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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Frontiers Media S.A.
2018-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.02385/full |
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| author | Yanyan Liu Kun Wang Xinjun Liang Yueqiang Li Ying Zhang Chunxiu Zhang Haotian Wei Ran Luo Shuwang Ge Gang Xu |
| author_facet | Yanyan Liu Kun Wang Xinjun Liang Yueqiang Li Ying Zhang Chunxiu Zhang Haotian Wei Ran Luo Shuwang Ge Gang Xu |
| author_sort | Yanyan Liu |
| collection | DOAJ |
| 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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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-10T22:26:29Z |
| publishDate | 2018-10-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-aee3260e264f453482e998a1580e11072022-12-22T01:31:10ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-10-01910.3389/fimmu.2018.02385400643Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A SecretionYanyan Liu0Kun Wang1Xinjun Liang2Yueqiang Li3Ying Zhang4Chunxiu Zhang5Haotian Wei6Ran Luo7Shuwang Ge8Gang Xu9Division of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDivision of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaHubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDivision of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDivision of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDivision of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDivision of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDivision of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDivision of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDivision of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaComplement 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.https://www.frontiersin.org/article/10.3389/fimmu.2018.02385/fullcomplement component 3macrophagerenal fibrosis (RF)IL-17AIgAN |
| spellingShingle | Yanyan Liu Kun Wang Xinjun Liang Yueqiang Li Ying Zhang Chunxiu Zhang Haotian Wei Ran Luo Shuwang Ge Gang Xu Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion Frontiers in Immunology complement component 3 macrophage renal fibrosis (RF) IL-17A IgAN |
| 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 | complement component 3 macrophage renal fibrosis (RF) IL-17A IgAN |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.02385/full |
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