The Journal of investigative dermatology最新文献

Dermatomyositis (DM) is an autoimmune disease classically affecting the skin, muscles, and lungs. Patients with DM have poor QOL, and current treatments fail to work in half of patients with DM. There is a need for an effective and safer therapeutic option. Lenabasum is a nonimmunosuppressive, nonpsychoactive cannabinoid receptor type 2 (CB2) agonist that promotes resolution of innate immune responses. The activation of CB2 reduces several proinflammatory cytokines implicated in DM. The purpose of this study was to conduct a multiplexed analysis of DM skin and PBMCs to examine the effect of lenabasum on inflammatory and itch-promoting cytokines. Our data show that lenabasum has anti-inflammatory effects, particularly on CD4+ T cells, T helper 1 cells, and myeloid cell lineages such as monocyte-derived dendritic cells. Lenabasum suppressed T helper 1-derived IL-31 and monocyte-derived dendritic cell-derived IL-31, a cytokine implicated in DM pruritus. CB2 knockdown of cells eluted from DM skin abrogated these anti-inflammatory effects. The higher CB2 expression and stronger lenabasum response in cells eluted from DM skin than from DM PBMCS indicate that local tissue environment shapes inflammatory cell behavior. Our results show that lenabasum acts through the CB2, promoting the downregulation of proinflammatory cytokines. This may explain lenabasum's greater effect on skin than in muscle in human studies.

Prurigo nodularis (PN) is a chronic pruritic skin disease characterized by hyperkeratotic nodules and intense itching, yet its pathological mechanisms remain unclear, especially at the protein level and in comparison with atopic dermatitis. We performed parallel analyses of proteomic data (4-dimensional data-independent acquisition) from lesions of PN, atopic dermatitis, and healthy controls. Single-cell RNA-sequencing data were integrated from publicly available datasets (eg, GSE222840) representing comparable cohorts. Our analysis revealed a PN-specific proteomic signature dominated by myeloid-driven immunity, profound tissue remodeling, and mitochondrial metabolic reprogramming. From this signature, we identified a set of PN-enriched molecules. Among them, ADGRE2 (adhesion G protein-coupled receptor E2)-a known mechanosensory receptor-emerged as the most selectively upregulated in PN myeloid subsets. Critically, the expression of ADGRE2 demonstrated a strong positive correlation with clinical itch severity, as measured by Peak Pruritus Numerical Rating Scale and Dermatology Life Quality Index. It was also further confirmed to be predominantly expressed in myeloid cells of PN lesions, showing higher abundance than in atopic dermatitis or healthy controls. This study refines the PN framework, highlighting myeloid-enriched molecules such as ADGRE2, which provides mechanistic insights into the unique inflammatory and sensory landscape and offers therapeutic avenues.

Itch is a sensory experience accompanied by negative emotions and evokes a strong desire to scratch. Under pathological conditions, severe and chronic itch-scratching and the associated negative emotions can form a vicious cycle, leading to treatment resistance and reduced quality of life. While the hippocampus regulates emotion and pain, its role in itch remains unclear. Using fiber photometry, we found that ventral hippocampal (vHPC) activity decreased during scratching and increased following the cessation of scratching. Pharmacogenetic activation of either global vHPC neurons or specific vHPC neurons projecting to the infralimbic cortex (IL) suppressed both scratching and itch-related conditioned place aversion (CPA). In contrast, selective activation of vHPC glutamatergic neurons projecting to the prelimbic cortex (PrL) produced the opposite effect-significantly increasing scratching behavior without altering CPA aversion. Circuit mapping showed that both pyramidal neurons and gamma-aminobutyric acidergic (GABAergic) neurons in the PrL and IL receive approximately equal inputs from the vHPC; the projection from the vHPC to the IL is denser than that to the PrL. These results provide initial evidence that global vHPC neuronal activity inhibits both itch-scratching behavior and its accompanying aversive states via the vHPC→IL pathway, rather than the vHPC→PrL pathway.

Recent advances have deepened our understanding of ferroptotic melanocyte death in vitiligo. Heat shock protein 70 (HSP70) has been identified as a key participant in the pathogenesis of vitiligo, but its direct role in the regulation of melanocyte cell death has been less explored. This study aimed to investigate the mechanism through which HSP70 directly regulates melanocyte ferroptosis. We found that HSP70 activates ferroptosis in melanocytes by binding to Toll-like receptor 2 (TLR2) and regulating the mitogen-activated protein kinase (MAPK) pathway. Our findings confirmed that ferroptosis is activated in the skin lesions of vitiligo patients. Additionally, we found that HSP70 significantly induced ferroptosis in melanocytes. By knocking down different receptor genes, we identified TLR2 as the primary receptor mediating HSP70-induced ferroptosis activation in melanocytes. Our results further uncovered that this process involved the inhibition of SLC7A11-GPX4 and FSP1. Subsequent mechanistic studies revealed that HSP70 promotes ferroptosis via the MAPK pathway, particularly engaging the activation of extracellular signal-regulated kinase (ERK) and p38 pathways. In summary, the HSP70/TLR2 axis triggers melanocytes ferroptosis by activating the MAPK, SLC7A11-GPX4, and FSP1 pathways, contributing to the onset of vitiligo. Therefore, targeting ferroptosis or TLR2 may provide a promising therapeutic approach for the management of vitiligo.

Scratch and tickle are universally experienced mechanical sensations arising from activation of unmyelinated cutaneous sensory fibers and having served protective evolutionary functions. Scratching is a self-directed motor response to itch that becomes maladaptive in chronic pruritus (CP), whereas tickle depends on external stimulation and remains paradoxically pleasurable and noxious, shaped by context and overlapping pain-pleasure circuits. Both sensations are processed by somatosensory, limbic, and reward-related brain regions. Despite overlapping neural pathways, topographical hotspots for scratching pleasurability and tickle sensation vary considerably. Understanding shared pathways highlights knowledge gaps and opportunities for research of novel therapies for CP and skin dysesthesias.

Oncostatin M (OSM), part of the IL-6 cytokine family, is critical in cancer, inflammation, and skin immunity. After being produced by neutrophils, T lymphocytes, dendritic cells, and macrophages after tissue damage or infection, OSM activates the phosphoinoside 3-kinase/protein kinase B, Jak/signal transducer and activator of transcription, MAPK, and JNK signaling pathways through type I (LIFRβ/gp130) or type II (OSMRβ/gp130) receptors. Although OSM has been widely studied in inflammatory diseases and cancers, its role in skin immunity has only recently gained attention as a therapeutic target, and the links between skin immunity and cancer remain underexplored. This review examines OSM's therapeutic potential in tumors and inflammatory diseases of the skin.

Fibroblasts have traditionally been regarded as structural cells responsible for extracellular matrix (ECM) synthesis and remodeling during skin homeostasis and repair. However, emerging research has redefined fibroblasts as dynamic, immunomodulatory cells that play pivotal roles in inflammation, fibrosis, and tumor progression. This review synthesizes current understanding of skin fibroblast heterogeneity, plasticity, and diverse functions across a spectrum of inflammatory skin diseases, including autoimmune, allergic, fibrotic, and neoplastic pathologies. Fibroblasts in these contexts adopt disease-specific phenotypes shaped by their local cellular, signaling, and biomechanical cues and prominently by their crosstalk with immune and epithelial cells. Fast-paced advances in single-cell and spatial transcriptomics have uncovered heterogenous fibroblast subsets with specialized roles in immune regulation, ECM remodeling, and signaling niche-dependent functions. Moreover, fibroblasts have emerged as key drivers of chronic disease persistence and contributors to therapeutic resistance. Despite these advances, knowledge gaps remain regarding lineage identity, functional plasticity, and phenotype-driving gene regulatory networks for cutaneous fibroblasts. Continued investigation into fibroblast biology will be essential for translating newly emerging insights into precision therapies and for redefining treatment strategies across inflammatory and fibrotic skin disorders.

Psoriasis vulgaris is a T-cell-mediated autoimmune skin condition affecting around 1 in 50 people worldwide. Although advanced immunomodulatory therapeutic options have become available in recent years, ongoing disease suppression is still required, with no curative treatment available to date. The HLA class I allele HLA-C∗06:02 is the main genetic risk determinant of psoriasis. HLA-C molecules present peptide antigens to CD8⁺ T cells and NK cells that in turn elicit and perpetuate the immune response, yet little is known about the ligands presented by HLA-C∗06:02. To gain an understanding of which HLA-C∗06:02-restricted peptides are presented by epidermal cell populations and might be initiators of the autoimmune response in psoriasis, we have conducted an in depth immunopeptidomic analysis of keratinocyte and melanocyte cell lines positive for HLA-C∗06:02 and either HLA-C∗07:01 or HLA-C∗07:02. Furthermore, we introduce an HLA-C∗06:02-transgenic mouse, which, in conjunction with the imiquimod model of psoriasis, allowed us to assess the ex vivo immunopeptidome of HLA-C∗06:02 in psoriasiform skin. Overall, we identified 20,812 high-confidence HLA-C-bound peptide ligands derived from HLA-C∗06:02 and highly similar HLA-C∗07:01/02 immunopeptidomes. Thus, we present a comprehensive HLA-C in vitro immunopeptidomic dataset and an HLA-C∗06:02 ex vivo dataset of psoriasis-relevant peptide antigens that may inform the development of novel antigen-specific, curative therapeutic approaches in psoriasis.