Granzyme B-Dependent Proteolysis Acts as a Switch to Enhance the Proinflammatory Activity of IL-1α

Afonina, Inna S.; Tynan, Graham A.; Logue, Susan E.; Cullen, Sean P.; Bots, Michael; Lüthi, Alexander U.; Reeves, Emer P.; McElvaney, Noel G.; Medema, Jan Paul; Lavelle, Ed C.; Martin, Séamus J.

doi:10.1016/j.molcel.2011.07.037

Cited by 246 publications

(235 citation statements)

References 41 publications

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“…S2). Moreover, other proteases, including granzymes, matrix metalloprotease 9, and mast cell chymase, have been shown to process IL-1α, IL-1β, and IL-18 precursors into active cytokines (1,3,36,44). It remains to be seen whether these or other proteases may also play a role in the processing of IL-33 into mature bioactive forms.…”

Section: Discussionmentioning

confidence: 99%

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

Lefrançais

Roga

Gautier

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

501

464

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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...

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Section: Discussionmentioning

confidence: 99%

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

Lefrançais

Roga

Gautier

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

501

464

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“…27,28,[31][32][33] GzmB can also regulate inflammation by cleaving and activating cytokines such as IL-18 and IL-1a. 34,35 Interestingly, it is also known that GzmB-mediated cleavage of IL-1a can occur extracellularly by GzmB derived from NK cells, 35 further highlighting the potential importance of perforin-independent GzmB activity in health and disease. In fact, both cytotoxic and non-cytotoxic activities of GzmB are suggested to have a role in many inflammatory disorders such as diabetes, cancer, transplant rejection, autoimmunity, cardiovascular and pulmonary diseases (reviewed in refs [36][37][38][39][40] ).…”

Section: Discussionmentioning

confidence: 99%

Granzyme B degrades extracellular matrix and contributes to delayed wound closure in apolipoprotein E knockout mice

Hiebert

Granville

2013

Cell Death Differ

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Chronic inflammation and excessive protease activity have a major role in the persistence of non-healing wounds. Granzyme B (GzmB) is a serine protease expressed during chronic inflammation that, in conjunction with perforin, has a well-established role in initiating apoptotic cell death. GzmB is also capable of acting extracellularly, independent of perforin and can degrade several extracellular matrix (ECM) proteins that are critical during wound healing. We used apolipoprotein E (ApoE) knockout (AKO) mice as a novel model of chronic inflammation and impaired wound healing to investigate the role of GzmB in chronic wounds. Wild-type and AKO mice were grown to 7 weeks (young) or 37 weeks (old) of age on a regular chow or high-fat diet (HFD), given a 1-cm diameter full thickness wound on their mid dorsum and allowed to heal for 16 days. Old AKO mice fed a HFD exhibited reduced wound closure, delayed contraction, chronic inflammation and altered ECM remodeling. Conversely, GzmB/ApoE double knockout mice displayed improved wound closure and contraction rates. In addition, murine GzmB was found to degrade both fibronectin and vitronectin derived from healthy mouse granulation tissue. In addition, GzmB-mediated degradation of fibronectin generated a fragment similar in size to that observed in non-healing mouse wounds. These results provide the first direct evidence that GzmB contributes to chronic wound healing in part through degradation of ECM.

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“…These findings imply that IL-1␣ precursor processing may be required for full function and suggest that the regulated expression and subsequent processing of IL-1␣ are of functional significance. Recent evidence in immune cells supports this possibility, demonstrating that the processed form of IL-1␣ is more effective in inducing the production of inflammatory mediators (10).…”

mentioning

confidence: 98%

Redox Control of the Senescence Regulator Interleukin-1α and the Secretory Phenotype

McCarthy

Clark

Bartling

et al. 2013

Journal of Biological Chemistry

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Background:The senescent microenvironment is permissive to disease progression, and the role of oxidants in this process remains uncharacterized. Results: Senescent fibroblasts promote tumor invasion through redox/calcium regulation of the cytokine IL-1␣. Conclusion: Senescence-associated oxidants and calcium drive the secretory phenotype, altering the microenvironment. Significance: Targeting senescent cells with antioxidant-based therapeutics may restrict inflammation and combat age-related disease progression.

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Granzyme B-Dependent Proteolysis Acts as a Switch to Enhance the Proinflammatory Activity of IL-1α

Cited by 246 publications

References 41 publications

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

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

Granzyme B degrades extracellular matrix and contributes to delayed wound closure in apolipoprotein E knockout mice

Redox Control of the Senescence Regulator Interleukin-1α and the Secretory Phenotype

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