TY - JOUR
T1 - Glucose metabolism controls disease-specific signatures of macrophage effector functions
AU - Watanabe, Ryu
AU - Hilhorst, Marc
AU - Zhang, Hui
AU - Zeisbrich, Markus
AU - Berry, Gerald J.
AU - Wallis, Barbara B.
AU - Harrison, David G.
AU - Giacomini, John C.
AU - Goronzy, Jörg J.
AU - Weyand, Cornelia M.
PY - 2018/10/18
Y1 - 2018/10/18
N2 - 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.
AB - 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.
KW - Cardiovascular disease
KW - Glucose metabolism
KW - Metabolism
KW - Monocytes
KW - Vascular Biology
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U2 - 10.1172/jci.insight.123047
DO - 10.1172/jci.insight.123047
M3 - Article
C2 - 30333306
AN - SCOPUS:85058848979
SN - 2379-3708
VL - 3
JO - JCI Insight
JF - JCI Insight
IS - 20
ER -