Glucose metabolism controls disease-specific signatures of macrophage effector functions

JCI Insight. 2018 Oct 18;3(20):e123047. doi: 10.1172/jci.insight.123047.

Abstract

Background: In inflammatory blood vessel diseases, macrophages represent a key component of the vascular infiltrates and are responsible for tissue injury and wall remodeling.

Methods: To examine whether inflammatory macrophages in the vessel wall display a single distinctive effector program, we compared functional profiles in patients with either coronary artery disease (CAD) or giant cell arteritis (GCA).

Results: Unexpectedly, monocyte-derived macrophages from the 2 patient cohorts displayed disease-specific signatures and differed fundamentally in metabolic fitness. Macrophages from CAD patients were high producers for T cell chemoattractants (CXCL9, CXCL10), the cytokines IL-1β and IL-6, and the immunoinhibitory ligand PD-L1. In contrast, macrophages from GCA patients upregulated production of T cell chemoattractants (CXCL9, CXCL10) but not IL-1β and IL-6, and were distinctly low for PD-L1 expression. Notably, disease-specific effector profiles were already identifiable in circulating monocytes. The chemokinehicytokinehiPD-L1hi signature in CAD macrophages was sustained by excess uptake and breakdown of glucose, placing metabolic control upstream of inflammatory function.

Conclusions: We conclude that monocytes and macrophages contribute to vascular inflammation in a disease-specific and discernible pattern, have choices to commit to different functional trajectories, are dependent on glucose availability in their immediate microenvironment, and possess memory in their lineage commitment.

Funding: Supported by the NIH (R01 AR042527, R01 HL117913, R01 AI108906, P01 HL129941, R01 AI108891, R01 AG045779 U19 AI057266, R01 AI129191), I01 BX001669, and the Cahill Discovery Fund.

Keywords: Cardiovascular disease; Glucose metabolism; Metabolism; Monocytes; Vascular Biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Arteries / immunology
  • Arteries / pathology
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism
  • Cells, Cultured
  • Cohort Studies
  • Coronary Artery Disease / blood
  • Coronary Artery Disease / immunology*
  • Coronary Artery Disease / pathology
  • Cytokines / immunology
  • Cytokines / metabolism
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation / immunology
  • Giant Cell Arteritis / blood
  • Giant Cell Arteritis / immunology*
  • Giant Cell Arteritis / pathology
  • Glucose / immunology
  • Glucose / metabolism*
  • Glycolysis / immunology
  • Humans
  • Immunologic Memory
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Male
  • Middle Aged
  • Primary Cell Culture

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Cytokines
  • Glucose