Innate type 2 immunity controls hair follicle commensalism by Demodex mites [2019]. Innate type 2 immunity controls hair follicle commensalism by Demodex mites [2019]

Demodex mites are obligate commensal parasites of hair follicles (HF) in mammals. Normally asymptomatic, inflammatory outgrowth of mites can accompany malnutrition, immune dysfunction and aging, but mechanisms restricting Demodex outgrowth and pathogenesis are not defined. Here, we show that control over mite HF colonization of mice requires ILC2s, IL-13, and its receptor IL-4Ra, but not IL-4 or the adaptive immune system. Epithelial HF-associated ILC2s elaborate IL-13 that attenuates HF and epithelial cell proliferation at anagen onset; in their absence, Demodex colonization leads to increased epithelial proliferation and replacement of gene programs for repair by aberrant inflammatory programs leading to loss of barrier function and premature HF exhaustion over time. Humans with rhinophymatous acne rosacea, a nasal inflammatory condition associated with a high burden of Demodex, had increased HF inflammatory cells with decreased type 2 cytokines, consistent with the inverse relationship seen in mice. Our studies uncover a critical role for skin ILC2s and IL-13, which comprise an immune checkpoint necessary to sustain cutaneous integrity and restrict pathologic infestation by colonizing HF mites. Overall design: 2-month-old female WT (uninfected), IL-4Ra-/- (Dedmodex +) or IL-4/IL-13-/- (Demodex +) mice were used to sort CD45+ and CD45- cells from full thickness back skin.

毛囊蠕形螨（Demodex mites）是哺乳动物毛囊（hair follicles, HF）的专性共生寄生虫。该类螨通常无临床症状，但当宿主出现营养不良、免疫功能紊乱或衰老时，可引发螨类炎性增生；然而目前尚不明确限制毛囊蠕形螨增殖与致病的分子机制。本研究证实，小鼠毛囊螨定植的免疫调控依赖于2型固有淋巴细胞（ILC2s）、白细胞介素13（IL-13）及其受体白细胞介素4受体α（IL-4Ra），而非白细胞介素4（IL-4）或适应性免疫系统。与毛囊上皮相关的2型固有淋巴细胞可分泌白细胞介素13，在毛发生长期起始时抑制毛囊与上皮细胞的增殖；当该类细胞缺失时，毛囊蠕形螨定植会导致上皮细胞增殖异常，并使修复相关基因表达程序被异常炎症程序取代，最终引发皮肤屏障功能丧失，并随时间推移导致毛囊过早耗竭。伴有高负荷毛囊蠕形螨定植的鼻部炎症性疾病——鼻赘型酒渣鼻（rhinophymatous acne rosacea）患者，其毛囊炎症细胞增多而2型细胞因子水平降低，这与小鼠模型中观察到的负相关关系一致。本研究揭示了皮肤2型固有淋巴细胞与白细胞介素13的关键作用：二者构成了维持皮肤屏障完整性、限制毛囊蠕形螨定植引发病理性感染的免疫检查点。实验设计：本研究选用2月龄雌性野生型（wild type, WT，未感染组）、IL-4Ra基因敲除（IL-4Ra-/-，毛囊蠕形螨定植阳性组）以及IL-4与IL-13双基因敲除（IL-4/IL-13-/-，毛囊蠕形螨定植阳性组）小鼠，从其全层背部皮肤中分选CD45阳性（CD45+）与CD45阴性（CD45-）细胞。