FAM49B, restrained by miR-22, relieved hepatic ischemia/reperfusion injury by inhibiting TRAF6/IKK signaling pathway in a Rac1-dependent manner

Mol Immunol. 2022 Mar:143:135-146. doi: 10.1016/j.molimm.2022.01.015. Epub 2022 Feb 4.

Abstract

Hepatic ischemia/reperfusion (I/R) injury plays a pivotal pathogenic role in trauma, hepatectomy, and liver transplantation. However, the whole mechanism remains undescribed. The objective of this study is to investigate the internal mechanism by which microRNA-22 (miR-22) targets family with sequence similarity 49 member B (FAM49B), thus aggravating hepatic I/R injury. Here, we found that miR-22 was upregulated while FAM49B was reduced in hepatic I/R injury. Inhibition of miR-22 in vitro was able to intensify expression of FAM49B, thus reducing phosphorylation of inhibitors of nuclear factor kappa-B kinase (IKK) and downstream pro-inflammatory proteins. A dual luciferase reporter assay indicated that miR-22 directly targeted FAM49B. Remission of hepatic pathologic alterations, apoptosis, and release of cytokines derived from constraints of miR-22 were abolished in vivo by repressing FAM49B. Further interference of Ras-related C3 botulinum toxin substrate 1 (Rac1) reversed the function of FAM49B inhibition, thus achieving anti-inflammatory consequences.

Keywords: FAM49B; IKK; Inflammation; Ischemia/reperfusion injury; MiR-22.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation
  • I-kappa B Kinase* / antagonists & inhibitors
  • I-kappa B Kinase* / metabolism
  • Inflammation / genetics
  • Inflammation / pathology
  • Intracellular Signaling Peptides and Proteins* / metabolism
  • Liver* / blood supply
  • Liver* / metabolism
  • Liver* / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Pyrazoles / pharmacology
  • RAW 264.7 Cells
  • Reperfusion Injury* / genetics
  • Signal Transduction
  • TNF Receptor-Associated Factor 6* / metabolism
  • rac1 GTP-Binding Protein* / antagonists & inhibitors
  • rac1 GTP-Binding Protein* / metabolism

Substances

  • 4-(3'-(2'-chlorophenyl)-2'-propen-1'-ylidene)-1-phenyl-3,5-pyrazolidinedione
  • I-kappa B Kinase
  • Intracellular Signaling Peptides and Proteins
  • MicroRNAs
  • Mirn22 microRNA, mouse
  • Pyrazoles
  • rac1 GTP-Binding Protein
  • TNF Receptor-Associated Factor 6
  • CYRIB protein, mouse