2. Academic Validation
  3. Bi-directional communication between intrinsic enteric neurons and ILC2s inhibits host defense against helminth infection

Bi-directional communication between intrinsic enteric neurons and ILC2s inhibits host defense against helminth infection

  • Immunity. 2025 Feb 11;58(2):465-480.e8. doi: 10.1016/j.immuni.2025.01.004.
Yinsheng Wang 1,  Xiaoyu Zhang 2,  Shaorui Liu 3,  Zhijie Gu 4,  Zijia Sun 3,  Yang Zang 3,  Xiaobao Huang 5,  Yi Wang 6,  Qiang Wang 7,  Qingxia Lin 7,  Ruichao Liu 4,  Suhua Sun 8,  Hongkai Xu 2,  Jiali Wang 4,  Tao Wu 4,  Yan Wang 3,  Yu Li 3,  Hui Li 3,  Zirun Tang 2,  Yifan Qu 2,  Li Wu 4,  Xiaoyu Hu 9,  Xiaohuan Guo 2,  Fang Wang 10,  Lei Zhou 7,  Danyang He 11,  Hai Qi 12,  Heping Xu 13,  Coco Chu 14
Affiliations

Affiliations

  • 1 Fudan University, Shanghai 200433, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China; Laboratory of System Immunology, School of Medicine, Westlake University, Hangzhou 310024, China; Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China.
  • 2 Institute for Immunology, Tsinghua University, Beijing 100084, China; School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China.
  • 3 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China; Laboratory of System Immunology, School of Medicine, Westlake University, Hangzhou 310024, China; Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China.
  • 4 Institute for Immunology, Tsinghua University, Beijing 100084, China; School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.
  • 5 Department of Dermatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
  • 6 Institute for Immunology, Tsinghua University, Beijing 100084, China; School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China.
  • 7 Shanghai Immune Therapy Institute, Shanghai Jiaotong University School of Medicine-Affiliated Renji Hospital, Shanghai 200127, China.
  • 8 Institute for Immunology, Tsinghua University, Beijing 100084, China; School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China; Changping Laboratory, Beijing 102206, China.
  • 9 Institute for Immunology, Tsinghua University, Beijing 100084, China; School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China; The State Key Laboratory of Membrane Biology, Beijing 100084, China.
  • 10 Department of Dermatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510060, China.
  • 11 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China.
  • 12 Institute for Immunology, Tsinghua University, Beijing 100084, China; School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China; Changping Laboratory, Beijing 102206, China; School of Life Sciences, Tsinghua University, Beijing 100084, China; Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing 100084, China; SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China.
  • 13 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China; Laboratory of System Immunology, School of Medicine, Westlake University, Hangzhou 310024, China; Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China. Electronic address: xuheping@westlake.edu.cn.
  • 14 Institute for Immunology, Tsinghua University, Beijing 100084, China; School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China; SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China; State Key Lab of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China. Electronic address: cchu@tsinghua.edu.cn.
PMID: 39889704 DOI: 10.1016/j.immuni.2025.01.004
Abstract

Emerging studies reveal that neurotransmitters and neuropeptides play critical roles in regulating anti-helminth immune responses, hinting at the potential of intrinsic enteric neurons (iENs) in orchestrating intestinal immunity. Whether and how iENs are activated during Infection and the potential neuroimmune interactions involved remain poorly defined. Here, we found that helminth Infection activated a subset of iENs. Single-nucleus RNA Sequencing (snRNA-seq) of iENs revealed alterations in the transcriptional profile of interleukin (IL)-13R+ intrinsic primary afferent neurons (IPANs), including the upregulation of the neuropeptide β-calcitonin gene-related peptide (CGRP). Using genetic mouse models and engineered viral tools, we demonstrated that group 2 innate lymphoid cell (ILC2)-derived IL-13 was required to activate iENs via the IL-13R, leading to iEN production of β-CGRP, which subsequently inhibited ILC2 responses and anti-helminth immunity. Together, these results reveal a previously unrecognized bi-directional neuroimmune crosstalk in the intestine between a subset of iENs and ILC2s, which influences pathogen clearance.

Keywords

AAV-MaCPNS2; ILC2s; group 2 innate lymphoid cells; iENs; intrinsic enteric neurons; neuro-immune crosstalk; single-nucleus RNA sequencing; snRNA-seq.

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