Brain-derived neurotrophic factor promotes airway smooth muscle cell proliferation in asthma through regulation of transient receptor potential channel-mediated autophagy

Mol Immunol. 2023 Jun:158:22-34. doi: 10.1016/j.molimm.2023.04.004. Epub 2023 Apr 22.

Abstract

Objective: Increased proliferation of airway smooth muscle cells (ASMCs) is a key feature of airway remodeling in asthma. This study aims to determine whether brain-derived neurotrophic factor (BDNF) regulates ASMC proliferation and airway remodeling via the transient receptor potential channels (TRPCs)/autophagy axis.

Methods: Human ASMCs were isolated and passively sensitized with human asthmatic serum. Protein levels of BDNF and its receptor TrkB, TRPC1/3/6, autophagy markers, intracellular Ca2+ concentration ([Ca2+]i), LC3 immunofluorescence, cell proliferation, cell cycle population were examined. Wistar rats were sensitized with OVA to establish asthma models.

Results: In asthmatic serum-sensitized human ASMCs, BDNF overexpression or recombinant BDNF (rhBDNF) increased TrkB/TRPC1/3/6 axis, [Ca2+]i, autophagy level, cell proliferation, cell number in the S+G2/M phase and decreased cell number in the G0/G1 phase, whereas BDNF knockdown exerted the opposite effects. Furthermore, TRPC channel blocker SKF96365 and TRPC1/3/6 knockdown reversed the effects of the rhBDNF-mediated induction of [Ca2+]i, autophagy level, cell proliferation and cell number in the S+G2/M phase. Moreover, the autophagy inhibitor (3-MA) rescued the rhBDNF-mediated induction of cell proliferation and cell number in the S+G2/M phase. Further in vivo assays revealed that BDNF altered the pathology of airway remodeling, promoted the infiltration of inflammatory cells, promoted the proliferation of ASMCs, and upregulated the protein levels of TrkB, TRPC1/3/6, and autophagy markers in asthma model rats.

Conclusion: We conclude that BDNF promotes ASMCs proliferation in asthma through TRPC-mediated autophagy induction.

Keywords: Airway smooth muscle cell; Asthma; Autophagy; Brain-derived neurotrophic factor; Transient receptor potential channels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Airway Remodeling
  • Animals
  • Asthma* / pathology
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cell Proliferation
  • Humans
  • Myocytes, Smooth Muscle / metabolism
  • Rats
  • Rats, Wistar
  • Transient Receptor Potential Channels* / metabolism

Substances

  • Brain-Derived Neurotrophic Factor
  • Transient Receptor Potential Channels
  • BDNF protein, human
  • Bdnf protein, rat