Sensory neurons promote immune homeostasis in the lung

Masato Tamari, Kate L. Del Bel, Aaron M. Ver Heul, Lydia Zamidar, Keisuke Orimo, Masato Hoshi, Anna M. Trier, Hiroshi Yano, Ting Lin Yang, Catherine M. Biggs, Kenichiro Motomura, Rintaro Shibuya, Chuyue D. Yu, Zili Xie, Hisato Iriki, Zhen Wang, Kelsey Auyeung, Gargi Damle, Deniz Demircioglu, Jill K. GregoryDan Hasson, Jinye Dai, Rui B. Chang, Hideaki Morita, Kenji Matsumoto, Sanjay Jain, Steven Van Dyken, Joshua D. Milner, Dusan Bogunovic, Hongzhen Hu, David Artis, Stuart E. Turvey, Brian Kim

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPβ was dependent on JAK1 in the vagus nerve, and CGRPβ suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future.

Original languageEnglish
Pages (from-to)44-61.e17
JournalCell
Volume187
Issue number1
DOIs
StatePublished - Jan 4 2024

Keywords

  • AAV
  • CGRP
  • ILC2
  • JAK1
  • afferent nerves
  • allergic lung inflammation
  • atopic disorders
  • neuropeptide
  • sensory neurons
  • vagus nerve

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