Role of fibroblasts in nonfibrotic autoimmune skin diseases.

Autoimmune diseases, a disease characterized by immune imbalance caused by the human immune system mistakenly attacking its own components, include vitiligo, psoriasis and atopic dermatitis (AD). Previous studies on autoimmune diseases have focused mainly on immune cells, keratinocytes and endothelial cells. Fibroblasts, the main cells that secrete the extracellular matrix (ECM) in the dermis, have been studied thoroughly in terms of fibrosis and wound healing. However, an increasing number of studies have shown that fibroblasts play an important role in nonfibrotic autoimmune skin diseases. In this article, the previously reported role of fibroblasts in nonfibrous autoimmune skin diseases such as psoriasis, vitiligo and AD is summarized to provide new ideas for the treatment of this disease.

He Y ，Han Z ，Zhang Q ，Liu L ，Chang J ... -  《-》

The role of dermal fibroblasts in autoimmune skin diseases.

Fibroblasts are an important subset of mesenchymal cells in maintaining skin homeostasis and resisting harmful stimuli. Meanwhile, fibroblasts modulate immune cell function by secreting cytokines, thereby implicating their involvement in various dermatological conditions such as psoriasis, vitiligo, and atopic dermatitis. Recently, variations in the subtypes of fibroblasts and their expression profiles have been identified in these prevalent autoimmune skin diseases, implying that fibroblasts may exhibit distinct functionalities across different diseases. In this review, from the perspective of their fundamental functions and remarkable heterogeneity, we have comprehensively collected evidence on the role of fibroblasts and their distinct subpopulations in psoriasis, vitiligo, atopic dermatitis, and scleroderma. Importantly, these findings hold promise for guiding future research directions and identifying novel therapeutic targets for treating these diseases.

Shi Z ，Liu Z ，Wei Y ，Zhang R ，Deng Y ，Li D ... -  《Frontiers in Immunology》

Fibroblast: A Novel Target for Autoimmune and Inflammatory Skin Diseases Therapeutics.

Fibroblasts are crucial components of the skin structure. They were traditionally believed to maintain the skin's structure by producing extracellular matrix and other elements. Recent research illuminated that fibroblasts can respond to external stimuli and exhibit diverse functions, such as the secretion of pro-inflammatory factors, adipogenesis, and antigen presentation, exhibiting remarkable heterogeneity and plasticity. This revelation positions fibroblasts as active contributors to the pathogenesis of skin diseases, challenging the traditional perspective that views fibroblasts solely as structural entities. Based on their diverse functions, fibroblasts can be categorized into six subtypes: pro-inflammatory fibroblasts, myofibroblasts, adipogenic fibroblasts, angiogenic fibroblasts, mesenchymal fibroblasts, and antigen-presenting fibroblasts. Cytokines, metabolism, and epigenetics regulate functional abnormalities in fibroblasts. The dynamic changes fibroblasts exhibit in different diseases and disease states warrant a comprehensive discussion. We focus on dermal fibroblasts' aberrant manifestations and pivotal roles in inflammatory and autoimmune skin diseases, including psoriasis, vitiligo, lupus erythematosus, scleroderma, and atopic dermatitis, and propose targeting aberrantly activated fibroblasts as a potential therapeutic strategy for inflammatory and autoimmune skin diseases.

Chen X ，Wu Y ，Jia S ，Zhao M ... -  《-》

Anatomically distinct fibroblast subsets determine skin autoimmune patterns.

The skin serves as a physical barrier and an immunological interface that protects the body from the external environment1-3. Aberrant activation of immune cells can induce common skin autoimmune diseases such as vitiligo, which are often characterized by bilateral symmetric lesions in certain anatomic regions of the body4-6. Understanding what orchestrates the activities of cutaneous immune cells at an organ level is necessary for the treatment of autoimmune diseases. Here we identify subsets of dermal fibroblasts that are responsible for driving patterned autoimmune activity, by using a robust mouse model of vitiligo that is based on the activation of endogenous auto-reactive CD8+ T cells that target epidermal melanocytes. Using a combination of single-cell analysis of skin samples from patients with vitiligo, cell-type-specific genetic knockouts and engraftment experiments, we find that among multiple interferon-γ (IFNγ)-responsive cell types in vitiligo-affected skin, dermal fibroblasts are uniquely required to recruit and activate CD8+ cytotoxic T cells through secreted chemokines. Anatomically distinct human dermal fibroblasts exhibit intrinsic differences in the expression of chemokines in response to IFNγ. In mouse models of vitiligo, regional IFNγ-resistant fibroblasts determine the autoimmune pattern of depigmentation in the skin. Our study identifies anatomically distinct fibroblasts with permissive or repressive IFNγ responses as the key determinant of body-level patterns of lesions in vitiligo, and highlights mesenchymal subpopulations as therapeutic targets for treating autoimmune diseases.

Xu Z ，Chen D ，Hu Y ，Jiang K ，Huang H ，Du Y ，Wu W ，Wang J ，Sui J ，Wang W ，Zhang L ，Li S ，Li C ，Yang Y ，Chang J ，Chen T ... -  《-》

Immunohistochemical analysis of FOXP3+ regulatory T cells in healthy human skin and autoimmune dermatoses.

Regulatory T cells (Tregs) play an important role in autoimmune diseases. In skin, the presence of Tregs is thought to be mandatory for suppression of autoreactive T cells. Here, we assess the number of Tregs in skin of healthy subjects and patients with an autoimmune dermatosis. Immunohistochemical stainings for CD3 and FOXP3 on skin biopsies of healthy subjects and subjects with psoriasis, vitiligo, pemphigus vulgaris, bullous pemphigoid, and halo nevus to assess the number of T and regulatory T cells, respectively. Low numbers of CD3+ and FOXP3+ cells were seen in the skin of healthy controls (median = 0.5%). A significantly higher frequency of Tregs was seen in lesional skin of patients with psoriasis (median = 12.4%) and patients with bullous pemphigoid (median = 10.1%) as compared to controls. In vitiligo (median = 0.0%), pemphigus vulgaris (median = 5.2%), and halo nevi (median = 5.4%), no significant difference in number of FOXP3+ cells was observed when compared to controls. As confirmed in the literature, few Tregs were seen in healthy skin. A high number of Tregs were present in lesional skin from patients with psoriasis and bullous pemphigoid. These results support the hypothesis that not a decrease in number but rather a decrease in function of Tregs would be at the basis of autoimmune skin diseases, which could result in unrestrained activation autoreactive T cells in skin of patients with autoimmune dermatoses.

Terras S ，Gambichler T ，Moritz RK ，Altmeyer P ，Lambert J ... -  《-》