Complement receptor 3 mediates renal protection in experimental C3 glomerulopathy(1)
C3 glomerulopathy (C3G) is a category of kidney diseases that includes dense-deposit disease, C3 glomerulonephritis, and complement factor H–related protein 5 (CFHR5) nephropathy. C3G is defined by the presence of isolated or dominant complement C3 within the glomerulus. Mice with homozygous deficiency of FH (Cfh–/–) have proved to be an informative experimental model of C3G. Cfh–/– mice spontaneously develop low plasma C3 and C5 levels and linear staining of C3 and C9 along the glomerular basement membrane (GBM). Complement receptor 3 (CR3) mediates diverse cellular functions including phagocytosis of iC3b-coated particles, cytotoxicity, chemotaxis, and cell adhesion, which play a critical role in regulating inflammation and antimicrobial immunity.
At 8 months, Cfh–/– recipients of Itgam–/– BM-derived cells showed significantly increased plasma urea, glomerular cellularity, and glomerular macrophage counts.
Two days after injection of nephrotoxic serum, hematuria was detectable in 7 of the 8 Itgam–/– mice but absent in all wild-type animals. Ten days after administration of nephrotoxic serum, when all animals were culled, the Itgam–/– mice had significantly greater hematuria, plasma urea levels, and glomerular crescents.
Preincubation with iC3b-gRBCs resulted in reduced secretion of interleukin-6 (IL-6), but enhanced secretion of IL-10.
In both cell types iC3b pre-ligation downmodulated the proinflammatory cytokine profile triggered by LPS and promoted an anti-inflammatory response. In contrast, the cytokine effect of iC3b-coated beads on TLR4-stimulated neutrophils was proinflammatory with significantly increased production of IL-8 and CCL3 (MIP-1α).
Disease exacerbation was more marked in non-SPF compared to SPF housing conditions. This protective effect was dependent on CR3 expression on BM-derived cells. Glomerular macrophages were increased in Cfh–/– animals reconstituted with Itgam–/– BM-derived cells, suggesting that these macrophages were contributing to the protective effect. C3-deficient animals developed greater renal injury during the autologous phase of heterologous NTN. In the same study C3 deficiency was also associated with exacerbation of renal injury in ANTN. Pre-ligation with a synthetic CD11b agonist has also been shown to inhibit human macrophage secretion of tumor necrosis factor-α in response to synthetic TLR7/8 ligands. ANTN has been extensively characterized in C57BL/6 mice as involving a T helper 1–predominant, delayed-type hypersensitivity–like nephritogenic immune response. T helper 17–directed cellular immune responses have also been implicated in several murine models of crescentic nephritis, including ANTN. CR3 may negatively regulate CFA-induced proinflammatory signaling, with renal injury in the ANTN model being dependent on the sensitization phase induced by IgG mixed with CFA. CFA is a recognized TLR agonist, and increased renal injury. CFA can induce a CD11b-positive splenic cell population with immunosuppressive effects on T cell–mediated immunity.