Neurons protect against fibrosis

Abstract

Nociceptors in the lung limit inflammation during infection and in models of asthma, but whether they are involved in the development of pulmonary fibrosis is unclear. In Immunity, Hiroki et al. show that TRPV1⁺ nociceptors control inflammation and are protective in a bleomycin-induced mouse model of lung fibrosis. Depletion of TRPV1⁺ sensory neurons before bleomycin-induced lung fibrosis resulted in reduced survival, increased levels of fibrosis and increased production of TGFβ and vasoactive intestinal peptide (VIP). By contrast, survival of the nociceptor-depleted mice improved if alveolar macrophages were unable to produce VIP. Nociceptor depletion led to an increase in Siglec-F⁺ neutrophils, which was dependent on VIP and TGFβ. In the lung, increased levels of VIP induced TGFβ production. In nociceptor-depleted mice with PF, there was an increase in soluble neutrophil extracellular traps (NETs) and NET-producing Siglec-F⁺ neutrophils; if mice were treated with a NET blocker survival improved. Blocking either VIP or TGFβ reduced NET formation in the lung. Together, the authors suggest that lung nociceptors regulate inflammation that exacerbates pulmonary fibrosis; depletion of nociceptors increased alveolar macrophage production of VIP, which induced TGFβ production and resulted in increased Siglec-F⁺ neutrophils and NET formation.

Original reference: Immunity https://doi.org/10.1016/j.immuni.2025.05.002 (2025)