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Bullous pemphigoid (BP) is an autoimmune bullous skin disease characterized by autoantibodies against the hemidesmosomal proteins in the skin and mucous membranes. The efficiency of B-cell‒targeting biologics in BP indicates the important role of B cells in its pathogenesis. However, abnormal B-cell migration and differentiation in BP require further elucidation. We showed that the number of antibody-secreting cells increased in the circulation and skin lesions of patients with BP and was correlated with disease severity. Bulk RNA sequencing of the peripheral B cells identified 171 upregulated and 408 downregulated genes in patients with BP compared with those in healthy controls, among which CXCR4 was significantly upregulated. Notably, CXCR4 + B cells were enriched in BP skin lesions and exhibited antibody-secreting cell characteristics. Correspondingly, an elevated level of CXCL12, the CXCR4 ligand, was detected in the blister fluid and serum of patients with BP, mediating the chemotaxis and accumulation of CXCR4 + B cells to BP skin lesions. Moreover, CXCL12 activated the transcription factor c-Myc, thus promoting B-cell differentiation into antibody-secreting cells and facilitating autoantibody production, which was blocked by CXCR4 inhibitor in vitro. Collectively, our study reveals that the CXCL12/CXCR4 axis plays a pathogenic role in modulating B-cell trafficking and differentiation, thus targeting CXCR4 represents a potential strategy for treating BP and other autoimmune diseases., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Lipocalins are a family of secreted adipokines that regulate cell lipid metabolism and immune responses. Although we have previously revealed that LCN2 modulates neutrophil activation in psoriasis, the other roles of LCN2 in psoriatic local inflammation have remained elusive. In this study, we found that 24p3R, the well-known specific receptor of LCN2, was highly expressed in the lesional epidermis of patients with psoriasis. Silencing 24p3R (also known as slc22a17) alleviated hyperkeratosis, inflammatory cell infiltration, and overexpression of inflammatory mediators in an imiquimod-induced psoriasis-like mouse model. In vitro, LCN2 enhanced the expression of proinflammatory factors in primary keratinocytes, such as IL-1β, IL-23, CXCL1, and CXCL10, which was paralleled by enforced cholesterol biosynthetic signaling. Importantly, taking in vivo and in vitro approaches, we discovered the SREBP2, a vital transcriptional factor in cholesterol synthesis pathway, as the critical mediator of LCN2-induced keratinocyte activation, which bound to the promoter region of NLRC4. Suppressing SREBP2 in mice attenuated NLRC4 signaling and psoriasis-like dermatitis. Taken together, this study identifies the critical role of LCN2‒SREBP2‒NLRC4 axis in the pathogenesis of psoriasis and proposes 24p3R or SREBP2 as a potential therapeutic target for psoriasis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Psoriasis is a systemic disease that is associated with metabolic disorders, which may contribute to abnormal adipokine levels. However, the underlying mechanism is largely unknown. Here, we investigated the role of the adipokine CTRP3 in the pathogenesis of psoriasis and comorbidities. The circulating CTRP3 level in patients with psoriasis was significantly lower than that in healthy controls and negatively correlated with metabolic risk factors. Rescuing CTRP3 levels with the GLP-1 receptor agonist exendin-4 in diet-induced obese mice could alleviate its more severe psoriatic symptoms in an imiquimod-induced mouse model. Topical application of CTRP3 also exerted a protective effect on imiquimod-induced normal diet mice. Moreover, CTRP3 could directly inhibit the inflammatory responses of psoriatic keratinocytes by blocking phosphorylation of signal transducer and activator of transcription 3 via LAMP1 in vitro. We identified the critical psoriatic cytokines, including IL-17A and TNF-α, that impaired adipocyte differentiation and sufficient CTRP3 secretion. In sum, our study reveals that adipocyte dysfunction and low level of CTRP3 caused by IL-17A exacerbates psoriasis progression and related metabolic syndrome, implying a mechanism underlying the vicious cycle between psoriasis and metabolic disorders. Pharmacological agents that improve CTRP3 level in obese patients with psoriasis may be considered as a potential strategy for psoriasis treatment., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Excessive activation of CD4 + T cells and T helper type (Th) 17/Th1 cell differentiation are critical events in psoriasis pathogenesis, but the associated molecular mechanism is still unclear. Here, using quantitative proteomics analysis, we found that cyclin-dependent kinase 7 (CDK7) expression was markedly increased in CD4 + T cells from patients with psoriasis compared with healthy controls and was positively correlated with psoriasis severity. Meanwhile, genetic or pharmacological inhibition of CDK7 ameliorated the severity of psoriasis in the imiquimod-induced psoriasis-like mouse model and suppressed CD4 + T-cell activation as well as Th17/Th1 cell differentiation in vivo and in vitro. Furthermore, the CDK7 inhibitor also reduced the enhanced glycolysis of CD4 + T cells from patients with psoriasis. Proinflammatory cytokine IL-23 induced increased CDK7 expression in CD4 + T cells and activated the protein kinase B/mTOR/HIF-1α signaling pathway, enhancing glycolytic metabolism. Correspondingly, CDK7 inhibition significantly impaired IL-23-induced glycolysis via the protein kinase B/mTOR/HIF-1α pathway. In summary, this study shows that CDK7 promotes CD4 + T-cell activation and Th17/Th1 cell differentiation by regulating glycolysis, thus contributing to the pathogenesis of psoriasis. Targeting CDK7 might be a promising immunosuppressive strategy to control skin inflammation mediated by IL-23., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Psoriasis is a T lymphocyte-driven systemic inflammatory disease. Regulatory T cells (Tregs) are essential for establishing and maintaining immune tolerance. In this study, we found that patients with psoriasis and healthy controls had comparable percentages of circulating CD4 + CD25 + FOXP3 + Tregs, but psoriatic Tregs had reduced suppressive function. Thereafter, mRNA arrays were performed to study the gene expression profile of psoriatic Tregs. Psoriatic Tregs expressed high levels of a T helper type 1-like transcription factor and cytokines such as T-bet and IFN-γ. Furthermore, we found that FOXO1 can bind to the promoter of TBX21 to inhibit its expression, thus keeping the suppressive function of Tregs. However, an increase in protein kinase B-mediated phosphorylation of FOXO1 was observed in psoriatic Tregs, which subsequently caused FOXO1 inactivation by nuclear exclusion. In addition, incubation of healthy Tregs with psoriatic serum led to the activation of protein kinase B, nuclear exclusion of FOXO1, and the loss of FOXO1 transcription activity. The role of FOXO1 in regulating the function of Tregs was corroborated using a psoriasis-like mouse model in which Foxo1-deficient Tregs failed to protect mice from developing psoriasis. In conclusion, our findings reveal that the dysregulation of the protein kinase B-FOXO1 pathway may be a critical cause of Treg dysfunction in psoriasis., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)