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 Gregory; Dan 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 S Kim

doi:10.1016/j.cell.2023.11.027

Sensory neurons promote immune homeostasis in the lung

Cell. 2024 Jan 4;187(1):44-61.e17. doi: 10.1016/j.cell.2023.11.027. Epub 2023 Dec 21.

Authors

Masato Tamari¹, Kate L Del Bel², Aaron M Ver Heul³, Lydia Zamidar⁴, Keisuke Orimo⁵, Masato Hoshi⁶, Anna M Trier⁷, Hiroshi Yano⁸, Ting-Lin Yang⁷, Catherine M Biggs², Kenichiro Motomura⁵, Rintaro Shibuya⁴, Chuyue D Yu⁹, Zili Xie¹⁰, Hisato Iriki⁴, Zhen Wang⁴, Kelsey Auyeung⁴, Gargi Damle¹¹, Deniz Demircioglu¹¹, Jill K Gregory¹², Dan Hasson¹³, Jinye Dai¹⁴, Rui B Chang¹⁵, Hideaki Morita¹⁶, Kenji Matsumoto⁵, Sanjay Jain⁶, Steven Van Dyken¹⁷, Joshua D Milner¹⁸, Dusan Bogunovic¹⁹, Hongzhen Hu¹⁰, David Artis²⁰, Stuart E Turvey², Brian S Kim²¹

Affiliations

¹ Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Jikei University School of Medicine, Minato-ku, Tokyo 1058471, Japan; Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo 1578535, Japan.
² Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
³ Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁴ Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁵ Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo 1578535, Japan.
⁶ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁷ Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁸ Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.
⁹ Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA.
¹⁰ Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹¹ Tisch Cancer Institute Bioinformatics for Next Generation Sequencing (BiNGS) Core, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Skin Biology and Disease Resource-based Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹² Digital and Technology Partners, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹³ Tisch Cancer Institute Bioinformatics for Next Generation Sequencing (BiNGS) Core, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Skin Biology and Disease Resource-based Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹⁴ Department of Pharmacological Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹⁵ Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA; Allen Discovery Center for Neuroimmune Interactions, New York, NY 10029, USA.
¹⁶ Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo 1578535, Japan; Allergy Center, National Center for Child Health and Development, Setagaya-ku, Tokyo 1578535, Japan.
¹⁷ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹⁸ Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
¹⁹ Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute Bioinformatics for Next Generation Sequencing (BiNGS) Core, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
²⁰ Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Allen Discovery Center for Neuroimmune Interactions, New York, NY 10029, USA; Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.
²¹ Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Allen Discovery Center for Neuroimmune Interactions, New York, NY 10029, USA. Electronic address: itchdoctor@mountsinai.org.

PMID: 38134932
PMCID: PMC10811756 (available on 2025-01-04)
DOI: 10.1016/j.cell.2023.11.027

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 (JAK1^GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1^GoF 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.

Keywords: AAV; CGRP; ILC2; JAK1; afferent nerves; allergic lung inflammation; atopic disorders; neuropeptide; sensory neurons; vagus nerve.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cytokines
Dermatitis, Atopic* / immunology
Humans
Immunity, Innate*
Inflammation
Lung* / immunology
Lymphocytes
Mice
Sensory Receptor Cells* / enzymology

Substances

Cytokines
JAK1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding