Melatonin suppresses TLR4-mediated RSV infection in the central nervous cells by inhibiting NLRP3 inflammasome formation and autophagy

J Cell Mol Med. 2024 May;28(9):e18338. doi: 10.1111/jcmm.18338.

Abstract

Respiratory syncytial virus (RSV) infects neuronal cells in the central nervous system (CNS), resulting in neurological symptoms. In the present study, we intended to explore the mechanism of RSV infection-induced neuroinflammatory injury from the perspective of the immune response and sought to identify effective protective measures against the injury. The findings showed that toll-like receptor 4 (TLR4) was activated after RSV infection in human neuronal SY5Y cells. Furthermore, TLR4 activation induced autophagy and apoptosis in neuronal cells, promoted the formation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, and increased the secretion of downstream inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-18 (IL-18) and tumour necrosis factor-α (TNF-α). Interestingly, blockade of TLR4 or treatment with exogenous melatonin significantly suppressed TLR4 activation as well as TLR4-mediated apoptosis, autophagy and immune responses. Therefore, we infer that melatonin may act on the TLR4 to ameliorate RSV-induced neuronal injury, which provides a new therapeutic target for RSV infection.

Keywords: SH‐SY5Y cells; TLR4; autophagy; inflammasome; melatonin; respiratory syncytial virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis* / drug effects
  • Autophagy* / drug effects
  • Cell Line, Tumor
  • Central Nervous System / drug effects
  • Central Nervous System / metabolism
  • Central Nervous System / pathology
  • Central Nervous System / virology
  • Cytokines / metabolism
  • Humans
  • Inflammasomes* / drug effects
  • Inflammasomes* / metabolism
  • Melatonin* / pharmacology
  • NLR Family, Pyrin Domain-Containing 3 Protein* / drug effects
  • NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / virology
  • Respiratory Syncytial Virus Infections* / drug therapy
  • Respiratory Syncytial Virus Infections* / immunology
  • Respiratory Syncytial Virus Infections* / metabolism
  • Respiratory Syncytial Virus Infections* / pathology
  • Respiratory Syncytial Virus Infections* / virology
  • Respiratory Syncytial Viruses / drug effects
  • Respiratory Syncytial Viruses / physiology
  • Toll-Like Receptor 4* / drug effects
  • Toll-Like Receptor 4* / metabolism

Substances

  • Cytokines
  • Inflammasomes
  • Melatonin
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 4