IL-1α cleavage by inflammatory caspases of the noncanonical inflammasome controls the senescence-associated secretory phenotype.
Wiggins, Kimberley A
Cassidy, Liam D
Blackwell Publishing Inc.
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Wiggins, K. A., Parry, A., Cassidy, L. D., Humphry, M., Webster, S., Goodall, J., Narita, M., & et al. (2019). IL-1α cleavage by inflammatory caspases of the noncanonical inflammasome controls the senescence-associated secretory phenotype.. Aging cell, 18 (3), e12946. https://doi.org/10.1111/acel.12946
Interleukin-1 alpha (IL-1α) is a powerful cytokine that modulates immunity, and requires canonical cleavage by calpain for full activity. Mature IL-1α is produced after inflammasome activation and during cell senescence, but the protease cleaving IL-1α in these contexts is unknown. We show IL-1α is activated by caspase-5 or -11 cleavage at a conserved site. Caspase-5 drives cleaved IL-1α release after human macrophage inflammasome activation, while IL-1α secretion from murine macrophages only requires caspase-11, with IL-1β release needing caspase-11 and -1. Importantly, senescent human cells require caspase-5 for the IL-1α-dependent senescence-associated secretory phenotype (SASP) in vitro, while senescent mouse hepatocytes need caspase-11 for the SASP-driven immune surveillance of senescent cells in vivo. Together, we identify IL-1α as a novel substrate of non-canonical inflammatory caspases, and finally provide a mechanism for how IL-1α is activated during senescence. Thus, targeting caspase-5 may reduce inflammation and limit the deleterious effects of accumulated senescent cells during disease and aging.
Cells, Cultured, Hela Cells, Animals, Mice, Inbred C57BL, Humans, Mice, Inflammation, Caspases, Female, Interleukin-1alpha, Inflammasomes, Cellular Senescence
Work was funded by British Heart Foundation grants FS/13/3/30038, FS/18/19/33371 and RG/16/8/32388 (MC); Cancer Research UK Cambridge Institute Core Grant C14303/A17197, Medical Research Council grants MR/M013049/1 and MR/R010013/1 (MN); and the Cambridge NIHR Biomedical Research Centre.
British Heart Foundation (FS/09/005/26845)
British Heart Foundation (FS/13/3/30038)
British Heart Foundation (RG/16/8/32388)
British Heart Foundation (FS/18/19/33371)
Medical Research Council (MR/M013049/1)
Cancer Research UK (C14303_do not transfer)
Medical Research Council (MR/M020134/1)
British Heart Foundation (BHF-FS/18/19/33371)
Embargo Lift Date
External DOI: https://doi.org/10.1111/acel.12946
This record's URL: https://www.repository.cam.ac.uk/handle/1810/290196