TREM-1-targeting LP17 attenuates cerebral ischemia-induced neuronal injury by inhibiting oxidative stress and pyroptosis

Biochem Biophys Res Commun. 2020 Aug 27;529(3):554-561. doi: 10.1016/j.bbrc.2020.05.056. Epub 2020 Jul 15.

Abstract

Stroke ranks as the second leading cause of disability and death globally. Trigger receptors expressed on myeloid cells (TREM) -1 are responsible for the activation of the innate immune response and also play a critical role in inflammation. In this study, we reported the contribution of TREM-1 after ischemic damage in a rat middle cerebral artery occlusion (MCAO) model. This study also demonstrated that TREM-1 expression was upregulated following cerebral infarction in rats. TREM-1 inhibition was determined using its selective inhibitor, LP17, which indicated a neuroprotective effect on cerebral infarction damage. The findings revealed that inhibition of TREM-1 by administering LP17 improved cerebral damage and decreased ischemic areas and brain water contents. Moreover, LP17 decreased MCAO-induced microglial activation and neurodegeneration, evidenced by a reduction in the expression of microglial Iba-1 and FJ-B positive cells, and reversed neuronal loss. Besides, the contribution of LP17 to ischemic neuronal damage may be associated with a decrease in the production of pro-inflammatory cytokines, and enhanced production of anti-inflammatory cytokine IL-10. Both in vivo and in vitro studies showed that inhibiting TREM-1 attenuated ROS accumulation, lipid per-oxidation (LPO) contents such as malondialdehyde (MDA) and enhanced the superoxide dismutase (SOD) activity after ischemia. Inhibiting TREM-1 alleviated inflammation and pyroptosis found in MCAO rats. This was achieved through the inhibition of the levels of NLRP3, caspase-1, ASC (an apoptosis-associated speck-like protein containing a CARD) and gasdermin D. These results confirmed that inhibiting TREM-1 protects against ischemia-induced neuronal damage and alleviates microglial mediated neuro-inflammation by reducing oxidative stress and pyroptosis. Therefore, blocking TREM-1 expression provides an effective intervention for improving ischemic stroke.

Keywords: Ischemic stroke; LP17; Oxidative stress; Pyroptosis; TREM-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Ischemia / complications*
  • Cell Line
  • Cerebral Infarction / etiology
  • Cerebral Infarction / metabolism
  • Cerebral Infarction / prevention & control
  • Cytokines / metabolism
  • Infarction, Middle Cerebral Artery / complications*
  • Malondialdehyde / metabolism
  • Mice
  • Microglia / metabolism
  • Neurodegenerative Diseases / etiology
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / prevention & control*
  • Neuroprotective Agents / pharmacology*
  • Oxidative Stress / drug effects*
  • Pyroptosis / drug effects
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Stroke / etiology
  • Stroke / metabolism
  • Stroke / prevention & control
  • Triggering Receptor Expressed on Myeloid Cells-1 / antagonists & inhibitors*
  • Triggering Receptor Expressed on Myeloid Cells-1 / genetics
  • Triggering Receptor Expressed on Myeloid Cells-1 / metabolism

Substances

  • Cytokines
  • Neuroprotective Agents
  • Reactive Oxygen Species
  • Triggering Receptor Expressed on Myeloid Cells-1
  • Malondialdehyde