Impetigo herpetiformis (IH) is a rare pustular dermatosis. It can be life‐threatening for both the mother and fetus and often causes therapeutic problems. However, there is no specific guideline for the treatment of IH and the evidence regarding the efficacy of treatments for IH has not been established. Herein, we report two cases of IH, which were successfully treated with anti‐tumor necrosis factor (TNF)‐α drugs. The serum levels of the drugs in the infants and mothers were examined using enzyme‐linked immunosorbent assay (ELISA). Case 1 was a 35‐year‐old, gravida 2, para 1, female patient in week 20 of pregnancy; she was treated with adalimumab (ADA) until delivery. Case 2 was a 26‐year‐old, gravida 1, para 0, female patient in week 30 of pregnancy; she was treated with certolizumab pegol (CZP) until delivery. In both cases, the skin lesions started regressing considerably after administration of the biologic agents. We examined the serum levels of the biologic agents in the mothers and infants using ELISA. In case 1, the ADA serum level in the infant was as high as that in the mother at birth; it then decreased below the lower limit of quantification at week 12 post‐delivery. In case 2, the CZP serum level in the infant was below the lower limit of quantification at birth. In this report, we revealed that biologic agents could be an effective treatment for severe IH and that CZP treatment can be considered safe for the mothers and fetuses.

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 ...

Loss-of-function mutations in the interleukin (IL)-36 gene IL36RN are associated with psoriasis. The importance of neutrophil extracellular traps (NETs), web-like structures composed of neutrophil DNA, in the pathogenesis of psoriasis has been unclear. Here, we aimed to clarify the role of NET signaling in the deficiency of IL36 receptor antagonist (DITRA). We evaluated the severity of psoriasis-like lesions induced by imiquimod cream treatment in Il36rn−/− mice. The mRNA levels of psoriasis-related cytokines were measured via real-time reverse transcription polymerase chain reaction, and the effects of Cl-amidine, a peptidyl arginine deiminase 4 (PAD4) inhibitor, on psoriasis-like lesions were evaluated. PAD4 is a histone-modifying enzyme that is involved in NET formation. Psoriasis area and severity index scores, epidermal thickness, and infiltrated neutrophil counts were significantly increased in Il36rn−/− mice; NET formation was confirmed pathologically. Several cytokines and chemokines were upregulated in the skin lesions of Il36rn−/− mice and Cl-amidine treatment improved these psoriasis-like lesions. These results suggest that NET formation plays an important role in the pathology of psoriasis-like lesions in these mice and might represent a promising therapeutic target for DITRA.

Loss-of-function homozygous or compound heterozygous mutations in IL36RN, which encodes interleukin-36 receptor antagonist (IL-36Ra), have been implicated in the pathogenesis of various skin disorders. Previous findings showed that IL-36γ promoted wound healing in mice; however, the pathogenic role of IL-36Ra in wound healing remains unclear. We elucidated the role of IL-36Ra, a regulator of IL-36 in tissue repair by investigating the recruitment of inflammatory cells and cytokine production in the absence of IL-36Ra. Full-thickness excisional wounds were made on the back of Il36rn−/− mice and healing was assessed by monitoring macroscopic wound sizes, numbers of infiltrated cells, and gene expression of inflammatory cytokines. Macroscopic wound healing, re-epithelialization, and granulation tissue formation were delayed by 3 days post-injury in Il36rn−/− mice. This delay was associated with increased infiltrations of neutrophils and macrophages, and increased expression of cytokines, such as IL-36γ, C-X-C motif chemokine ligand 1 (CXCL1), and transforming growth factor (TGF)-β. Importantly, administration of TAK-242, a toll-like receptor 4 (TLR4) inhibitor, caused normalization of wound healing in Il36rn−/− mice, abrogating the initial delay in tissue repair. These results showed that targeting TLR4- mediated infiltrations of immune cells and cytokine production could be beneficial in regulating wound healing in IL-36Ra-deficient skin disorders.

Background Loss-of-function homozygous or compound heterozygous mutations in IL36RN, which encodes interleukin-36 receptor antagonist (IL-36Ra), has been implicated in the pathogenesis of skin disorders. However, the pathogenic role of IL-36Ra in cutaneous ischemia-reperfusion (I/R) injury remains unclear.Objectives We investigated the role of IL36Ra in cutaneous I/R injury.Methods We examined I/R injury in Il36rn À/À mice. The area of wounds, numbers of infiltrated cells, apoptotic cells and neutrophil extracellular trap (NET) formation were assessed. The expression levels of various genes were analysed using real-time RT-PCR. The expression of high mobility group box 1 (HMGB1), an endogenous toll-like receptor (TLR) 4 ligand, was confirmed using immunohistology, and serum HMGB1 levels were measured by ELISA. Cytokine production by stimulated cultured J774A.1 and HaCaT cells was examined.Results IL-36Ra deficiency resulted in significantly delayed wound healing and increased neutrophil and macrophage infiltration into the wound tissues. Il36rn À/À mice had increased mRNA expression levels of CXCL1, CXCL2, CCL4, TNF-a, TGF-b, IL-1b, IL-6 and IL-36c relative to wild-type mice. Apoptosis was identified in keratinocytes by TUNEL assay. HMGB1 expression in the I/R site was decreased in both keratinocytes and adnexal cells, while serum HMGB1 levels were significantly elevated after reperfusion. The mRNA levels of various cytokines, including IL-1b, were elevated in J774A.1 cells through TLR4 signalling by HMGB1 stimulation. In addition, HaCaT cells stimulated with IL-1b showed significantly increased CXCL1, TNF-a, IL-6, IL-36b and IL-36c mRNA expression. Furthermore, NET formation was increased by IL-36Ra deficiency. Finally, either the blockade of TLR4 signalling by TAK-242 or inhibition of NET formation by Cl-amidine normalized exacerbated I/R injury in Il36rn À/À mice.Conclusions This study indicated that IL-36Ra deficiency exacerbates cutaneous I/R injury due to excessive inflammatory cell recruitment, NET formation, and excessive cytokine and chemokine production via the TLR4 pathway by HMGB1 released from epidermal apoptotic cells.

Combination therapy with BRAF and MEK inhibitors (BRAFi/ MEKi) have dramatically improved prognosis among patients with BRAF-mutant metastatic melanoma as against traditional treatments, such as chemotherapy. 1,2 However, acquired resistance to BRAFi/MEKi therapy still limits the long-term survival of patients with advanced BRAF-mutant melanoma. Thus, effective treatment strategies for BRAFi/MEKi-resistant melanoma are needed.Recently, it has been reported that the ligand-independent phosphorylation of erythropoietin-producing hepatocellular receptor A2 (EphA2) at Ser-897 signaling is a driver of BRAF inhibitor resistance in melanoma, leading to increased permeability of endothelial cell monolayers, and stimulated melanoma transendothelial cell migration. 3 Herein, we report a case of melanoma that was initially resistant to dabrafenib plus trametinib therapy, but showed a remarkable response to rechallenge with encorafenib plus binimetinib therapy administrated after nivolumab plus ipilimumab therapy. Additionally, we have examined EphA2, phospho-EphA2 (p-EphA2; Ser-897), and epidermal growth factor receptor

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