PAC1 constrains type 2 inflammation through promotion of CGRP signaling in ILC2s
Yuan Jin, … , Yan Jin, Yuxin Yin
Yuan Jin, … , Yan Jin, Yuxin Yin
Published September 17, 2024
Citation Information: J Clin Invest. 2024;134(21):e180109. https://doi.org/10.1172/JCI180109.
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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 2

PAC1 exhibits a suppressive effect on ILC2 responses.

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PAC1 exhibits a suppressive effect on ILC2 responses. (A) Violin plot of...
(A) Violin plot of PAC1 expression levels in human ILC2s sorted from peripheral blood of patients with GPAs and NACs. The scCITE-Seq data were obtained from GSE163367 (30). (B and C) Frequency (B) and absolute number (C) of lung T-bet+ ILC1s, GATA3+ ILC2s, and RORγT+ ILC3s from Pac1+/+ (n = 6) and Pac1–/– mice (n = 6) in the cell resting states. (D) Experimental protocol followed for in vivo ILC2 activation using IL-33. The data shown in E–P were obtained on day 4 after IL-33 administration. (E) Absolute number of lung ILC2s in Pac1+/+ (n = 8) and Pac1–/– mice (n = 6). (F and G) Frequency (F) and absolute number (G) of lung Ki67+ ILC2s from Pac1+/+ (n = 7) and Pac1–/– mice (n = 6). (H and I) Frequency (H) and absolute number (I) of lung IL-5+IL-13+ ILC2s from Pac1+/+ (n = 8) and Pac1–/– mice (n = 6). (J) MFI of IL-5 or IL-13 in lung ILC2s from Pac1+/+ (n = 8) and Pac1–/– mice (n = 6). (K and L) Frequency (K) and absolute number (L) of BALF eosinophils from Pac1+/+ (n = 8) and Pac1–/– mice (n = 8). (M and N) Frequency (M) and absolute number (N) of lung eosinophils from Pac1+/+ (n = 6) and Pac1–/– mice (n = 4). (O) Histological score for lungs from Pac1+/+ (n = 6) and Pac1–/– mice (n = 4). (P) Representative images of H&E-stained lung sections from Pac1+/+ and Pac1–/– mice. Scale bars: 50 μm. Data are shown as the mean ± SEM. Statistical significance was assessed using 1-way ANOVA followed by Tukey’s multiple-comparison test (A), 2-way ANOVA followed by Holm-Šidák multiple-comparison test (B and C), or 2-tailed, unpaired Student’s t test (E–O).