Functional mechanisms of interleukin-33, a cytokine playing a major role in innate immunity and allergy
Interleukin-33 (IL-33) is a nuclear cytokine from the IL-1 family with critical roles in tissue homeostasis and repair, type 2 immunity, viral infection, inflammation and allergy. It binds to the ST2 receptor expressed on cells of the innate and adaptive immune system. Major target cells of IL-33 include group 2 innate lymphoid cells (ILC2s), mast cells, and certain subsets of regulatory T cells. IL-33 plays a role in many important diseases. Particularly, several genome-wide association identified the genes of IL-33 and ST2 as major susceptibility loci for human asthma.
In collaboration with the team of J-P Girard at IPBS, we use mass spectrometry techniques to better characterize the mechanisms of IL-33 action.
Mechanisms of IL-33 activation by proteolytic maturation
|IL-33 contains a N-terminal chromatin-binding domain: it is mainly sequestered in the nucleus of epithelial end endothelial cells from barrier tissues, and is released upon cellular damage or necrose. On the other hand, its C-terminal part is composed of a bioactive IL1-like cytokine domain. The group of J-P Girard demonstrated that IL-33 is not regulated as IL-1b through maturation by caspase-1 (which rather inactivates IL-33 by cleaving inside the IL1-like domain), but through proteolytic maturation by inflammatory proteases.
We use mass spectrometry analysis to identify highly active mature forms of the protein resulting from processing by activator proteases, and map the cleavage sites in the central domain of IL-33.
|Detection of Neo-Nterminal peptides in maturated forms of IL-33 through quantitative comparison with peptides from full-length protein
Unbiased global proteomic studies to characterize IL-33 action
|Extracellular IL-33 is known to activate a growing number of target cells (including group 2 innate lymphoid cells, mast cells, regulatory T cells, and endothelial cells). We use large-scale proteomics to characterize the extracellular and intracellular role of IL-33 on these cells.
Lefrancais, E., Roga, S., Gautier, V., Gonzalez-de-Peredo, A., Monsarrat, B., Girard, J. P., and Cayrol, C. (2012) IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G. PNAS 109, 1673-1678.
Gautier et al (2016) Extracellular IL-33 cytokine, but not endogenous nuclear IL-33, regulates protein expression in endothelial cells. Sci Rep 6, 34255.
|Proteomic analysis of primary endothelial cells response to the stimulation with extracellular IL-33