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

Abstract

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-33 1-270 and generate mature forms IL-33 , and IL-33 . 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 fulllength 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.innate immunity | inflammatory protease | serine protease inhibitor | alveolar epithelium C ytokines of the IL-1 family (IL-1α, IL-1β, IL-18) play a major role in inflammatory, infectious, and autoimmune diseases (1-3). IL-33 [previously known as nuclear factor from high endothelial venule or NF-HEV (4, 5)], is a chromatin-associated nuclear cytokine from the IL-1 family (6, 7), which has been linked to important diseases (8-10), including asthma (11), rheumatoid arthritis (12, 13), ulcerative colitis (14), and cardiovascular diseases (15).IL-33 signals through the ST2 receptor (4), a member of the IL-1 receptor family, which is expressed (or induced) on various immune cell types, including mast cells, basophils, eosinophils, Thelper (Th)2 lymphocytes, invariant natural killer T (iNKT) and natural killer (NK) cells, macrophages, dendritic cells, and neutrophils (8-10). IL-33 stimulation of ST2 on Th2 cells induces secretion of the Th2 cytokines IL-5 and IL-13 (4, 16). Recently, IL-33 has been shown to drive production of extremely high amounts of these Th2 cytokines by type 2 innate lymphoid cells (ILCs) (natural helper cells, nuocytes, innate helper 2 cells), which play important roles in innate immune responses, after helminth infec...

AMCase is a crucial regulator of type 2 immune responses to inhaled house dust mites

“…Indeed, we observed elevated IL-33 in the BAL and enhanced type 2 immune responses in Casp7 −/− mice, suggesting a defect in IL-33 inactivation in the absence of caspase-7 although we cannot exclude the possibility of the role of other proteases and caspases (41)(42)(43). Considering the fact that IL-33 is a nuclear protein (31), it is possible that the activated caspase-7 that is translocated into the nucleus following activation by caspase-1 may play a role in IL-33 processing in the nucleus.…”

Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells

“…S3). In addition, we reported previously that neutrophil proteases, cathepsin G and elastase, can also process full-length IL-33 within the central domain and generate mature bioactive forms of the cytokine (38). Therefore, multiple proteases are able to activate IL-33 by cleavage within its central domain.…”

“…Interestingly, processing of IL-33 by mast cell (Fig. S1) and neutrophil (38) proteases was also observed in mouse, despite a lack of primary sequence conservation of the central domain between IL-33 orthologs (2).…”

“…with full-length IL-33 (38). Although neutrophils have been implicated in virus-induced exacerbations of asthma, they are unlikely to be involved in the processing of IL-33 during allergic inflammation.…”

Immunity to gastrointestinal nematode infections

“…In contrast, once IL-33 is released in the setting of tissue damage, it can be further activated by granulocyte-derived proteases to exert its function. 48,49 Much like IL-25, it is important for driving IL-13 production by ILC2 during infection 31,35 and can also be recognized by other cell types. [50][51][52][53] Furthermore, whereas exogenous administration of IL-33 at early time points after T. muris infection promotes worm clearance, injection at later stages of infection does not induce expulsion, 29 suggesting that there is an early window of opportunity in which it exerts its effects.…”