Takinib inhibits microglial M1 polarization and oxidative damage after subarachnoid hemorrhage by targeting TAK1-dependent NLRP3 inflammasome signaling pathway

Front Immunol. 2023 Nov 14:14:1266315. doi: 10.3389/fimmu.2023.1266315. eCollection 2023.

Abstract

Transforming growth factor-β-activated kinase 1 (TAK1) positively regulates oxidative stress and inflammation in different diseases. Takinib, a novel and specific TAK1 inhibitor, has beneficial effects in a variety of disorders. However, the effects of takinib on early brain injury (EBI) after subarachnoid hemorrhage (SAH) and the underlying molecular mechanisms remain unknown. Our study showed that takinib administration significantly inhibited phosphorylated TAK1 expression after SAH. In addition, takinib suppressed M1 microglial polarization and promoted M2 microglial polarization. Furthermore, blockade of TAK1 by takinib reduced neuroinflammation, oxidative damage, brain edema, and neuronal apoptosis, and improved neurological behavior after SAH. Mechanistically, we revealed that TAK1 inhibition by takinib mitigated reactive oxygen species (ROS) production and ROS-mediated nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation. In contrast, NLRP3 activation by nigericin abated the neuroprotective effects of takinib against EBI after SAH. In general, our study demonstrated that takinib could protect against EBI by targeting TAK1-ROS-NLRP3 inflammasome signaling. Inhibition of TAK1 might be a promising option in the management of SAH.

Keywords: NLRP3; TAK1; early brain injury; subarachnoid hemorrhage; takinib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Injuries* / metabolism
  • Inflammasomes / metabolism
  • Microglia / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Oxidative Stress
  • Rats
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Subarachnoid Hemorrhage* / drug therapy
  • Subarachnoid Hemorrhage* / metabolism

Substances

  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Reactive Oxygen Species
  • takinib

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from Beijing Friendship Hospital (No. PYZ21061).