SEMA3B inhibits TGFβ-induced extracellular matrix protein production and its reduced levels are associated with a decline in lung function in IPF

Am J Physiol Cell Physiol. 2024 Jun 1;326(6):C1659-C1668. doi: 10.1152/ajpcell.00681.2023. Epub 2024 Apr 22.

Abstract

Idiopathic pulmonary fibrosis (IPF) is marked by the activation of fibroblasts, leading to excessive production and deposition of extracellular matrix (ECM) within the lung parenchyma. Despite the pivotal role of ECM overexpression in IPF, potential negative regulators of ECM production in fibroblasts have yet to be identified. Semaphorin class 3B (SEMA3B), a secreted protein highly expressed in lung tissues, has established roles in axonal guidance and tumor suppression. However, the role of SEMA3B in ECM production by fibroblasts in the pathogenesis of IPF remains unexplored. Here, we show the downregulation of SEMA3B and its cognate binding receptor, neuropilin 1 (NRP1), in IPF lungs compared with healthy controls. Notably, the reduced expression of SEMA3B and NRP1 is associated with a decline in lung function in IPF. The downregulation of SEMA3B and NRP1 transcripts was validated in the lung tissues of patients with IPF, and two alternative mouse models of pulmonary fibrosis. In addition, we show that transforming growth factor-β (TGFβ) functions as a negative regulator of SEMA3B and NRP1 expression in lung fibroblasts. Furthermore, we demonstrate the antifibrotic effects of SEMA3B against TGFβ-induced ECM production in IPF lung fibroblasts. Overall, our findings uncovered a novel role of SEMA3B in the pathogenesis of pulmonary fibrosis and provided novel insights into modulating the SEMA3B-NRP1 axis to attenuate pulmonary fibrosis.NEW & NOTEWORTHY The excessive production and secretion of collagens and other extracellular matrix proteins by fibroblasts lead to the scarring of the lung in severe fibrotic lung diseases. This study unveils an antifibrotic role for semaphorin class 3B (SEMA3B) in the pathogenesis of idiopathic pulmonary fibrosis. SEMA3B functions as an inhibitor of transforming growth factor-β-driven fibroblast activation and reduced levels of SEMA3B and its receptor, neuropilin 1, are associated with decreased lung function in idiopathic pulmonary fibrosis.

Keywords: SEMA3B; TGFβ; extracellular matrix; fibroblasts; pulmonary fibrosis.

MeSH terms

  • Animals
  • Cells, Cultured
  • Extracellular Matrix / metabolism
  • Extracellular Matrix Proteins* / genetics
  • Extracellular Matrix Proteins* / metabolism
  • Female
  • Fibroblasts* / metabolism
  • Humans
  • Idiopathic Pulmonary Fibrosis* / genetics
  • Idiopathic Pulmonary Fibrosis* / metabolism
  • Idiopathic Pulmonary Fibrosis* / pathology
  • Lung* / metabolism
  • Lung* / pathology
  • Male
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Neuropilin-1* / genetics
  • Neuropilin-1* / metabolism
  • Semaphorins* / genetics
  • Semaphorins* / metabolism
  • Transforming Growth Factor beta* / metabolism

Substances

  • Extracellular Matrix Proteins
  • Membrane Glycoproteins
  • Neuropilin-1
  • NRP1 protein, human
  • SEMA3B protein, human
  • Semaphorins
  • Transforming Growth Factor beta
  • Sema3b protein, mouse