Intrinsic macrophage factor H plays a critical role in kidney homeostasis 4162

Abstract Description The complement cascade is a key component of the innate immune system. Dysfunction of the complement regulator, factor H (FH) is linked to kidney disease, often accompanied by macrophage infiltration. Hepatic FH regulates serum complement activation, while intrinsic FH in cells such as macrophages regulates complement activation and maintains local homeostasis. Macrophages are heterogeneous and influenced by their microenvironment, prompting us to investigate the role of macrophage-derived FH in kidney pathology and fibrosis. We generated FloxFH (FHfl/fl) mice and crossed them with CMVcre, CX3CR1cre, and Csfr1cre mice to produce conditional FH knockout (cKO) mice with no FH (FHfl/flCMVcre) and with FH absent in the macrophages (FHfl/flCX3CR1cre and FHfl/flCsfr1cre). The mice were treated with horse spleen apoferritin to induce chronic serum sickness. FHfl/flCMVcre mice exhibited a significant increase in immune complexes in the glomeruli compared to FHfl/fl controls. FHfl/flCX3CR1cre and FHfl/flCsfr1cre mice showed kidney dysfunction and immune deposits, with FHfl/flCX3CR1cre deposits resembling those seen in global FH knockouts. Additionally, TGF-β and laminin expression were significantly elevated in the kidneys of the cKO mice. Our results for the first time, highlight the critical role of macrophage-derived FH in limiting inflammation, preventing kidney pathology, as well as its involvement in the development of fibrosis in immune complex-mediated kidney disease. Funding Sources N/A Topic Categories Immune Mechanisms of Human Disease (HUM)