Skin uses interdependent cellular networks for barrier integrity and host immunity, but most underlying mechanisms remain obscure. Herein, we demonstrate that the human parasitic helminth Schistosoma mansoni inhibited pruritus evoked by itch-sensing afferents bearing the Mas-related G-protein-coupled receptor A3 (MrgprA3) in mice. MrgprA3 neurons controlled interleukin (IL)-17⁺ γδ T cell expansion, epidermal hyperplasia and host resistance against S. mansoni through shaping cytokine expression in cutaneous antigen-presenting cells. MrgprA3 neuron activation downregulated IL-33 but induced IL-1β and tumor necrosis factor in macrophages and type 2 conventional dendritic cells partially through the neuropeptide calcitonin gene-related peptide. Macrophages exposed to MrgprA3-derived secretions or bearing cell-intrinsic IL-33 deletion showed increased chromatin accessibility at multiple inflammatory cytokine loci, promoting IL-17/IL-23-dependent changes to the epidermis and anti-helminth resistance. This study reveals a previously unrecognized intercellular communication mechanism wherein itch-inducing MrgprA3 neurons initiate host immunity against skin-invasive parasites by directing cytokine expression patterns in myeloid antigen-presenting cell subsets.

皮肤使用相互依赖的细胞网络来实现屏障完整性和宿主免疫，但大多数潜在机制仍然不清楚。在此，我们证明人类寄生蠕虫曼氏血吸虫抑制了小鼠体内携带 Mas 相关 G 蛋白偶联受体 A3 （MrgprA3） 的瘙痒感应传入神经引起的瘙痒。MrgprA3 神经元通过塑造皮肤抗原呈递细胞中的细胞因子表达来控制白细胞介素 （IL）-17⁺ γδ T 细胞扩增、表皮增生和宿主对曼氏链球菌的耐药性。MrgprA3 神经元激活下调 IL-33，但部分通过神经肽降钙素基因相关肽诱导巨噬细胞和 2 型常规树突状细胞中的 IL-1β 和肿瘤坏死因子。暴露于 MrgprA3 衍生分泌物或携带细胞内源性 IL-33 缺失的巨噬细胞显示多个炎性细胞因子位点的染色质可及性增加，促进表皮的 IL-17/IL-23 依赖性变化和抗蠕虫耐药性。这项研究揭示了一种以前未被认识的细胞间通讯机制，其中瘙痒诱导的 MrgprA3 神经元通过指导髓样抗原呈递细胞亚群中的细胞因子表达模式来启动宿主对皮肤侵袭性寄生虫的免疫。