While the immune system plays a critical role in combating infection, inappropriate regulation of immunity has a pathogenic role in many diseases including autoimmunity, allergic disease and cancer. IL-33 is a member of the IL-1 family that is released by damaged endothelial and epithelial cells. IL-33 release acts as a “danger” signal to activate inflammation. It is involved in the response to both helminth and fungal infections and is also known to play a pathogenic role in allergic diseases such as asthma. IL-33 acts on a subset of immune cells, including type 2 innate lymphoid cells and mast cells. It has a number of effects on these cells including driving proliferation and the production of Th2 cytokines such as IL-13.
While IL-33 plays important roles in infection and disease, the intracellular signaling networks it uses are not fully understood. In mast cells we have previously shown a critical role for the p38 MAPK pathway in mediating IL-33 induced cytokine production (1). This project will expand on these findings and use global proteomic approaches to map signaling networks in IL-33 stimulated cells. This will then be used to delineate the pathways required for the effects of IL-33 on mast cell and type 2 innate lymphoid cell function. Interventions in these pathways will then be examined in the context of allergic disease to identify potential new targets for drug development.
1: McCarthy PC, Phair IR, Greger C, Pardali K, McGuire VA, Clark AR, Gaestel M & Arthur JS, (2018) IL-33 regulates cytokine production and neutrophil recruitment via the p38 MAPK-activated kinases MK2/3. Immunol Cell Biol. doi:10.1111/imcb.12200. PMID: 30171775.
2: Liew FY, Girard JP & Turnquist HR, (2016) Interleukin-33 in health and disease. Nat Rev Immunol. 16(11):676-689. PMID: 27640624.
3: Arthur JS & Ley SC, (2013) Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol. 13(9):679-92. PMID: 23954936.