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

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.