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Loss-of-function sequence variations in the IL36RN gene encoding IL-36 receptor antagonist cause familial generalized pustular psoriasis, which begins shortly after birth and is difficult to treat, and its effects on the epidermis are unclear. This study investigated the involvement of IL-36 receptor agonists in the epidermal formation of generalized pustular psoriasis. We found that the IL-36 receptor agonists, especially mature IL-36γ, stimulated IL-8 and pro-IL-36γ production in the epidermis while downregulating the genes encoding epidermal cornified envelope-related proteins, for example, corneodesmosin. IL-36 receptor antagonist and monoclonal anti-IL-36γ antibodies counteracted the effect of mature IL-36γ on corneodesmosin in keratinocytes in a dose-dependent manner. In the epidermis of patients with generalized pustular psoriasis with IL36RN loss-of-function sequence variations, pro-IL-36γ was overproduced in the epidermis, and corneodesmosin protein expression was markedly decreased in the region of giant subcorneal pustules (Kogoj's spongiform pustules), with high neutrophil infiltration. IL-8 induced by mature IL-36γ stimulated the infiltration of several neutrophils in the epidermis. The newly produced pro-IL-36γ is cleaved to the mature form by neutrophil proteases. This newly produced mature IL-36γ was predicted to further suppress the gene expression of corneodesmosin, leading to significant stratum corneum exfoliation and formation of the pustules. Overall, our results elucidate the mechanism underlying the formation of Kogoj's spongiform pustules in generalized pustular psoriasis., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Destruction of epidermal barrier function associated with atopic dermatitis or Darier's disease often causes severe secondary skin infections. Patients with skin barrier disorders often repeatedly acquire Kaposi varicelliform eruption, which is caused by herpes simplex virus, but the underlying mechanisms and effective preventive methods have yet to be found. Viral infection through an impaired epidermal barrier can be prevented by enhancing innate immunity and/or inhibiting viral entry. In this study, we established a three-dimensional skin barrier dysfunction model by silencing ATP2A2, which is mutated in some Darier's disease patients. We confirmed the loss of desmosomes and presence of histopathological clefts in the suprabasal layer. Herpes simplex virus 1 applied to the stratum corneum infected the deep epidermis. An innate immune reaction was assessed by evaluating the expression of IFNB1 and related genes. Pretreatment with polyinosinic-polycytidylic acid alone or plus the antimicrobial peptide, LL37 enhanced IFN-β production and suppressed viral replication. Furthermore, topical application of a white petrolatum ointment containing heparin, which binds viral glycoproteins related to virus entry, strongly inhibited viral replication, probably by inhibiting invasion. Our human barrier-dysfunctional model will have future application for identifying the mechanism of Kaposi varicelliform eruption onset, preventive methods, and therapies., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

In this study, we report that TIP39, a parathyroid hormone ligand family member that was recently identified to be expressed in the skin, can induce decorin expression and enhance wound repair. Topical treatment of mice with TIP39 accelerated wound repair, whereas TIP39-deficient mice had delayed repair that was associated with formation of abnormal collagen bundles. To study the potential mechanism responsible for the action of TIP39 in the dermis, fibroblasts were cultured in three-dimensional collagen gels, a process that results in enhanced decorin expression unless activated to differentiate to adipocytes, whereupon these cells reduce expression of several proteoglycans, including decorin. Small interfering RNA-mediated silencing of parathyroid hormone 2 receptor (PTH2R), the receptor for TIP39, suppressed the expression of extracellular matrix-related genes, including decorin, collagens, fibronectin, and matrix metalloproteases. Skin wounds in TIP39 -/- mice had decreased decorin expression, and addition of TIP39 to cultured fibroblasts induced decorin and increased phosphorylation and nuclear translocation of CREB. Fibroblasts differentiated to adipocytes and treated with TIP39 also showed increased decorin and production of chondroitin sulfate. Furthermore, the skin of PTH2R -/- mice showed abnormal extracellular matrix structure, decreased decorin expression, and skin hardness. Thus, the TIP39-PTH2R system appears to be a previously unrecognized mechanism for regulation of extracellular matrix formation and wound repair., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Genes related to the parathyroid hormone (PTH) influence cutaneous immune defense and development, but the full functions of the PTH family in cutaneous biology remain incompletely understood. In this study, we examined the expression and potential functions of the PTH second receptor (PTH2R) and its ligand, the tuberoinfundibular peptide of 39 residues (TIP39), in the skin. TIP39 and PTH2R mRNA and protein were detectable in both human and mouse skin, and in cultured keratinocytes and adipocytes. TIP39 was observed in the basal layer of human skin, whereas PTH2R was detected in the spinous to granular layer. The subcellular localization of TIP39 in keratinocytes changed during calcium-induced differentiation and shifted to colocalize with PTH2R at the membrane. The addition of recombinant TIP39 to normal human keratinocytes in culture induced an increase in intercellular calcium and triggered aspects of terminal differentiation including decreased keratin-14 and increased involucrin expression. Consistent with these observations, PTH2R(-/-) mice were observed to have increased epidermal thickness. In summary, identification of TIP39 and its receptor in the epidermis reveals an additional PTH family member that is expressed in the skin and may influence keratinocyte function., Competing Interests: The authors state no conflicts of interest., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Most previous studies have found no effects of cyclosporin A and FK-506 on active oxygen generation in human polymorphonuclear leukocytes. Recently various differences in biologic properties have been reported between unprimed peripheral blood human polymorphonuclear leukocytes and tissue or primed human polymorphonuclear leukocytes. In this study, we investigated the effects of cyclosporin A and FK-506 on superoxide (O(2)(-)) generation induced by the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine in human peripheral blood polymorphonuclear leukocytes primed or unprimed with tumor necrosis factor alpha. Neither cyclosporin A nor FK-506 suppressed N-formyl-L-methionyl-L-leucyl-L-phenylalanine-induced O(2)(-) generation in unprimed human polymorphonuclear leukocytes at concentrations between 0.1 nM and 10 microM, as in previous studies. Only at 1 microM of cyclosporin A and 100 nM of FK-506 were marginal suppressive effects observed. On the other hand, cyclosporin A and FK-506 both suppressed N-formyl-L-methionyl-L-leucyl-L-phenylalanine-induced O(2)(-) generation in tumor-necrosis-factor-alpha-primed human polymorphonuclear leukocytes, strongly and dose dependently, at concentrations between 1 nM and 1 microM. Neither cyclosporin A nor FK-506 influenced tyrosyl phosphorylation of 115 kDa protein, which is inducible during the priming process, suggesting that neither cyclosporin A nor FK-506 influenced the tumor-necrosis-factor-alpha-induced priming process itself, and instead modified the biologic response of primed human polymorphonuclear leukocytes.