Nociceptor neurons suppress alveolar macrophage-induced Siglec-F+ neutrophil-mediated inflammation to protect against pulmonary fibrosis

Carlos H Hiroki; Mortaza F Hassanabad; Manon Defaye; Nicole Sarden; Alexandria Bartlett; Raquel Farias; Angela P Nguyen; Idaira M Guerrero-Fonseca; Grace Yoon; Luke Brown; Caixia Ma; Hyungjun Yang; Darrel Belke; Ali Fatehi Hassanabad; Christopher McCoy; Nicole L Rosin; Dennis J Orton; Paul W M Fedak; Bruce A Vallance; Hongbing Yu; Kevan Jacobson; Nargis Khan; Christophe Altier; Margaret M Kelly; Bryan G Yipp

doi:10.1016/j.immuni.2025.05.002

Nociceptor neurons suppress alveolar macrophage-induced Siglec-F⁺ neutrophil-mediated inflammation to protect against pulmonary fibrosis

Immunity. 2025 May 22:S1074-7613(25)00221-3. doi: 10.1016/j.immuni.2025.05.002. Online ahead of print.

Authors

Carlos H Hiroki¹, Mortaza F Hassanabad¹, Manon Defaye², Nicole Sarden¹, Alexandria Bartlett³, Raquel Farias¹, Angela P Nguyen¹, Idaira M Guerrero-Fonseca¹, Grace Yoon¹, Luke Brown¹, Caixia Ma⁴, Hyungjun Yang⁴, Darrel Belke⁵, Ali Fatehi Hassanabad⁵, Christopher McCoy⁶, Nicole L Rosin⁷, Dennis J Orton⁸, Paul W M Fedak⁵, Bruce A Vallance⁴, Hongbing Yu⁹, Kevan Jacobson⁴, Nargis Khan³, Christophe Altier², Margaret M Kelly¹⁰, Bryan G Yipp¹¹

Affiliations

¹ Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
² Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.
³ Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, AB T2N 4N1, Canada.
⁴ Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The University of British Columbia, Vancouver, BC, Canada.
⁵ Section of Cardiac Surgery, Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada.
⁶ Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
⁷ Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada.
⁸ Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
⁹ Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, KS, USA.
¹⁰ Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
¹¹ Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. Electronic address: bgyipp@ucalgary.ca.

PMID: 40449484
DOI: 10.1016/j.immuni.2025.05.002

Abstract

Pulmonary fibrosis results from persistent and pathological tissue repair, which is therapeutically challenging to attenuate and often fatal. The immune processes involved in fibrosis remain ill defined. Using a bleomycin-induced lung fibrosis murine model, we discovered that vagal TRPV1⁺ nociceptors are protective. Pharmacological ablation or genetic deletion of nociceptors resulted in worsened fibrosis and outcomes. Without nociceptors, alveolar macrophages aberrantly produced vasoactive intestinal peptide (VIP), leading to cytokine TGF-β1-mediated alternative proinflammatory Siglec-F⁺ neutrophil recruitment to the lung with a high propensity for neutrophil extracellular trap (NET) formation. VIP inhibition or Vip deletion in hematopoietic cells improved outcomes and attenuated Siglec-F⁺ neutrophil recruitment to the lungs in nociceptor-deficient mice, while VIP administration had the opposite effect. Thus, nociceptors are essential regulators of inflammation during pulmonary fibrosis. These findings provide mechanistic insights into how the nervous system impacts the progression of fibrotic lung diseases.

Keywords: NETs; TGF; TRPV1; VIP; lung inflammation; macrophages; neurocircuits; neuroinflammation; neuropeptides; neutrophil extracellular traps; neutrophils; nociceptors; pain sensory neurons; pulmonary fibrosis; tissue repair; type 2 immunity.