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JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia

ABSTRACT: The hair follicle stem cell niche is an immune-privileged microenvironment, characterized by reduced antigen presentation, thus shielding against permanent immune-mediated tissue damage. In this study, we demonstrated the protective role of hair follicle-specific epidermal growth factor receptor (EGFR) against scarring hair follicle destruction. Mechanistically, disruption of EGFR signalling generated a cell-intrinsic hypersensitivity within the JAK-STAT1 pathway, which, synergistically with interferon gamma expressing CD8 T-cell and NK-cell-mediated inflammation, compromised the stem cell niche. Hair follicle-specific genetic depletion of either JAK1/2 or STAT1 or therapeutic inhibition of JAK1/2 ameliorated the inflammation, restored skin barrier function and activated the residual stem cells to resume hair growth in mouse models of epidermal and hair follicle-specific EGFR deletion. Skin biopsies from EGFR inhibitor-treated and cicatricial alopecia patients revealed an active JAK-STAT1 signalling signature along with up-regulation of antigen presentation and down-regulation of key components of the EGFR pathway. Our findings offer molecular insights and highlight a mechanism-based therapeutic strategy for addressing chronic folliculitis associated with EGFR-inhibitor anti-cancer therapy and cicatricial alopecia.

SUBMITTER: Dr. Karoline Strobl

PROVIDER: S-SCDT-10_1038-S44321-024-00166-3 | biostudies-other |

REPOSITORIES: biostudies-other

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JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia

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JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia (scRNA-seq)

Project description:The hair follicle stem cell niche is an immune-privileged microenvironment, characterized by reduced antigen presentation, thus shielding against permanent immune-mediated tissue damage. In this study, we demonstrated the protective role of hair follicle-specific epidermal growth factor receptor (EGFR) against scarring hair follicle destruction. Mechanistically, disruption of EGFR signalling generated a cell-intrinsic hypersensitivity within the JAK-STAT1 pathway, which, synergistically with interferon gamma expressing CD8 T-cell and NK-cell-mediated inflammation, compromised the stem cell niche. Hair follicle-specific genetic depletion of either JAK1/2 or STAT1 or therapeutic inhibition of JAK1/2 ameliorated the inflammation, restored skin barrier function and activated the residual stem cells to resume hair growth in mouse models of epidermal and hair follicle-specific EGFR deletion. Skin biopsies from EGFR inhibitor-treated and cicatricial alopecia patients indicated active STAT1 signalling and interferon target expression. Notably, a case study of folliculitis decalvans, characterized by progressive hair loss, scaling and perifollicular erythema, demonstrated successful treatment with JAK1/2 inhibition. Our findings offer molecular insights and present a mechanism-based therapeutic strategy for addressing chronic folliculitis associated with EGFR-inhibitor anti-cancer therapy and cicatricial alopecia.

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JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia (RNA-seq of HFSC)

2024-07-31 | GSE273571 | GEO

JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia (scRNA-seq)

Project description:JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia (scRNA-seq)

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JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia (RNA-seq of HFSC)

Project description:JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia (RNA-seq of HFSC)

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Ferroptosis as a Potential Therapeutic Target for Reducing Inflammation and Corneal Scarring in Bacterial Keratitis.

Project description:PurposeBacterial keratitis (BK) is a serious ocular infection that can cause severe inflammation and corneal scarring, leading to vision loss. In this study, we aimed to investigate the involvement of ferroptosis in the pathogenesis of BK.MethodsTranscriptome analysis was performed to evaluate ferroptosis-related gene expression in human BK corneas. Subsequently, the ferroptosis in mouse models of Pseudomonas aeruginosa keratitis and corneal stromal stem cells (CSSCs) were validated. The mice were treated with levofloxacin (LEV) or levofloxacin combined with ferrostatin-1 (LEV+Fer-1). CSSCs were treated with lipopolysaccharide (LPS) or LPS combined Fer-1. Inflammatory cytokines, α-SMA, and ferroptosis-related regulators were evaluated by RT-qPCR, immunostaining, and Western blot. Iron and reactive oxygen species (ROS) were measured.ResultsTranscriptome analysis revealed significant alterations in ferroptosis-related genes in human BK corneas. In the BK mouse models, the group treated with LEV+Fer-1 exhibited reduced inflammatory cytokines (MPO, TNF-α, and IFN-γ), decreased corneal scarring and α-SMA expression, and lower Fe3+ compared to the BK and LEV groups. Notably, the LEV+Fer-1 group showed elevated GPX4 and SLC7A11 in contrast to the BK and LEV group. In vitro, Fer-1 treatment effectively restored the alterations of ROS, Fe2+, GPX4, and SLC7A11 induced by LPS in CSSCs.ConclusionsFerroptosis plays a crucial role in the pathogenesis of BK. The inhibition of ferroptosis holds promise for mitigating inflammation, reducing corneal scarring, and ultimately enhancing the prognosis of BK. Consequently, this study provides a potential target for innovative therapeutic strategies for BK, which holds immense potential to transform the treatment of BK.

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TNF-α/IFN-γ synergy amplifies senescence-associated inflammation and SARS-CoV-2 receptor expression via hyper-activated JAK/STAT1.

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Project description:Alopecia Areata (AA) is a common autoimmune disease characterized by non-scarring hair loss ranging from patches on the scalp to complete hair loss involving the entire body. Disease onset is hypothesized to follow the collapse of immune privilege of the hair follicle, which results in an increase in self-peptide/MHC expression along the follicular epithelium. Hair loss is associated with infiltration of the hair follicle with putatively self-reactive T cells. This process is thought to skew the hair follicle microenvironment away from a typically homeostatic immune state towards one of active inflammation. This imbalance is mediated in part by the dominating presence of specific cytokines. While interferon-γ (IFNγ) has been identified as the key player in AA pathogenesis, many other cytokines have also been shown to play pivotal roles. Mechanistic studies in animal models have highlighted the contribution of common gamma chain (γc) cytokines such as IL-2, IL-7, and IL-15 in augmenting disease. IFNγ and γc cytokines signal through pathways involving receptor activation of Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). Based on these findings, JAK/STAT pathways have been targeted for the purposes of therapeutic intervention in the clinical setting. Case reports and series have described use of small molecule JAK inhibitors leading to hair regrowth among AA patients. Furthermore, emerging clinical trial results show great promise and position JAK inhibitors as a treatment strategy for patients with severe or recalcitrant disease. Demonstrated efficacy from large-scale clinical trials of the JAK inhibitor baricitinib led to the first-in-disease FDA-approved treatment for AA in June of 2022. This review aims to highlight the JAK/STAT signaling pathways of various cytokines involved in AA and how targeting those pathways may impact disease outcomes in both laboratory and clinical settings.

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