Gilhar, A. | Search bioRxiv

bioRxiv2024

Perceived stress exacerbates psoriasis in human skin in vivo: Insights from a humanized psoriasis mouse model

IntroductionThe widely held belief that psychoemotional stress triggers or exacerbates psoriatic skin lesions lacks sufficient scientific evidence. This study investigated this concept using a psoriasis humanized mouse model. MethodsHealthy human skin was grafted onto SCID/beige mice (n=25), and one month later, psoriatic lesions were induced by intradermal injection of autologous, in vitro IL-2- preactivated PBMCs. Following lesion development, topical dexamethasone (DEX) was applied to induce lesion remission. After lesions disappeared, the mice were exposed to either sonic or sham stress for 24 hours. ResultsSonic stress led to the relapse of psoriatic lesions in all human skin xenografts within 14 days. This relapse was associated with significant changes in psoriasis-related skin characteristics: increased epidermal thickness, K16 expression, keratinocyte proliferation, antimicrobial peptide expression (S100A7, h{beta}2-defensin), and immune activation markers (HLA-DR, ICAM-1, CD1d, MICA-NKG2D). Additionally, epidermal and dermal immune cells (CD3+, CD8+, CD11c+, CD56+, ILC3, c-KIT+ or tryptase+ cells) and psoriasis-associated pro-inflammatory mediators (CXCL10, IL-22, IL-15, IL-17A/F, IFN-{gamma}, and TNF) were found to be increased. Neurogenic inflammation biomarkers (NGF, NK1-R, and substance P) were also significantly upregulated in stressed mice. Treatment with the FDA-approved neurokinin-1 receptor antagonist, aprepitant, prevented stress-induced psoriatic relapses in 4 out of 5 mice and normalized most inflammatory and neurobiological markers. ConclusionsThese findings provide novel, conclusive evidence that perceived stress can trigger psoriatic lesions in human skin xenografts in vivo and highlight the role of substance P-dependent neurogenic inflammation in this process.

immunology↗

bioRxiv2022

Involvement of ILC1-like innate lymphocytes in human autoimmunity, lessons from alopecia areata

Here, we have explored the involvement of innate lymphoid cells-type 1 (ILC1) in the pathogenesis of alopecia areata (AA), because we found them to be significantly increased around lesional and non-lesional HFs of AA patients. To further explore these unexpected findings, we first co-cultured autologous circulating ILC1-like cells (ILC1lc) with healthy, but stressed, organ-cultured human scalp hair follicles (HFs). ILClc induced all hallmarks of AA ex vivo: they significantly promoted premature, apoptosis-driven HF regression (catagen), HF cytotoxicity/dystrophy and most important for AA pathogenesis, collapse of the HFs physiological immune privilege. NKG2D-blocking or IFN{gamma}-neutralizing antibodies antagonized this. In vivo, intradermal injection of autologous activated, NKG2D+/IFN{gamma}-secreting ILC1lc into healthy human scalp skin xenotransplanted onto SCID/beige mice sufficed to rapidly induce characteristic AA lesions. This provides the first evidence that ILC1lc suffice to induce AA in previously healthy human HFs ex vivo and in vivo, and further questions the conventional wisdom that AA is always an autoantigen-dependent, CD8+ T cell-driven autoimmune disease.

immunology↗