Loss of CD11b exacerbates murine complement-mediated tubulointerstitial nephritis.

Abstract

Acute complement activation occurs in the tubulointerstitium (TI) of kidneys transplanted from Crry(-/-)C3(-/-) mice into complement-sufficient wildtype mice, followed by marked inflammatory cell infiltration, tubular damage and interstitial fibrosis. We postulated iC3b-CD11b interactions were critical in this TI nephritis model. We transplanted Crry(-/-)C3(-/-) mouse kidneys into CD11b(-/-) and wildtype C57BL/6 mice. Surprisingly, there was greater inflammation in Crry(-/-)C3(-/-) kidneys in CD11b(-/-) recipients compared to those in wildtype hosts. Kidneys in CD11b(-/-) recipients had large numbers of CD11b-Ly6ChiCCR2hiF4/80+ cells consistent with inflammatory (M1) macrophages recruited from circulating monocytes of the host CD11b(-/-) animal. There was also an expanded population of CD11b(+)CD11c(+)Ly6C(-)F4/80(hi) cells. Since these cells were CD11b(+), they must have originated from the transplanted kidney; their surface protein expression and appearance within the kidney were consistent with the intrinsic renal mononuclear cellular population. These cells were markedly expanded relative to all relevant controls, including the contralateral donor kidney and Crry(-/-)C3(-/-) mouse kidneys in CD11b(+/+) wildtype recipients. Direct evidence for their in situ proliferation was the presence of nuclear Ki67 and PCNA in CD11b(+)F4/80(+) cells. Thus, in this experimental model in which there is unrestricted C3 activation, CD11b(+) monocytes limit their own infiltration into the kidney and prevent proliferation of endogenous mononuclear cells. This suggests a role for outside-in iC3b-CD11b signals in limiting intrinsic organ inflammation.