Basophils prime group 2 innate lymphoid cells for neuropeptide-mediated inhibition [RNA-seq]

Type 2 cytokine responses promote parasitic immunity and initiate tissue repair but, can also result in immunopathologies when not properly restricted. Basophilia is recognized as a common feature of type 2 inflammation, however, the roles basophils play in regulating these responses remain unknown. Here, we demonstrate that helminth-induced ILC2 responses are exaggerated in the absence of basophils, resulting in increased inflammation and diminished lung function. Additionally, we show that ILC2s from basophil-depleted mice express reduced levels of the receptor for the neuropeptide, neuromedin B (NMB). Critically, NMB stimulation inhibited ILC2 responses from control but not basophil-depleted mice, and basophils were sufficient to directly enhance NMB receptor (NMBR) expression on ILC2s. These studies suggest that basophils prime ILC2s to respond to neuron-derived signals necessary to maintain tissue integrity. Further, these data provide mechanistic insight into the functions of basophils and identify NMB as a potent inhibitor of type 2 inflammation. Overall design: Lung-resident ILC2s were sort-purified from WT mice infected with Nippostrongylus brasiliensis 7 days prior and treated with vehicle or recombinant Neuromedin B (NMB) for 24 hours. 3 biological replicates per experimental group were used from ILC2s sort-purified from 5 mice per biological sample.

2型细胞因子应答（Type 2 cytokine responses）可介导寄生虫免疫并启动组织修复，但如果调控失当，也可能引发免疫病理损伤。嗜碱性粒细胞增多（Basophilia）被认为是2型炎症的常见特征，然而嗜碱性粒细胞（basophils）在调控这类应答中的作用仍有待阐明。本研究证实，在缺失嗜碱性粒细胞的情况下，蠕虫诱导的2型固有淋巴细胞（Innate Lymphoid Cells 2, ILC2）应答会过度激活，进而加剧炎症反应并导致肺功能受损。此外，本研究发现，来自嗜碱性粒细胞缺失小鼠的2型固有淋巴细胞，其神经介素B（Neuromedin B, NMB）受体的表达水平显著降低。至关重要的是，神经介素B刺激可抑制对照组小鼠2型固有淋巴细胞的应答，但对嗜碱性粒细胞缺失小鼠无此效应；且嗜碱性粒细胞足以直接上调2型固有淋巴细胞表面的神经介素B受体（NMBR）表达。上述研究结果表明，嗜碱性粒细胞可致敏2型固有淋巴细胞，使其对维持组织完整性所需的神经元源性信号产生应答。此外，本研究数据为阐明嗜碱性粒细胞的功能提供了机制层面的见解，并证实神经介素B是2型炎症的强效抑制剂。实验设计：于感染巴西日圆线虫（Nippostrongylus brasiliensis）7天后的野生型小鼠（Wild Type, WT）体内分选纯化肺驻留2型固有淋巴细胞，分别用赋形剂或重组神经介素B（NMB）处理24小时。每个实验组设置3次生物学重复，每次生物学重复的细胞均来源于5只小鼠的分选纯化2型固有淋巴细胞。