| First Author | Zhang T | Year | 2020 |
| Journal | JCI Insight | Volume | 5 |
| Issue | 7 | PubMed ID | 32191644 |
| Mgi Jnum | J:301750 | Mgi Id | MGI:6505004 |
| Doi | 10.1172/jci.insight.134081 | Citation | Zhang T, et al. (2020) The C5a/C5aR2 axis promotes renal inflammation and tissue damage. JCI Insight 5(7) |
| abstractText | C5a is a potent inflammatory mediator that binds C5aR1 and C5aR2. Although pathogenic roles of the C5a/C5aR1 axis in inflammatory disorders are well documented, the roles for the C5a/C5aR2 axis in inflammatory disorders and underlying mechanisms remain unclear. Here, we show that the C5a/C5aR2 axis contributes to renal inflammation and tissue damage in a mouse model of acute pyelonephritis. Compared with WT littermates, C5ar2-/- mice had significantly reduced renal inflammation, tubular damage, and renal bacterial load following bladder inoculation with uropathogenic E. coli. The decrease in inflammatory responses in the kidney of C5ar2-/- mice was correlated with reduced intrarenal levels of high mobility group box-1 protein (HMGB1), NLRP3 inflammasome components, cleaved caspase-1, and IL-1beta. In vitro, C5a stimulation of macrophages from C5ar1-/- mice (lacking C5aR1 but expressing C5aR2) led to significant upregulation of HMGB1 release, NLRP3/cleaved caspase-1 inflammasome activation, and IL-1beta secretion. Furthermore, blockade of HMGB1 significantly reduced C5a-mediated upregulation of NLRP3/cleaved caspase-1 inflammasome activation and IL-1beta secretion in the macrophages, implying a HMGB1-dependent upregulation of NLRP3/cleaved caspase-1 inflammasome activation in macrophages. Our findings demonstrate a pathogenic role for the C5a/C5aR2 axis in renal injury following renal infection and suggest that the C5a/C5aR2 axis contributes to renal inflammation and tissue damage through upregulation of HMGB1 and NLRP3/cleaved caspase-1 inflammasome. |
