Aberrant activation of dermal fibroblasts during wound healing often leads to debilitating fibrotic changes in the skin, such as scleroderma and keloids. However, the underlying cellular and molecular mechanisms remain elusive. Here, we established a wound-induced skin fibrosis (WISF) mouse model in mature adult mice, characterised by excessive deposition of collagen bundles, loss of dermal adipocytes, and enrichment of DPP4+Ly6A+THY1+ hypodermal interstitial adipocyte progenitors (HI-APs) and pericytes, resembling human fibrotic skin diseases. This WISF model exhibited an age-dependent gain of fibrotic characteristics, contrasting with the wound-induced hair neogenesis observed in younger mice. Through comprehensive analyses of the WISF, we delineated a trajectory of fibroblast differentiation that originates from HI-APs. These progenitors highly expressed several extracellular matrix (ECM) genes and exhibited a TGFβ pathway signature. TGFβ was identified as the key signal to inhibit the adipogenic potential and maintain the fibrogenic potential of dermal APs. Additionally, administering a TGFβ receptor inhibitor to wound scar reduced the abundance of ECM-producing APs. Finally, analysis of human scleroderma skin tissues revealed a negative correlation between the expression of AP-, ECM-, and TGFβ pathway-related genes and PPARG. Overall, this study establishes a wound-induced skin fibrosis mouse model and demonstrates that TGFβ-mediated blockage of HI-AP differentiation is crucial for driving fibrotic pathology. Targeting HI-APs and adipogenesis may provide novel avenues for developing disease-modifying therapies for fibrotic skin diseases.

Allergic contact dermatitis (ACD), a prevalent inflammatory skin disease, is elicited upon repeated skin contact with protein-reactive chemicals through a complex and poorly characterized cellular network between immune cells and skin resident cells. Here, single-cell transcriptomic analysis of the murine hapten-elicited model of ACD reveals that upon elicitation of ACD, infiltrated CD4 + or CD8 + lymphocytes were primarily the IFNγ-producing type 1 central memory phenotype. In contrast, type 2 cytokines (IL4 and IL13) were dominantly expressed by basophils, IL17A was primarily expressed by δγ T cells, and IL1β was identified as the primary cytokine expressed by activated neutrophils/monocytes and macrophages. Furthermore, analysis of skin resident cells identified a sub-cluster of dermal fibroblasts with preadipocyte signature as a prominent target for IFNγ + lymphocytes and dermal source for key T cell chemokines CXCL9/10. IFNγ treatment shifted dermal fibroblasts from collagen-producing to CXCL9/10-producing, which promoted T cell polarization toward the type-1 phenotype through a CXCR3-dependent mechanism. Furthermore, targeted deletion of Ifngr1 in dermal fibroblasts in mice reduced Cxcl9/10 expression, dermal infiltration of CD8 + T cell, and alleviated ACD inflammation in mice. Finally, we showed that IFNγ + CD8 + T cells and CXCL10-producing dermal fibroblasts co-enriched in the dermis of human ACD skin. Together, our results define the cell type-specific immune responses in ACD, and recognize an indispensable role of dermal fibroblasts in shaping the development of type-1 skin inflammation through the IFNGR-CXCR3 signaling circuit during ACD pathogenesis.

The Supplementary Methods show the Synthesis of DIM-C-pPhCF3+MeSO3- (BI1071); Figure S1 shows BI1071 induces apoptosis in different cancer cell lines; Fig. S2 shows BI1071 induces apoptosis in different breast cancer cell lines; Fig. S3 shows BI1071 induces apoptosis in cancer cell lines but not in non-transformed cell lines; Fig. S4 shows BI1071 did't induce the body weight loss; Fi.g S5 shows overexpression of Nur77-LBD enhances the killing effect of BI1071; Fig. S6 shows BI1071 has no effect on other nuclear receptors; Fig. S7 shows the imparied effect of BI1071 could be rescued by re-expression of Bcl-2; Fig. S8 shows BI1071 binding to Nur77 promotes Nur77 interaction with Bcl-2 and mitochondrial localization

Dermal adipocyte lineage cells are highly plastic and can undergo reversible differentiation and dedifferentiation in response to various stimuli. Using single-cell RNA sequencing of developing or wounded mouse skin, we classify dermal fibroblasts (dFBs) into distinct non-adipogenic and adipogenic cell states. Cell differentiation trajectory analyses identify IL-1-NF-κB and WNT-β-catenin as top signaling pathways that positively and negatively associate with adipogenesis, respectively. Upon wounding, activation of adipocyte progenitors and wound-induced adipogenesis are mediated in part by neutrophils through the IL-1R-NF-κB-CREB signaling axis. In contrast, WNT activation, by WNT ligand and/or ablation of Gsk3, inhibits the adipogenic potential of dFBs but promotes lipolysis and dedifferentiation of mature adipocytes, contributing to myofibroblast formation. Finally, sustained WNT activation and inhibition of adipogenesis is seen in human keloids. These data reveal molecular mechanisms underlying the plasticity of dermal adipocyte lineage cells, defining potential therapeutic targets for defective wound healing and scar formation.

Infections are a major complication of obesity, but the mechanisms responsible for impaired defense against microbes are not well understood. Here, we found that adipocyte progenitors were lost from the dermis during diet-induced obesity (DIO) in humans and mice. The loss of adipogenic fibroblasts from mice resulted in less antimicrobial peptide production and greatly increased susceptibility to Staphylococcus aureus infection. The decrease in adipocyte progenitors in DIO mice was explained by expression of transforming growth factor-β (TGFβ) by mature adipocytes that then inhibited adipocyte progenitors and the production of cathelicidin in vitro. Administration of a TGFβ receptor inhibitor or a peroxisome proliferator-activated receptor-γ agonist reversed this inhibition in both cultured adipocyte progenitors and in mice and subsequently restored the capacity of obese mice to defend against S. aureus skin infection. Together, these results explain how obesity promotes dysfunction of the antimicrobial function of reactive dermal adipogenesis and identifies potential therapeutic targets to manage skin infection associated with obesity.

世界卫生组织在2020年1月31日宣布新型冠状病毒(SARS-CoV-2)引发的肺炎为国际关注的突发公共卫生事件,目前疫情已在全世界范围蔓延.肺部是SARS-CoV-2作用的主要靶器官,该病毒通过感染肺泡细胞诱发细胞因子风暴,导致组织损伤并最终造成严重急性呼吸综合征,而天然免疫是人体抗病毒的第一道防线.该文综述肺部宿主细胞通过激活其天然免疫应答抵御冠状病毒入侵以及免疫反应过激后导致肺组织损伤的分子机制,以期为SARS-CoV-2引发的肺损伤治疗提供创新的药物靶标,并为预防和治疗方案设计提供免疫学和病理学基础.

Located at the skin surface, keratinocytes (KCs) are constantly exposed to external stimuli and are the first responders to invading pathogens and injury. Upon skin injury, activated KCs secrete an array of alarmin molecules, providing a rapid and specific innate immune response against danger signals. However, dysregulation of the innate immune response of KCs may lead to uncontrolled inflammation and psoriasis pathogenesis. Keratins (KRT) are the major structural intermediate filament proteins in KCs and are expressed in a highly specific pattern at different differentiation stages of KCs. While KRT14-KRT5 is restricted to basal proliferative KCs, and KRT10-KRT1 is restricted to suprabasal differentiated KCs in normal skin epidermis, the wound proximal KCs downregulate KRT10-K1 and upregulate KRT16/KRT17-KRT6 upon skin injury. Recent studies have recognized KRT6/16/17 as key early barrier alarmins and upregulation of these keratins alters proliferation, cell adhesion, migration and inflammatory features of KCs, contributing to hyperproliferation and innate immune activation of KCs in response to an epidermal barrier breach, followed by the autoimmune activation of T cells that drives psoriasis. Here, we have reviewed how keratins are dysregulated during skin injury, their roles in wound repairs and in initiating the innate immune system and the subsequent autoimmune amplification that arises in psoriasis.

Abstract Nur77 (also called TR3 or NGFI-B), an orphan member of the nuclear receptor superfamily, induces apoptosis by translocating to mitochondria where it interacts with Bcl-2 to convert Bcl-2 from an antiapoptotic to a pro-apoptotic molecule. Nur77 posttranslational modification such as phosphorylation has been shown to induce Nur77 translocation from the nucleus to mitochondria. However, small molecules that can bind directly to Nur77 to trigger its mitochondrial localization and Bcl-2 interaction remain to be explored. Here, we report our identification and characterization of DIM-C-pPhCF3+MeSO3− (BI1071), an oxidized product derived from indole-3-carbinol metabolite, as a modulator of the Nur77-Bcl-2 apoptotic pathway. BI1071 binds Nur77 with high affinity, promotes Nur77 mitochondrial targeting and interaction with Bcl-2, and effectively induces apoptosis of cancer cells in a Nur77- and Bcl-2–dependent manner. Studies with animal model showed that BI1071 potently inhibited the growth of tumor cells in animals through its induction of apoptosis. Our results identify BI1071 as a novel Nur77-binding modulator of the Nur77-Bcl-2 apoptotic pathway, which may serve as a promising lead for treating cancers with overexpression of Bcl-2.

Retinoid X receptor alpha (RXRα), an important ligand-dependent transcription factor, plays a critical role in the development of various cancers and metabolic and neurodegenerative diseases. Therefore, RXRα represents one of the most important targets in modern drug discovery. In this study, Drugbank 2.0 with 1280 old drugs were virtually screened by Glide according to the crystal structure of ligand-binding domain (LBP) of RXRα. 15 compounds selected were tested for their binding and transcriptional activity toward RXRα by Biacore and reporter gene assay, respectively. The identified new scafford ligand of RXRα, Pitavastatin (1), was chemically optimized. Our results demonstrated that statin compounds Pitavastatin (1) and Fluvastatin (4) could bind to the LBP of RXRα (KD=13.30μM and 11.04μM, respectively) and serve as transcriptional antagonists of RXRα. On the contrary, compound (12) (domperidone) and (13) (rosiglitazone maleate) could bind to the LBP of RXRα (KD=8.80μM and 15.01μM, respectively) but serve as transcriptional agonists of RXRα.