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IRS-2 deficiency in macrophages promotes their accumulation in the vascular wall

Tomoya Mita1, Kosuke Azuma, Hiromasa Goto

  • 1Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.

Biochemical and Biophysical Research Communications
|November 15, 2011
PubMed

Insights

Insulin resistance in macrophages, specifically defects in insulin receptor substrate-2 (IRS-2), promotes macrophage accumulation in blood vessels. This finding suggests a link between impaired insulin signaling in macrophages and the early stages of atherosclerosis.

Area of Science:

  • Immunology
  • Endocrinology
  • Vascular Biology

Background:

  • Macrophage accumulation in the vascular wall is a key event in early atherosclerosis.
  • Insulin receptor substrate-2 (IRS-2) plays a role in insulin signaling pathways.
  • The specific role of IRS-2-mediated signaling in macrophages within the vascular context is not fully understood.

Purpose of the Study:

  • To investigate the role of IRS-2-mediated signaling in macrophages concerning their accumulation in the vascular wall.
  • To determine if IRS-2 deficiency in myeloid cells impacts macrophage behavior and vascular inflammation.

Main Methods:

  • Utilized a mouse model with myeloid cell-restricted IRS-2 deficiency (IRS-2(-/-) bone marrow transplantation).
  • Examined macrophage accumulation and expression of monocyte chemoattractant protein-1 (MCP-1) in the vascular wall.
  • Conducted experiments with cultured peritoneal macrophages to assess IRS-2 signaling pathways in response to insulin and inflammatory stimuli.

Main Results:

  • Mice lacking IRS-2 in myeloid cells exhibited increased accumulation of MCP-1-expressing macrophages in the vascular wall.
  • In cultured macrophages, IRS-2 signaling stimulated by insulin suppressed lipopolysaccharide-induced MCP-1 expression.
  • IRS-2 deficiency in macrophages led to enhanced vascular accumulation and increased expression of proinflammatory mediators.

Conclusions:

  • IRS-2-mediated signaling in macrophages is crucial for regulating their vascular wall accumulation.
  • Insulin resistance in macrophages, characterized by IRS-2 deficiency, promotes vascular inflammation and macrophage infiltration.
  • These findings suggest that macrophage insulin resistance may contribute to the pathogenesis of early atherosclerosis.

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