Complement Factor H regulates kidney function by modulating macrophages

Abstract The complement system is a powerful arm of the innate immune system. Complement factor H (CFH) is a critical regulator of the complement system and CFH abnormalities have been implicated in diseases such as dense deposit disease, atypical hemolytic syndrome and age related macular degeneration. Earlier studies from our lab showed that absence of CFH rendered the, normally resistant, C57BL6 mouse susceptible to immune complex mediated glomerulonephritis. CFH knockout mice developed proliferative glomerulonephritis with endocapillary F4/80+ macrophage (Mϕs) infiltration. Nanostring assessment of wild type (WT) and CFHKO kidneys using mouse myeloid panel and stringent analysis revealed that of the 754 genes on the array, 18 macrophage related genes were decreased with at least 1.5 fold change and p<0.05. We therefore studied the role of Mϕs in this setting. Depletion of Mϕs with liposomal clodronate was protective from disease pathology as assessed by BUN, histology, and reduced expression of laminin. For the first time, our studies show that Mϕs isolated from WT mice and grown in culture express intrinsic CFH. Therefore to understand whether the changes are induced by intrinsic Mϕ CFH or CFH in circulation, we have grown bone marrow derived Mϕs from CFH KO and WT mice. Metabolic bioenergetics was markedly impaired in Mϕs deficient in CFH. Since oxidative phosphorylation enables repolarization, our results suggest that modulation of mitochondrial function by complement and thereby reprogramming of inflammatory Mϕs could be a therapeutic avenue in this setting.