Journal of Investigative Dermatology最新文献

Bullous pemphigoid (BP) is an autoantibody-mediated blistering skin disease characterized by local inflammation and dermal–epidermal separation, with no approved targeted therapy. The Syk tyrosine kinase is critical for various functions of the immune response. Second-generation Syk inhibitors such as entospletinib are currently being tested for hematological malignancies. Our aim was to test the effect of entospletinib in a fully human model system of BP. Incubating BP serum–treated human frozen skin sections with normal human granulocytes and fresh plasma triggered dermal–epidermal separation that was dependent on complement, NADPH oxidase, and protease activity. Entospletinib dramatically reduced dermal–epidermal separation with a half-maximal inhibitory concentration of ≈16 nM. Entospletinib also reduced ROS production, granule release, and spreading of human granulocytes plated on immobilized immune complexes consisting either of a generic antigen–antibody pair or of recombinant collagen type XVII (BPAg2) and BP serum components (supposedly autoantibodies). However, entospletinib did not affect the chemotactic migration of human granulocytes or their responses to nonphysiological stimulation by phorbol esters. Entospletinib had no effect on the survival of granulocytes either. Taken together, entospletinib abrogates dermal–epidermal separation, likely through inhibition of granulocyte responsiveness to deposited immune complexes. Entospletinib or other Syk inhibitors may provide therapeutic benefits in BP.

Vulvar lichen sclerosus (VLS) is a progressive skin disease of unknown etiology. In this longitudinal case-control exploratory study, we evaluated the hormonal and microbial landscapes in 18 postmenopausal females (mean [SD] age: 64.4 [8.4] years) with VLS and controls. We reevaluated the patients with VLS after 10–14 weeks of daily topical class I steroid. We found that groin cutaneous estrone was lower in VLS than in controls (−22.33, 95% confidence interval [CI] = −36.96 to −7.70; P = .006); cutaneous progesterone was higher (5.73, 95% CI = 3.74–7.73; P < .0001). Forehead 11-deoxycortisol (−0.24, 95% CI = −0.42 to −0.06; P = .01) and testosterone (−7.22, 95% CI = −12.83 to −1.62; P = .02) were lower in disease. With treatment, cutaneous estrone (−7.88, 95% CI = −44.07 to 28.31; P = .62), progesterone (2.02, 95% CI = −2.08 to 6.11; P = .29), and 11-deoxycortisol (−0.13, 95% CI = −0.32 to 0.05; P = .15) normalized; testosterone remained suppressed (−7.41, 95% CI = −13.38 to −1.43; P = .02). 16S ribosomal RNA V1–V3 and ITS1 amplicon sequencing revealed bacterial and fungal microbiome alterations in disease. Findings suggest that cutaneous sex hormone and bacterial microbiome alterations may be associated with VLS in postmenopausal females.

Infantile hemangioma (IH) is the most prevalent vascular tumor during infancy, characterized by a rapid proliferation phase of disorganized blood vessels and spontaneous involution. IH possibly arises from a special type of multipotent stem cells called hemangioma stem cells (HemSCs), which could differentiate into endothelial cells, pericytes, and adipocytes. However, the underlying mechanisms that regulate the cell fate determination of HemSCs remain elusive. In this study, we unveil KLF2 as a candidate transcription factor involved in the control of HemSCs differentiation. KLF2 exhibits high expression in endothelial cells in proliferating IH but diminishes in adipocytes in involuting IH. Using a combination of in vitro culture of patient-derived HemSCs and HemSCs implantation mouse models, we show that KLF2 governs the proliferation, apoptosis, and cell cycle progression of HemSCs. Importantly, KLF2 acts as a crucial determinant of HemSC fate, directing their differentiation toward endothelial cells while inhibiting adipogenesis. Knockdown of KLF2 induces a proadipogenic transcriptome in HemSCs, leading to impaired blood vessel formation and accelerated adipocyte differentiation. Collectively, our findings highlight KLF2 as a critical regulator controlling the progression and involution of IH by modulating HemSC fate decisions.