TAK-242 ameliorates contact dermatitis exacerbated by IL-36 receptor antagonist deficiency

Abstract

Loss-of-function mutations in IL36RN cause generalized pustular psoriasis (GPP), which is characterized by neutrophil-infiltrated lesions. Neutrophils are important during contact hypersensitivity in mice. However, it has never been determined whether interleukin-36 receptor antagonist (IL-36Ra) deficiency is an exacerbating factor in contact dermatitis. We examined whether a loss-of-function IL36RN mutation exacerbates contact dermatitis and evaluated the changes in contact dermatitis-related cytokines. Wild-type and Il36rn −/− mice were treated with 1-fluoro-2,4-dinitorobenzene (DNFB) and evaluated for ear thickness, histopathological features, numbers of infiltrated neutrophils, and numbers of CD4 + and CD8 + T cells. Furthermore, mRNA levels of contact dermatitis-related cytokines were measured by real-time polymerase chain reaction, and effects of TAK-242, a toll-like receptor 4 (TLR4) inhibitor, on the contact hypersensitivity (CHS) response were evaluated. We found that the ear thickness, cytokine expression, and neutrophil infiltration significantly increased in Il36rn −/− mice compared with that in wild-type mice. TAK-242 alleviated CHS and prevented neutrophil infiltration, cytokine expression, and ear thickening in Il36rn −/− mice. These data indicate that Il36rn −/− mutations are an exacerbating factor for CHS and that TAK-242 can reduce the inflammatory responses that are associated with the CHS response.Homozygous or compound heterozygous IL36RN gene mutations underlie the pathogenesis of psoriasis-related pustular eruptions, including generalised pustular psoriasis, palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau, and acute generalised exanthematous pustular eruptions 1 . Loss-of-function mutations in IL36RN define a recessively inherited autoinflammatory disease called "deficiency of interleukin-36 receptor antagonist (IL-36Ra)" (DITRA), which is a type of autoinflammatory keratinization disease 2-7 . Previously, we generated Il36rn −/− mice and established a DITRA murine model 8 . The IL36RN gene encodes IL-36Ra, a protein in the IL-1 cytokine family responsible for the tight regulation of IL-36 signalling. The IL-36 pathway is activated when one of the three IL-36 agonists (IL-36α, β, and γ) binds to their common but specific receptor interleukin 1 receptor-related protein 2 (IL-1Rrp2), which recruits the co-receptor, IL-1 receptor accessory protein (IL-1RacP), and triggers downstream activation of NF-κB and MAPK kinase signalling pathways to ultimately enhance transcription and release of pro-inflammatory cytokines 9,10 that initiate the recruitment of inflammatory cells, including neutrophils, T cells, and myeloid dendric cells, in the skin. Abnormal IL-36 receptor (IL-36R) signalling results in transient skin inflammation characterised by acanthosis, hyperkeratosis, and neutrophil-dominant mixed-cell infiltration [11][12][13] .According to the Human Genetic Variation Database, two IL36RN founder mutations (c.28 C > T (p.Arg10X) and c.115 + 6 T > C (p.ArgfsX1)) are found ...

Neutrophil extracellular traps are induced in a psoriasis model of interleukin-36 receptor antagonist-deficient mice

“…Mice. Il36rn −/− mice were generated as previously reported 11 . All experiments were repeated twice using fertile and healthy mice that displayed no evidence of disease or infection.…”

“…Loss-of-function mutations in IL36RN cause a recessively inherited autoinflammatory keratinization disease known as deficiency of IL-36Ra (DITRA) [4][5][6][7][8][9] . We previously prepared Il36rn −/− mice and established a DITRA murine model by treating mice with a TLR4 agonist 10 , a severe contact hypersensitivity model by treatment with 1-fluoro-2,4-dinitorobenzene 11 , and a delayed cutaneous wound healing model 12 . It has been known that deficiency of IL36Ra induces severe epidermal proliferation and neutrophil infiltration in imiquimod (IMQ)induced psoriasis-like lesions 13,14 .…”

IL-36 receptor antagonist deficiency resulted in delayed wound healing due to excessive recruitment of immune cells

“…The pathogenic roles of IL-36 in skin inflammatory diseases including atopic dermatitis, blistering disease, and allergic dermatitis have studied 15 – 17 . We found that deficiency of IL-36Ra increased the contact hypersensitivity response by eliciting excessive infiltration of neutrophils into the skin, a result of the activation of IL-36R-mediated sustained inflammatory signaling 13 . Thus, loss-of function mutations of IL36RN may potentially be an underlying cause of various skin inflammatory diseases including generalized pustular psoriasis.…”

“…In the previous report, Il36rn −/− mice was generated and DITRA mouse model was established 11 . Aberrant interleukin-36 receptor (IL-36R) signaling causes transient skin inflammation including hyperkeratosis, acanthosis, and neutrophil-dominant mixed-cell infiltration 11 – 13 .…”

Interleukin‐36 (IL‐36) system in the 1‐fluoro‐2,4‐dinitrobenzene (DNFB) mouse model of allergic contact dermatitis

“…However, it remains a possibility that different allergens and/or genetic backgrounds could reveal a role for the IL-36 system in initiation of allergies. Interestingly, a more recent study revealed a role for IL-36Ra 48 hours post-challenge, 9 which suggests involvement in chronic disease. Hence, future studies should be designed accordingly.…”