背景:皮肤屏障对于防止环境威胁(包括由皮肤驻留的微生物引起的损害)是至关重要的。这种屏障的失调是特应性皮炎(AD)和鱼鳞病的标志,对宿主免疫控制定殖共生菌和机会性病原体具有不同的后果。虽然马拉色菌是皮肤中最丰富的共生真菌,对这种真菌在炎症性皮肤病中的宿主控制知之甚少。
方法:在本实验研究中,MC903处理的小鼠定植有马拉色菌。评估特应性皮炎中宿主-真菌的相互作用。AD和鱼鳞病的其他小鼠模型,包括胶带剥离,K5-Nrf2过表达和片状尾巴小鼠,被用来确认和扩大调查结果。对皮肤真菌计数进行计数。高参数流式细胞术用于表征AD样皮肤中的抗真菌反应。通过块状皮肤的组织学和转录组学确定皮肤屏障的结构和功能改变。最后,定量了变应性和对照皮肤中马拉色菌代谢基因的差异表达。
结果:马拉色菌在AD样皮肤中过度生长。真菌过度生长可能,然而,不能用特应性皮肤的免疫状态改变来解释。相反,我们发现通过上调改变的皮肤小生境中的关键代谢基因,马拉色菌获得了增强的适应性,可以有效地定居受损的皮肤屏障。
结论:这项研究提供了证据,表明功能失调的表皮屏障环境的结构和代谢变化提供了增加的可及性和改变的脂质分布。脂质依赖性酵母适应于增强的营养同化。我们的发现揭示了对常见皮肤屏障疾病发病机理中分枝杆菌群的含义的基本见解。
The skin barrier is vital for protection against environmental threats including insults caused by skin-resident microbes. Dysregulation of this barrier is a hallmark of atopic dermatitis (AD) and ichthyosis, with variable consequences for host immune control of colonizing commensals and opportunistic pathogens. While Malassezia is the most abundant commensal fungus of the skin, little is known about the host control of this fungus in inflammatory skin diseases.
In this experimental study, MC903-treated mice were colonized with Malassezia spp. to assess the host-fungal interactions in atopic dermatitis. Additional murine models of AD and ichthyosis, including tape stripping, K5-Nrf2 overexpression and flaky tail mice, were employed to confirm and expand the findings. Skin fungal counts were enumerated. High parameter flow cytometry was used to characterize the antifungal response in the AD-like skin. Structural and functional alterations in the skin barrier were determined by histology and transcriptomics of bulk skin. Finally, differential expression of metabolic genes in Malassezia in atopic and control skin was quantified.
Malassezia grows excessively in AD-like skin. Fungal overgrowth could, however, not be explained by the altered immune status of the atopic skin. Instead, we found that by upregulating key metabolic genes in the altered cutaneous niche, Malassezia acquired enhanced fitness to efficiently colonise the impaired skin barrier.
This study provides evidence that structural and metabolic changes in the dysfunctional epidermal barrier environment provide increased accessibility and an altered lipid profile, to which the lipid-dependent yeast adapts for enhanced nutrient assimilation. Our findings reveal fundamental insights into the implication of the mycobiota in the pathogenesis of common skin barrier disorders.