Inhibition of TREM-1 alleviates neuroinflammation by modulating microglial polarization via SYK/p38MAPK signaling pathway after traumatic brain injury

Brain Res. 2024 Jul 1:1834:148907. doi: 10.1016/j.brainres.2024.148907. Epub 2024 Apr 1.

Abstract

Background: Traumatic brain injury (TBI), as a major public health problem, is characterized by high incidence rate, disability rate, and mortality rate. Neuroinflammation plays a crucial role in the pathogenesis of TBI. Triggering receptor expressed on myeloid cells-1 (TREM-1) is recognized as an amplifier of the inflammation in diseases of the central nervous system (CNS). However, the function of TREM-1 remains unclear post-TBI. This study aimed to investigate the function of TREM-1 in neuroinflammation induced by TBI.

Methods: Brain water content (BWC), modified neurological severity score (mNSS), and Morris Water Maze (MWM) were measured to evaluate the effect of TREM-1 inhibition on nervous system function and outcome after TBI. TREM-1 expression in vivo was evaluated by Western blotting. The cellular localization of TREM-1 in the damaged region was observed via immunofluorescence staining. We also conducted Western blotting to examine expression of SYK, p-SYK and other downstream proteins.

Results: We found that inhibition of TREM-1 reduced brain edema, decreased mNSS and improved neurobehavioral outcomes after TBI. It was further determined that TREM-1 was expressed on microglia and modulated subtype transition of microglia. Inhibition of TREM-1 alleviated neuroinflammation, which was associated with SYK/p38MAPK signaling pathway.

Conclusions: These findings suggest that TREM-1 can be a potential clinical therapeutic target for alleviating neuroinflammation after TBI.

Keywords: Microglia; Neuroinflammation; TREM-1; Traumatic brain injury (TBI); p38MAPK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Edema / drug therapy
  • Brain Edema / metabolism
  • Brain Injuries, Traumatic* / drug therapy
  • Brain Injuries, Traumatic* / metabolism
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microglia* / drug effects
  • Microglia* / metabolism
  • Neuroinflammatory Diseases* / drug therapy
  • Neuroinflammatory Diseases* / metabolism
  • Signal Transduction / drug effects
  • Syk Kinase* / antagonists & inhibitors
  • Syk Kinase* / metabolism
  • Triggering Receptor Expressed on Myeloid Cells-1* / antagonists & inhibitors
  • Triggering Receptor Expressed on Myeloid Cells-1* / metabolism
  • p38 Mitogen-Activated Protein Kinases* / metabolism

Substances

  • Triggering Receptor Expressed on Myeloid Cells-1
  • Syk Kinase
  • p38 Mitogen-Activated Protein Kinases
  • TREM1 protein, mouse
  • Syk protein, mouse