JAK-STAT-dependent regulation of scavenger receptors in LPS-activated murine macrophages

Eur J Pharmacol. 2020 Mar 15:871:172940. doi: 10.1016/j.ejphar.2020.172940. Epub 2020 Jan 20.

Abstract

In atherosclerosis progression, atherosclerotic plaques develop upon accumulated foam cells derived from macrophages that take up modified low-density lipoprotein (LDL). CD36 and CD204 are the principal scavenger receptors responsible for the uptake of modified LDL. Lipopolysaccharide (LPS) exacerbates atherosclerosis by enhancing the expression of scavenger receptors and thus increasing the uptake of modified LDL into macrophages. However, the signaling pathways that mediate LPS and scavenger receptor expression have not been fully elucidated. We used mouse bone marrow-derived macrophages and investigated the effects of LPS in vitro. LPS enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription-1 (STAT-1). Inhibitors of the mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) pathway (U0126 and PD0325901) suppressed the uptake of acetylated-LDL (Ac-LDL) and the expression of CD204 but not CD36 in LPS-activated macrophages. Inhibitors of the Janus tyrosine kinase (JAK)-STAT pathway (ruxolitinib and tofacitinib) suppressed the uptake of Ac-LDL and the expression of both CD36 and CD204 in LPS-activated macrophages. We next injected LPS into the peritoneal cavity of mice and analyzed the effects of LPS. MEK inhibitor U0126 suppressed the uptake of Ac-LDL and the expression of CD204 but not CD36 in LPS-activated macrophages. JAK inhibitor ruxolitinib suppressed the uptake of Ac-LDL and the expression of both CD36 and CD204 in LPS-activated macrophages. These results suggest that scavenger receptors in LPS-activated mouse macrophages are regulated through a JAK-STAT-dependent pathway. Although further evaluation is necessary, JAK-STAT inhibition could be useful in atherosclerosis therapy, at least for atherosclerosis exacerbated by LPS.

Keywords: Atherosclerosis; Janus tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT) pathway; Lipopolysaccharide (LPS); Macrophages; Scavenger receptors.

MeSH terms

  • Animals
  • CD36 Antigens / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation / drug effects
  • Janus Kinases / metabolism*
  • Lipopolysaccharides / pharmacology*
  • Macrophage Activation / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation / drug effects
  • Receptors, Scavenger / metabolism*
  • STAT Transcription Factors / metabolism*
  • Scavenger Receptors, Class A / metabolism

Substances

  • CD36 Antigens
  • Lipopolysaccharides
  • Msr1 protein, mouse
  • Receptors, Scavenger
  • STAT Transcription Factors
  • Scavenger Receptors, Class A
  • Janus Kinases
  • Extracellular Signal-Regulated MAP Kinases