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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:744567 |
| Date | January 2018 |
| Creators | Wiggins, Kimberley Anne |
| Contributors | Clarke, Murray |
| Publisher | University of Cambridge |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.repository.cam.ac.uk/handle/1810/273664 |
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