We investigate how cell death and other cellular processes affects the local tissue environment, and in particular how necrosis can induce sterile inflammation. We have a special interest in atherosclerotic plaques, which are characterized by chronic inflammation and an accumulation of apoptotic and necrotic cells. Much of our work focuses on the activation and control of the apical inflammatory cytokine IL-1. IL-1α acts as a powerful danger signal when released from dead cells, and also controls the senescence-associated secretory phenotype, while IL-1β is activated and released in large amounts by the inflammasomes. Our recent work shows that multiple systems are needed to keep basal IL-1 activity under control and that small aberrations in IL-1 signalling can lead to immune dysfunction under the steady state.
Burzynski LC, Humphry M, Wiggins KA, Summers C, Tatham KC, Martin PB, Bennett MR, Clarke MCH. The coagulation and immune system are directly linked through the activation of interleukin-1α by thrombin. Immunity. 2019; 50, 1–10, April 16.
Wiggins KA, Parry AJ, Cassidy L, Webster SJ, Humphry M, Goodall JC, Narita M, Clarke MCH. IL-1α cleavage by inflammatory caspases of the non-canonical inflammasome controls the senescence-associated secretory phenotype. Aging Cell. 2019. e12946.
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.