, Yueqiang, Zhang, Ying, Zhang, Chunxiu, Wei, Haotian, Luo, Ran, Ge, Shuwang, Xu, Gang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204358/
https://www.ncbi.nlm.nih.gov/pubmed/30405606
http://dx.doi.org/10.3389/fimmu.2018.02385
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author Liu, Yanyan
Wang, Kun
Liang, Xinjun
Li, Yueqiang
Zhang, Ying
Zhang, Chunxiu
Wei, Haotian
Luo, Ran
Ge, Shuwang
Xu, Gang
author_facet Liu, Yanyan
Wang, Kun
Liang, Xinjun
Li, Yueqiang
Zhang, Ying
Zhang, Chunxiu
Wei, Haotian
Luo, Ran
Ge, Shuwang
Xu, Gang
author_sort Liu, Yanyan
collection PubMed
description Complement synthesis in cells of origin is strongly linked to the pathogenesis and progression of renal disease. Multiple studies have examined local C3 synthesis in renal disease and elucidated the contribution of local cellular sources, but the contribution of infiltrating inflammatory cells remains unclear. We investigate the relationships among C3, macrophages and Th17 cells, which are involved in interstitial fibrosis. Here, we report that increased local C3 expression, mainly by monocyte/macrophages, was detected in renal biopsy specimens and was correlated with the severity of renal fibrosis (RF) and indexes of renal function. In mouse models of UUO (unilateral ureteral obstruction), we found that local C3 was constitutively expressed throughout the kidney in the interstitium, from which it was released by F4/80(+)macrophages. After the depletion of macrophages using clodronate, mice lacking macrophages exhibited reductions in C3 expression and renal tubulointerstitial fibrosis. Blocking C3 expression with a C3 and C3aR inhibitor provided similar protection against renal tubulointerstitial fibrosis. These protective effects were associated with reduced pro-inflammatory cytokines, renal recruitment of inflammatory cells, and the Th17 response. in vitro, recombinant C3a significantly enhanced T cell proliferation and IL-17A expression, which was mediated through phosphorylation of ERK, STAT3, and STAT5 and activation of NF-kB in T cells. More importantly, blockade of C3a by a C3aR inhibitor drastically suppressed IL-17A expression in C3a-stimulated T cells. We propose that local C3 secretion by macrophages leads to IL-17A-mediated inflammatory cell infiltration into the kidney, which further drives fibrogenic responses. Our findings suggest that inhibition of the C3a/C3aR pathway is a novel therapeutic approach for obstructive nephropathy.
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spelling pubmed-62043582018-11-07 Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion Liu, Yanyan Wang, Kun Liang, Xinjun Li, Yueqiang Zhang, Ying Zhang, Chunxiu Wei, Haotian Luo, Ran Ge, Shuwang Xu, Gang Front Immunol Immunology Complement synthesis in cells of origin is strongly linked to the pathogenesis and progression of renal disease. Multiple studies have examined local C3 synthesis in renal disease and elucidated the contribution of local cellular sources, but the contribution of infiltrating inflammatory cells remains unclear. We investigate the relationships among C3, macrophages and Th17 cells, which are involved in interstitial fibrosis. Here, we report that increased local C3 expression, mainly by monocyte/macrophages, was detected in renal biopsy specimens and was correlated with the severity of renal fibrosis (RF) and indexes of renal function. In mouse models of UUO (unilateral ureteral obstruction), we found that local C3 was constitutively expressed throughout the kidney in the interstitium, from which it was released by F4/80(+)macrophages. After the depletion of macrophages using clodronate, mice lacking macrophages exhibited reductions in C3 expression and renal tubulointerstitial fibrosis. Blocking C3 expression with a C3 and C3aR inhibitor provided similar protection against renal tubulointerstitial fibrosis. These protective effects were associated with reduced pro-inflammatory cytokines, renal recruitment of inflammatory cells, and the Th17 response. in vitro, recombinant C3a significantly enhanced T cell proliferation and IL-17A expression, which was mediated through phosphorylation of ERK, STAT3, and STAT5 and activation of NF-kB in T cells. More importantly, blockade of C3a by a C3aR inhibitor drastically suppressed IL-17A expression in C3a-stimulated T cells. We propose that local C3 secretion by macrophages leads to IL-17A-mediated inflammatory cell infiltration into the kidney, which further drives fibrogenic responses. Our findings suggest that inhibition of the C3a/C3aR pathway is a novel therapeutic approach for obstructive nephropathy. Frontiers Media S.A. 2018-10-22 /pmc/articles/PMC6204358/ /pubmed/30405606 http://dx.doi.org/10.3389/fimmu.2018.02385 Text en Copyright © 2018 Liu, Wang, Liang, Li, Zhang, Zhang, Wei, Luo, Ge and Xu. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Liu, Yanyan
Wang, Kun
Liang, Xinjun
Li, Yueqiang
Zhang, Ying
Zhang, Chunxiu
Wei, Haotian
Luo, Ran
Ge, Shuwang
Xu, Gang
Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion
title Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion
title_full Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion
title_fullStr Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion
title_full_unstemmed Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion
title_short Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion
title_sort complement c3 produced by macrophages promotes renal fibrosis via il-17a secretion
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204358/
https://www.ncbi.nlm.nih.gov/pubmed/30405606
http://dx.doi.org/10.3389/fimmu.2018.02385
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