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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), which play an important role in asthma. 
In collaboration with the team of J-P Girard at IPBS, we apply mass spectrometry techniques to better characterize the mechanisms of IL-33 action.


Il-33 is activated by proteolytic maturation. We used sensitive mass spectrometry to analyze highly active mature forms of the protein resulting from proteolytic cleavage by activator inflammatory proteases, and map the cleavage sites in the central domain of IL-33 (1). We used similar approaches to finely dissect the mechanisms of IL-33 activation by a large range of environmental allergens (2).


In addition, using large-scale, unbiased proteomic methods, we study the response of target cells upon stimulation with IL-33 and co-stimulatory cytokines.

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Mass spectrometry workflow for identification of cleavages sites. Using highly sensitive mass spectrometry, we identified the N-terminal peptides characteristic of the cleavages generated on IL-33 by a whole panel of allergens. These cleavage events induce activation of the cytokine, finally triggering asthma.
 

Selected publications

  1. Lefrancais et al. IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G. Proc Natl Acad Sci U S A 2012. https://doi.org/10.1073/pnas.1115884109
  2. Cayrol et al. Environmental allergens induce allergic inflammation through proteolytic maturation of IL-33. Nat. Immunol. 2018. https://doi.org/10.1038/s41590-018-0067-5