The role of HHIP in COPD lymphocytic inflammation

Chronic obstructive pulmonary disease (COPD) is characterized by persistent and amplified inflammation to cigarette smoke in vulnerable subjects. The genetic risk of persistent inflammation is poorly understood. A mouse model targeting hedgehog interacting protein (HHIP)(Hhip+--), a genetic risk factor for COPD, displays progressive, persistent inflammation resembling human cases, providing a valuable model to study the contribution of the genetic risk factor HHIP to inflammation in COPD. By single cell RNA sequencing of Hhip+-- lungs at different disease stages, we identified induction of IFN-gamma in activated CD8+T cells possibly driving the inflammatory phenotype in Hhip+-- lungs. Hhip expression was restricted to lung fibroblasts, which interaction with CD8+T cells were mediated by increased levels of IL-18 from Hhip+-- fibroblasts. Our finding provides insight into how a common genetic variation contributes to the amplified lymphocytic inflammation in COPD. single cell RNA sequencing of Hhip+-- and Hhip+-+ mouse lungs at 4 different age points慢性阻塞性肺疾病（Chronic obstructive pulmonary disease, COPD）以易感个体对香烟烟雾产生持续性且过度放大的炎症反应为核心特征。目前，学界对持续性炎症相关遗传风险的机制尚未得到充分阐明。靶向刺猬相互作用蛋白（hedgehog interacting protein, HHIP）——一种COPD的遗传风险因子——的Hhip+--小鼠模型，可呈现出与人类COPD患者相似的进行性持续性炎症表型，为探究遗传风险因子HHIP在COPD炎症发生发展中的调控贡献提供了极具价值的研究工具。通过对不同疾病阶段的Hhip+--小鼠肺部开展单细胞RNA测序（single cell RNA sequencing），本研究鉴定出活化的CD8+T细胞（CD8+ T cell）中γ干扰素（IFN-gamma）的诱导表达，该过程可能驱动了Hhip+--小鼠肺部的炎症表型。进一步研究发现，HHIP的表达仅局限于肺成纤维细胞（lung fibroblast），而Hhip+--小鼠的肺成纤维细胞可通过上调白细胞介素18（IL-18）的表达水平，介导其与CD8+T细胞的相互作用。本研究发现为阐明常见遗传变异如何介导COPD中过度放大的淋巴细胞炎症提供了全新的认知视角。本研究同时对4个不同年龄点的Hhip+--与Hhip+-+小鼠肺部开展了单细胞RNA测序。