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bioRxiv2023

Scarring hair follicle destruction is driven by the collapse of EGFR-protected JAK-STAT1-sensitive stem cell immune privilege

The hair follicle stem cell niche is an immune-privileged microenvironment, characterised by suppressed antigen presentation, thus shielding against permanent immune-mediated tissue damage. In this study, we demonstrate the protective role of hair follicle-specific epidermal growth factor receptor (EGFR) from scarring hair follicle degeneration. Mechanistically, disruption of EGFR signalling generates a cell intrinsic hypersensitivity within the JAK-STAT1 pathway, compromising the immune privilege in the context of CD8 T cell and NK cell-mediated inflammation. Genetic depletion of either JAK1/2 or STAT1 or topical therapeutic inhibition of JAK1/2 restores the immune privilege and activates stem cells to resume hair growth in mouse models of epidermal and hair follicle specific EGFR deletion. Skin biopsies from EGFR inhibitor-treated and from EGFR-independent cicatricial alopecia patients indicate active STAT1 signalling within the hair follicles. Notably, a case study of folliculitis decalvans, characterised by progressive hair loss, scaling and perifollicular erythema, demonstrates successful treatment with systemic JAK1/2 inhibition. Our findings offer mechanistic insights and present a therapeutic strategy for addressing scarring hair follicle destruction associated with EGFR-inhibitor therapy and cicatricial alopecia.

immunology↗

bioRxiv2023

Advanced methodology for bacterial colonization of 3D organotypic epidermal models: a gateway to long-term host-microbe interaction and intervention studies

BackgroundFollowing descriptive studies on skin microbiota in health and disease, mechanistic studies on the interplay between skin and microbes are on the rise, for which experimental models are in great demand. Here, we present a novel methodology for microbial colonization of organotypic skin and analysis thereof. ResultsAn inoculation device ensured a standardized application area on the stratum corneum and a homogenous distribution of bacteria, while preventing infection of the basolateral culture medium even during prolonged co-culture periods for up to two weeks at a specific culture temperature and humidity. Hereby, host-microbe interactions and antibiotic interventions could be studied, revealing diverse host responses to various skin-related bacteria and pathogens. ConclusionsOur methodology is easily transferable to a wide variety of organotypic skin or mucosal models and different microbes at every cell culture facility at low costs. We envision that this study will kick-start skin microbiome studies using human organotypic skin cultures, providing a powerful alternative to experimental animal models in pre-clinical research.

microbiology↗