Regulation and function of interleukin‐36 cytokines

Bassoy, Esen Yonca; Towne, Jennifer E.; Gabay, Cem

doi:10.1111/imr.12610

Cited by 161 publications

(189 citation statements)

References 87 publications

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“…IL-36a, -b, and -g (hence IL-36) are group of IL-1 family cytokines that are mainly produced by keratinocytes, monocytes, and dendritic cells (Bassoy et al, 2018). IL-36 signaling plays an important role in epithelial immune homeostasis, and its deregulation has been repeatedly implicated in the pathogenesis of psoriasis vulgaris (PV), a common and chronic, immune-mediated skin disorder (Bassoy et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis

Catapano

Vergnano

Romano

et al. 2020

Journal of Investigative Dermatology

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Psoriasis is an immune-mediated skin disorder associated with severe systemic comorbidities. Whereas IL-36 is a key disease driver, the pathogenic role of this cytokine has mainly been investigated in skin. Thus, its effects on systemic immunity and extracutaneous disease manifestations remain poorly understood. To address this issue, we investigated the consequences of excessive IL-36 activity in circulating immune cells. We initially focused our attention on generalized pustular psoriasis (GPP), a clinical variant associated with pervasive upregulation of IL-36 signaling. By undertaking blood and neutrophil RNA sequencing, we demonstrated that affected individuals display a prominent IFN-I signature, which correlates with abnormal IL-36 activity. We then validated the association between IL-36 deregulation and IFN-I over-expression in patients with severe psoriasis vulgaris (PV). We also found that the activation of IFN-I genes was associated with extracutaneous morbidity, in both GPP and PV. Finally, we undertook mechanistic experiments, demonstrating that IL-36 acts directly on plasmacytoid dendritic cells, where it potentiates toll-like receptor (TLR)-9 activation and IFN-a production. This effect was mediated by the upregulation of PLSCR1, a phospholipid scramblase mediating endosomal TLR-9 translocation. These findings identify an IL-36/ IFN-I axis contributing to extracutaneous inflammation in psoriasis.

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Section: Introductionmentioning

confidence: 99%

IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis

Catapano

Vergnano

Romano

et al. 2020

Journal of Investigative Dermatology

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“…These family members share between 15–85% sequence similarity at the amino acid level, with IL-36α and IL-36γ being the most similar among the cytokines [20]. Despite similarity among the three agonists, the differential expression patterns of the IL-36 family members suggest that these cytokines may have cell- and/or tissue-specific functions [21, 22]. IL-36α, - β, and -γ are all expressed in nonhematopoietic cells, including keratinocytes and mucosal epithelial cells, but are induced in response to different inflammatory stimuli [23].…”

Section: Introductionmentioning

confidence: 99%

IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

Gardner

Herbst-Kralovetz

2018

Cytokine

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Herpes simplex virus 2 (HSV-2) causes a persistent, lifelong infection that increases risk for sexually transmitted infection acquisition. Both the lack of a vaccine and the need for chronic suppressive therapies to control infection presents the need to further understand immune mechanisms in response to acute HSV-2 infection. The IL-36 cytokines are recently identified members of the IL-1 family and function as inflammatory mediators at epithelial sites. Here, we first used a well-characterized three-dimensional (3-D) human vaginal epithelial cell (VEC) model to understand the role of IL-36γ in the context of HSV-2 infection. In 3-D VEC, IL-36γ is induced by HSV-2 infection, and pretreatment with exogenous IL-36γ significantly reduced HSV-2 replication. To assess the impact of IL-36γ treatment on HSV-2 disease pathogenesis, we employed a lethal genital infection model. We showed that IL-36γ treatment in mice prior to lethal intravaginal challenge significantly limited vaginal viral replication, delayed disease onset, decreased disease severity, and significantly increased survival. We demonstrated that IL-36γ treatment transiently induced pro-inflammatory cytokines, chemokines, and antimicrobial peptides in murine lower female reproductive tract (FRT) tissue and vaginal lavages. Induction of the chemokines CCL20 and KC in IL-36γ treated mice also corresponded with increased polymorphonuclear (PMN) leukocyte infiltration observed in vaginal smears. Altogether, these studies demonstrate that IL-36γ drives the transient production of immune mediators and promotes PMN recruitment in the vaginal microenvironment that increases resistance to HSV-2 infection and disease. Our data indicate that IL-36γ may participate as a key player in host defense mechanisms against invading pathogens in the FRT.

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“…IL-36 family includes three agonistic cytokines, IL-36α, IL-36β, and IL-36γ, and one antagonistic molecule, IL-36RA, all of them signaling through the dimer composed of IL-36R and IL-1R accessory protein. This cytokine family is involved in the activation of myeloid cells (including monocytes and dendritic cells) and epithelial cells, such as skin keratinocytes, contributing to leukocyte recruitment or AMP secretion (Gresnigt and van de Veerdonk, 2013;Jensen, 2017;Bassoy et al, 2018;Swindell et al, 2018).…”

Section: Role Of Il-36 Cytokines In Anti-candida Responsesmentioning

confidence: 99%