PAC1 constrains type 2 inflammation through promotion of CGRP signaling in ILC2s
Yuan Jin, Bowen Liu, Qiuyu Li, Xiangyan Meng, Xiaowei Tang, Yan Jin, Yuxin Yin
Yuan Jin, Bowen Liu, Qiuyu Li, Xiangyan Meng, Xiaowei Tang, Yan Jin, Yuxin Yin
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Research Article Immunology

PAC1 constrains type 2 inflammation through promotion of CGRP signaling in ILC2s

Abstract

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.

Authors

Yuan Jin, Bowen Liu, Qiuyu Li, Xiangyan Meng, Xiaowei Tang, Yan Jin, Yuxin Yin

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Figure 3

PAC1 plays a cell-intrinsic inhibitory role in ILC2s.

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PAC1 plays a cell-intrinsic inhibitory role in ILC2s. (A) Experimental p...
(A) Experimental protocol for adoptive transfer of mixed ILC2s into Rag2–/– Il2rg–/– mice. The data in B–D were obtained in recipient mice (n = 6) on day 4 after IL-33 administration. (B) Frequency of lung CD45.2+ Pac1+/+ ILC2s and CD45.1+ Pac1–/– ILC2s. (C) Frequency of lung CD45.2+ Pac1+/+ Ki67+ ILC2s and CD45.1+ Pac1–/– Ki67+ ILC2s. (D) Frequency of lung CD45.2+ Pac1+/+ IL-13+ ILC2s and CD45.1+ Pac1–/– IL-13+ ILC2s. (E) Frequency and absolute number of lung ILC2s from R5/+ Pac1+/+ and R5/+ Pac1fl/fl mice in the cell resting state (R5/+ Pac1+/+, n = 5; R5/+ Pac1fl/fl, n = 5) or on day 4 after IL-33 administration (R5/+ Pac1+/+, n = 4; R5/+ Pac1fl/fl, n = 5). (F–H) Frequency of lung Ki67+ ILC2s (F), frequency of lung IL-5+ IL-13+ ILC2s (G), and MFI of IL-13 in lung ILC2s (H) from R5/+ Pac1+/+ (n = 4) and R5/+ Pac1fl/fl mice (n = 5) on day 4 after IL-33 administration. The data shown in I–N were obtained on day 4 after A. alternata administration. (I–M) Absolute number of lung ILC2s (I), frequency of lung IL-5+ IL-13+ ILC2s (J), MFI of IL-13 in lung ILC2s (K), frequency and absolute number of BALF eosinophils (L), and histological score for lungs (M) in recipient Rag2–/– Il2rg–/– mice, which had received equal numbers of Pac1+/+ lung ILC2s (n = 5) or Pac1–/– lung ILC2s (n = 5). (N) Representative H&E-stained lung sections from recipient Rag2–/– Il2rg–/– mice, which had received equal numbers of Pac1+/+ lung ILC2s or Pac1–/– lung ILC2s. Scale bars: 50 μm. Data are shown as the mean ± SEM. Statistical significance was assessed using a 2-tailed paired Student’s t test (B–D), 2-way ANOVA followed by Holm-Šidák multiple-comparison test (E), or 2-tailed, unpaired Student’s t test (F–M). Scale bars: 50 μm.