Neutrophil-Derived Proteases Escalate Inflammation through Activation of IL-36 Family Cytokines

Henry, Conor M.; Sullivan, Graeme P.; Clancy, Danielle M.; Afonina, Inna S.; Kulms, Dagmar; Martin, Séamus J.

doi:10.1016/j.celrep.2015.12.072

Cited by 278 publications

(348 citation statements)

References 43 publications

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“…2), most likely because of lack of N-terminal processing 35 . In agreement with previous findings 25,36 , IL-36 can be activated by proteases that are released by activated neutrophils, including elastase (Supplementary Fig. S7).…”

Section: Discussionsupporting

confidence: 79%

“…This indicated that sufficient IL-17A was still present in these supernatants that stimulated gene expression. As mentioned above, IL-36 cytokines require processing to gain biological activity [34][35][36] . IL-36 can be processed and activated by proteases derived from neutrophils 25,36 .…”

Section: Resultsmentioning

confidence: 99%

“…As mentioned above, IL-36 cytokines require processing to gain biological activity [34][35][36] . IL-36 can be processed and activated by proteases derived from neutrophils 25,36 . Elastase, one of these proteases, was capable of activating DEFB4A, IL36G, and S100A7A gene expression in naïve NHEK monolayer cultures cooperatively with IL-17A-treated NHEK supernatants ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…α1-antitrypsin was not fully repressing the cooperative effects suggesting that these are not the only neutrophilic proteases involved. IL-36α and β are expressed in the NHEKs in response to IL-17A and might also contribute to the cooperative effects, particularly as they are activated by distinct proteases 25,36 . The importance of neutrophil-derived proteases was further demonstrated by the activation of latent IL-36γ in the presence of neutrophil supernatants or by elastase as measured by DEFB4A and S100A7A expression ( Supplementary Fig.…”

mentioning

confidence: 99%

“…Importantly and similar to other IL-1 family cytokines, the different IL-36 proteins need to be processed to become biologically active. This occurs by truncating the N-termini, removing a few amino acids in response to several different proteases [34][35][36] . Thus, in addition to IL-17, IL-36 cytokines are also thought to participate in the inflammatory progression of psoriasis.…”

mentioning

confidence: 99%

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301 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

Pfaff

Kluwig

Marquardt

et al. 2017

Journal of Investigative Dermatology

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Psoriasis is a T H 17-driven inflammatory disease affecting a significant proportion of the world population. The molecular consequences of IL-17 signaling in the skin are only partially understood. Therefore, we evaluated the IL-17A effects on organotypic 3-dimensional skin models and observed that IL-17A interfered with keratinocyte differentiation. In agreement with this phenotype, IL-17A repressed the expression of many genes encoding structural proteins. Moreover, genes encoding anti-microbial peptides were induced, resulting in a strengthening of the chemical barrier. Finally, we observed enhanced expression of the three IL-36 cytokines IL-36α, β and γ. We found that IL-36γ was secreted from keratinocytes in an inactive form and that neutrophilic proteases, including elastase, were capable of activating this cytokine. Functionally and similar to IL-17A, truncated IL-36 cytokines interfered with keratinocyte differentiation in 3D models. The molecular analysis revealed strong cooperative effects of IL-17A and IL-36 cytokines in regulating target genes, which was dependent on the proteolytic activation of the latter. Together these findings suggest an amplification cycle that can be initiated by IL-17A, involving IL-36 cytokines and immune cell derived proteases and resulting in active IL-36 cytokines which synergize with IL-17A. This amplification cycle might be relevant for a persistent psoriatic phenotype.Psoriasis, a chronic autoimmune disease of the skin, affects approximately 2% of the population. Psoriasis is associated with systemic inflammatory processes including inflammatory arthritis, inflammatory bowel disease, and metabolic syndrome 1,2 . A typical manifestation of the disease is the hyperproliferation of keratinocytes with premature differentiation. This results in incomplete cornification with retention of nuclei in the stratum corneum, referred to as parakeratosis. Functionally this correlates with increased infiltrations of immune cells due to dendritic cells, macrophages, neutrophils and different subpopulations of T cells. These cells modify the cytokine milieu and thus affect the behavior of keratinocytes resulting in altered differentiation [1][2][3]

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Section: Discussionsupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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301 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

Pfaff

Kluwig

Marquardt

et al. 2017

Journal of Investigative Dermatology

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Spesolimab Response in a Patient With Steroid-Resistant Sweet Syndrome

Pang,

Wu,

Liu

et al. 2024

JAMA Dermatol

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Identification of small‐molecule elastase inhibitors as antagonists of IL‐36 cytokine activation

et al. 2018

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IL‐1 family cytokines act as apical initiators of inflammation in many settings and can promote the production of a battery of inflammatory cytokines, chemokines and other inflammatory mediators in diverse cell types. IL‐36α, IL‐36β and IL‐36γ, which belong to the extended IL‐1 family, have been implicated as key initiators of skin inflammation in psoriasis. IL‐36γ is highly upregulated in lesional skin from psoriatic individuals, and heritable mutations in the natural IL‐36 receptor antagonist result in a severe form of psoriasis. IL‐36 family cytokines are initially expressed as inactive precursors that require proteolytic processing for activation. The neutrophil granule‐derived protease elastase proteolytically processes and activates IL‐36α and IL‐36γ, increasing their biological activity ~ 500‐fold, and also robustly activates IL‐1α and IL‐33 through limited proteolytic processing. Consequently, inhibitors of elastase activity may have potential as anti‐inflammatory agents through antagonizing the activation of multiple IL‐1 family cytokines. Using in silico screening approaches, we have identified small‐molecule inhibitors of elastase that can antagonize activation of IL‐36γ by the latter protease. The compounds reported herein may have utility as lead compounds for the development of inhibitors of elastase‐mediated activation of IL‐36 and other IL‐1 family cytokines in inflammatory conditions, such as psoriasis.

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Neutrophil-Derived Proteases Escalate Inflammation through Activation of IL-36 Family Cytokines

Cited by 278 publications

References 43 publications

301 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

301 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

Spesolimab Response in a Patient With Steroid-Resistant Sweet Syndrome

Identification of small‐molecule elastase inhibitors as antagonists of IL‐36 cytokine activation

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