IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G

E Lefrançais, S Roga, V Gautier… - Proceedings of the …, 2012 - National Acad Sciences
E Lefrançais, S Roga, V Gautier, A Gonzalez-de-Peredo, B Monsarrat, JP Girard, C Cayrol
Proceedings of the National Academy of Sciences, 2012National Acad Sciences
Interleukin-33 (IL-33)(NF-HEV) is a chromatin-associated nuclear cytokine from the IL-1
family, which has been linked to important diseases, including asthma, rheumatoid arthritis,
ulcerative colitis, and cardiovascular diseases. IL-33 signals through the ST2 receptor and
drives cytokine production in type 2 innate lymphoid cells (ILCs)(natural helper cells,
nuocytes), T-helper (Th) 2 lymphocytes, mast cells, basophils, eosinophils, invariant natural
killer T (iNKT), and natural killer (NK) cells. We and others recently reported that, unlike IL-1β …
Interleukin-33 (IL-33) (NF-HEV) is a chromatin-associated nuclear cytokine from the IL-1 family, which has been linked to important diseases, including asthma, rheumatoid arthritis, ulcerative colitis, and cardiovascular diseases. IL-33 signals through the ST2 receptor and drives cytokine production in type 2 innate lymphoid cells (ILCs) (natural helper cells, nuocytes), T-helper (Th)2 lymphocytes, mast cells, basophils, eosinophils, invariant natural killer T (iNKT), and natural killer (NK) cells. We and others recently reported that, unlike IL-1β and IL-18, full-length IL-33 is biologically active independently of caspase-1 cleavage and that processing by caspases results in IL-33 inactivation. We suggested that IL-33, which is released upon cellular damage, may function as an endogenous danger signal or alarmin, similar to IL-1α or high-mobility group box 1 protein (HMGB1). Here, we investigated the possibility that IL-33 activity may be regulated by proteases released during inflammation. Using a combination of in vitro and in vivo approaches, we demonstrate that neutrophil serine proteases cathepsin G and elastase can cleave full-length human IL-331–270 and generate mature forms IL-3395–270, IL-3399–270, and IL-33109–270. These forms are produced by activated human neutrophils ex vivo, are biologically active in vivo, and have a ∼10-fold higher activity than full-length IL-33 in cellular assays. Murine IL-33 is also cleaved by neutrophil cathepsin G and elastase, and both full-length and cleaved endogenous IL-33 could be detected in the bronchoalveolar lavage fluid in an in vivo model of acute lung injury associated with neutrophil infiltration. We propose that the inflammatory microenvironment may exacerbate disease-associated functions of IL-33 through the generation of highly active mature forms.
National Acad Sciences