Loss of IL36RN Function Does Not Confer Susceptibility to Psoriasis Vulgaris

Berki, Dorottya M.; Mahil, Satveer K.; Burden, A. D.; Trembath, Richard C.; Smith, Catherine; Capon, Francesca; Barker, Jonathan

doi:10.1038/jid.2013.285

Cited by 28 publications

(20 citation statements)

References 12 publications

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“…As IL-36 cytokines further induce mRNA expression and secretion of IL-36 cytokines, this leads to vicious self-sustaining cycle of inflammation, and therefore this axis is best classified as being autoinflammatory in nature. IL36RN mutations have also been demonstrated in localized pustular forms of psoriasis[33], but, interestingly, IL36RN mutations do not appear to increase susceptibility to chronic plaque psoriasis[34]. Other genetic mutations identified to contribute to pustular forms of psoriasis include AP1S3 [35] and CARD14 [36].…”

Section: Neutrophils Il-36 and Autoinflammatory Responses In Psoriasismentioning

confidence: 99%

Psoriasis: a mixed autoimmune and autoinflammatory disease

Liang

Sarkar

Tsoi

et al. 2017

Current Opinion in Immunology

195

140

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In recent years marked progress has been made in our understanding of the critical biologic and immunologic pathways involved in psoriasis. Genetic studies have demonstrated that susceptibility to psoriasis involves components of both the adaptive and innate immune system and not surprisingly activation of both of these arms of the immune system is found in psoriatic skin. While adaptive immune responses predominate in chronic plaque psoriasis, innate and autoinflammatory responses dominate in pustular forms of psoriasis, with other clinical subtypes extending on a spectrum between plaque and pustular psoriasis. This makes psoriasis a unique disease where both autoimmune and autoinflammatory responses co-exist, with the balance between the two being critical in shaping its clinical presentation.

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Section: Neutrophils Il-36 and Autoinflammatory Responses In Psoriasismentioning

confidence: 99%

Psoriasis: a mixed autoimmune and autoinflammatory disease

Liang

Sarkar

Tsoi

et al. 2017

Current Opinion in Immunology

195

140

View full text Add to dashboard Cite

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“…Nonetheless, so far no specific data regarding effectiveness of IL-6 inhibitors in IL36RN -dependent PP are available. Overall, recessive IL36RN mutations are associated with increased risk of PP alone, but not PV [57, 65–67]; both phenotypic variance and incomplete penetrance have been observed, supporting the notion that IL36RN mutations are able to induce manifest disease only in the presence of specific environmental factors and/or further genetic defects at a second disease locus [25, 53, 65]. All genetic follow-up studies of PP patients have found evidence of genetic heterogeneity, proving that IL36RN mutations account for only a minority of sporadic PP cases [25, 57, 66].…”

Section: Psoriasis Pathogenesis: Current Conceptsmentioning

confidence: 99%

IL-6 as a Druggable Target in Psoriasis: Focus on Pustular Variants

Saggini

Chimenti

Chiricozzi

2014

Journal of Immunology Research

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Psoriasis vulgaris (PV) is a cutaneous inflammatory disorder stemming from abnormal, persistent activation of the interleukin- (IL-)23/Th17 axis. Pustular psoriasis (PP) is a clinicopathological variant of psoriasis, histopathologically defined by the predominance of intraepidermal collections of neutrophils. Although PP pathogenesis is thought to largely follow that of (PV), recent evidences point to a more central role for IL-1, IL-36, and IL-6 in the development of PP. We review the role of IL-6 in the pathogenesis of PV and PP, focusing on its cross-talk with cytokines of the IL-23/Th17 axis. Clinical inhibitors of IL-6 signaling, including tocilizumab, have shown significant effectiveness in the treatment of several inflammatory rheumatic diseases, including rheumatoid arthritis and juvenile idiopathic arthritis; accordingly, anti-IL-6 agents may potentially represent future promising therapies for the treatment of PP.

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“…While the aforementioned clinical and preclinical data suggest that IL‐36 cytokines may play an important role in the pathogenesis of psoriasis, clinical proof‐of‐concept (PoC) studies with IL‐36R antagonists in patients with psoriasis (including GPP and PV) have not been reported yet but are ongoing with a human IL‐36R antibody in GPP (Clinical trials.gov). It should be noted that there are also data showing that IL‐36RN mutations are only observed in 25% of GPP cases and are not associated with PV . Therefore, whether IL‐36 cytokines are a pathogenic factor or a biomarker in psoriasis is still an outstanding question in the field.…”

Section: Introductionmentioning

confidence: 99%

IL‐36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis

Paulsboe

Wetter

et al. 2018

Experimental Dermatology

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Psoriasis vulgaris (PV) results from activation of IL‐23/Th17 immune pathway and is further amplified by cytokines/chemokines from skin cells. Among skin‐derived pro‐inflammatory cytokines, IL‐36 family members are highly upregulated in PV patients and play a critical role in general pustular psoriasis. However, there is limited data showing crosstalk between the IL‐23 and IL‐36 pathways in PV. Herein, potential attenuation of skin inflammation in the IL‐23‐induced mouse model of psoriasiform dermatitis by functional inhibition of IL‐36 receptor (IL‐36R) was interrogated. Anti‐mouse IL‐36R monoclonal antibodies (mAbs) were generated and validated in vitro by inhibiting IL‐36α‐induced secretion of CXCL1 from NIH 3T3 cells. Antibody target engagement was demonstrated by inhibition of CXCL1 production in a novel acute model of IL‐36α systemic injection in mice. In addition, anti‐IL‐36R mAbs inhibited tissue inflammation and inflammatory gene expression in an IL‐36α ear injection model of psoriasiform dermatitis demonstrating engagement of the target in the ear skin. To elucidate the possible role of IL‐36 signalling in IL‐23/Th17 pathway, the ability of anti‐IL‐36R mAbs to inhibit skin inflammation in an IL‐23 ear injection model was assessed. Inhibiting the IL‐36 pathway resulted in significant attenuation of skin thickening and psoriasis‐relevant gene expression. Taken together, these data suggest a role for IL‐36 signalling in the IL‐23/Th17 signalling axis in PV.

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Loss of IL36RN Function Does Not Confer Susceptibility to Psoriasis Vulgaris

Cited by 28 publications

References 12 publications

Psoriasis: a mixed autoimmune and autoinflammatory disease

Psoriasis: a mixed autoimmune and autoinflammatory disease

IL-6 as a Druggable Target in Psoriasis: Focus on Pustular Variants

IL‐36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis

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