Sublytic membrane attack complex drives glycolysis and mitochondrial dysfunction with inflammatory consequences in human monocyte-derived macrophages

Abstract

The complement system is an ancient and critical element of the innate immune system. The terminal step in the complement pathway, the membrane attack complex (MAC), has previously been linked to inflammasome activation and is linked to the pathogenesis of multiple diseases including rheumatoid arthritis and neurodegeneration. Using both metabolomic and proteomic approaches, here we show that in human monocyte-derived macrophages a sublytic concentration of MAC mediates a previously uncharacterised metabolic shift, mitochondrial dysfunction and upregulation of glycolysis-promoting genes. This skewing of metabolism coupled with mitochondrial dysfunction drives ROS-mediated NLRP3 inflammasome activation and subsequent gasdermin D activation and pro-inflammatory cytokine production and release. Together, these data elucidate a novel immunometabolic signalling cascade in MAC-stimulated human macrophages, the consequences of which have implications in considering much needed novel therapeutic options for diseases linked to aberrant complement activation