Institute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
School of Medicine, Chinese University of Hong Kong (Shenzhen), Guangdong, China.
J Clin Invest. 2024 Sep 17;134(21):e180109. doi: 10.1172/JCI180109.
Dysfunction of group 2 innate lymphoid cells (ILC2s) plays an important role in the development of type 2 inflammation-related diseases such as asthma and pulmonary fibrosis. Notably, neural signals are increasingly recognized as pivotal regulators of ILC2s. However, how ILC2s intrinsically modulate their responsiveness to these neural signals is still largely unknown. Here, using single-cell RNA-Seq, we found that the immune-regulatory molecule phosphatase of activated cells 1 (PAC1) selectively promoted the signaling of the neuropeptide calcitonin gene-related peptide (CGRP) in ILC2s in a cell-intrinsic manner. Genetic ablation of PAC1 in ILC2s substantially impaired the inhibitory effect of CGRP on proliferation and IL-13 secretion. PAC1 deficiency significantly exacerbated allergic airway inflammation induced by Alternaria alternata or papain in mice. Moreover, in human circulating ILC2s, the expression level of PAC1 was also significantly negatively correlated with the number of ILC2s and their expression level of IL13. Mechanistically, PAC1 was necessary for ensuring the expression of CGRP response genes by influencing chromatin accessibility. In summary, our study demonstrated that PAC1 is an important regulator of ILC2 responses, and we propose that PAC1 is a potential target for therapeutic interventions in type 2 inflammation-related diseases.
2 型固有淋巴细胞 (ILC2s) 的功能障碍在哮喘和肺纤维化等 2 型炎症相关疾病的发展中起着重要作用。值得注意的是，神经信号越来越被认为是 ILC2s 的关键调节因子。然而，ILC2s 如何内在地调节其对这些神经信号的反应仍知之甚少。在这里，我们使用单细胞 RNA-Seq 发现，免疫调节分子激活细胞磷酸酶 1 (PAC1) 以细胞内在的方式选择性地促进神经肽降钙素基因相关肽 (CGRP) 在 ILC2s 中的信号传递。在 ILC2s 中敲除 PAC1 会显著削弱 CGRP 对增殖和 IL-13 分泌的抑制作用。PAC1 缺陷显著加重了烟曲霉或木瓜蛋白酶诱导的小鼠过敏性气道炎症。此外，在人类循环 ILC2s 中，PAC1 的表达水平也与 ILC2s 的数量及其 IL13 的表达水平呈显著负相关。从机制上讲，PAC1 通过影响染色质可及性来确保 CGRP 反应基因的表达。总之，我们的研究表明 PAC1 是 ILC2 反应的重要调节剂，我们提出 PAC1 是 2 型炎症相关疾病治疗干预的潜在靶点。
