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Novel Proteases That Regulate Interleukin-1 Alpha Activity During Inflammation And Senescence 10.17863/CAM.20722 Wiggins, Kimberley Anne Clarke, Murray Interleukin-1 alpha (IL-1a) is a powerful inflammatory cytokine that modulates both innate and adaptive immunity. As such, IL-1a is implicated in the development of multiple inflammatory and autoimmune diseases including atherosclerosis, arthritis and cancer. Therefore, understanding the mechanisms that regulate IL-1a activity is extremely important. For many years, pro-IL-1a was considered to be a fully active alarmin. However, we have previously shown that the removal of the pro-domain by calpain, a protease that is activated upon necrosis, significantly increases IL-1a bioactivity. The work presented in this thesis demonstrates that multiple proteases from diverse biological systems cleave and activate IL-1a. We therefore suggest that IL-1a is an important signalling hub that integrates diverse proteolytic danger signals to alert the immune system. In particular we have identified the inflammatory caspase, caspase-5, as a novel and potent activator of IL-1a. We show that caspase-5 directly cleaves pro-IL-1a during the activation of the non-canonical inflammasome by cytosolic LPS, which mimics intracellular bacterial infection. We also demonstrate that caspase-5-cleaved IL-1a mediates the senescence-associated secretory phenotype (SASP), which drives the deleterious effects of senescent cells in multiple age-related diseases. Therefore, therapeutically targeting caspase-5 may be of interest for pathologies mediated by the non-canonical inflammasome and/or senescent cells. Finally we find that rs17561, a common IL1A polymorphism, reduces active IL-1a release. We find that blood from minor allele homozygotes releases significantly less IL-1a than major allele homozygotes upon LPS stimulation. Therefore, genotyping patients under consideration for anti-IL-1a therapy could predict who would be likely to respond well to the treatment. In conclusion, the work presented in this thesis enhances our understanding of how IL-1a activity is regulated. The identification of both the caspase-5-mediated pathway of IL-1a activation and the defect conferred by the rs17561 SNP could have important clinical implications for the treatment of multiple inflammatory diseases. University of Cambridge 2018-04-11 Thesis Doctoral Doctor of Philosophy (PhD) en My PhD was generously funded by the British Heart Foundation. https://www.repository.cam.ac.uk/handle/1810/273664 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/208a33fb-dd28-4a11-8de6-e52aef402a7d/download 87eda9de84448d1f82354d60eee3eb5f https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/f2b8e96b-4b04-4c28-86d2-810b6ddc7792/download e685701fe4fa7fbc164f8747acf5375f https://www.rioxx.net/licenses/all-rights-reserved/ Inflammasomes Cytokines IL-1 Immunity Inflammation Single Nucleotide Polymorphisms Senescence Caspase Proteases