We investigate how cell death affects the local tissue environment and in particular how necrosis drives sterile inflammation. We have a special interest in the pathogenesis of atherosclerotic plaques, which are characterized by chronic inflammation and an accumulation of apoptotic and necrotic cells. Much of our work focuses on the key inflammatory cytokine IL-1α, which acts as a powerful danger signal upon release from dead cells. However, our recent work has shown that an elaborate molecular system controls IL-1α in a conditional and cell type-dependent manner to prevent inappropriate activation.
Gardner SE, Humphry M, Bennett MR, Clarke MCH. Senescent vascular smooth muscle cells drive inflammation through an interleukin-1α-dependent senescence-associated secretory phenotype. ATVB. 2015; 35(9):1963-74.
Zhang Y, Humphry M, Maguire JJ, Bennett MR, Clarke MCH: Intracellular IL-1 receptor 2 binding prevents cleavage and activity of IL-1α, controlling necrosis-induced sterile inflammation. Immunity. 2013; 38:2, 285.
Clarke, MCH, Figg, N, Maguire, JJ, Davenport, AP, Goddard, M, Littlewood, TD, Bennett, MR. Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis. Nature Med. 2006; 12:1075-1080.