Complement C3 exacerbates renal interstitial fibrosis by facilitating the M1 macrophage phenotype in a mouse model of unilateral ureteral obstruction

Abstract

The impact of the renal microenvironment on macrophage phenotype determination can contribute to the progression or resolution of renal fibrosis. Although the complement proteins affect macrophage polarization, whether complement component 3 (C3) can induce macrophage polarization and regulate renal interstitial fibrosis remains undetermined. In the present study, we investigated the contribution of C3 on macrophage polarization and renal fibrosis in C3-deficient mice with unilateral ureteral obstruction and bone marrow-derived macrophages. C3-deficient mice exhibited attenuated renal fibrosis and ameliorated peritubular capillary rarefaction. Lack of C3 contributed to M2 macrophage polarization, increased IL-10 and VEGF164, and decreased TNF-α and soluble VEGF receptor 1 expression in the obstructed kidneys at the early stages of unilateral ureteral obstruction. C3a facilitated LPS-induced M1 polarization and inflammatory factor production in bone marrow-derived macrophages in vitro, accompanied by increased ERK, NF-κB, and STAT1 phosphorylation. The ERK-specific inhibitor PD98059 inhibited the phosphorylation of ERK, NF-κB, and STAT1 and attenuated M1 polarization-related inflammatory factor production. Furthermore, the culture supernatant from M1 macrophages and C3a-treated M2 macrophages were more detrimental to angiogenesis compared with M2 macrophage supernatants. Thus, complement C3 exacerbates renal interstitial fibrosis by facilitating macrophage M1 polarization, promoting proinflammatory cytokine expression, and deteriorating peritubular capillary rarefaction in the kidney.

The HSP GRP94 interacts with macrophage intracellular complement C3 and impacts M2 profile during ER stress

“…Indeed, C3b binding to CD46 CYT1 is well-known to contribute to IFNγ secretion in T cells 38 and induces NO production in mouse macrophages expressing CYT1 but not CYT2 39 . C3a induces pSTAT1, pNFkB and TNFα production in murine macrophages and decreases M2 markers during cotreatment with IL-4 40 .…”

Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis

“…C3-/-mice were also protected from fibrosis and peritubular rarefaction in a model of unilateral ureteral obstruction and authors proposed that macrophages polarization could be involved with C3a induced M1 macrophages responsible in vitro for angiogenesis suppression. 48 Therefore, complement C3 and/or downstream components are directly pathogenic for tubular cells and act in cooperation with macrophages to promote renal injury. However, specific cell types where inflammatory and apoptotic pathways are activated cannot be defined by the bulk RNA sequencing approach.…”

Cardio- and reno-protective effects of dipeptidyl peptidase III in diabetic mice

“…C3-derived molecules, such as C3a, C3b, and C3f, have diverse bioactivities, and their uncontrolled overactivation induces injury in tissues and organs. In contrast, C3 deficiency significantly reduces renal interstitial fibrosis by inhibiting inflammatory responses in the mouse ureteral obstruction model (64). C3 is cleaved by C3 convertase and is divided into two fragments: C3a, a smaller fragment and C3b, a larger fragment.…”