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. 2023 Jun 1;133(11):e167670.
doi: 10.1172/JCI167670.

IL-6 helps weave the inflammatory web during acute coronary syndromes

Tetsushi Nakao  1   2   3   4 , Peter Libby  1
Affiliations

IL-6 helps weave the inflammatory web during acute coronary syndromes

Tetsushi Nakao et al. J Clin Invest. .

Abstract

The cytokine IL-6 has well-known proinflammatory roles in aging and ischemic heart disease. In this issue of the JCI, Alter and colleagues used mouse experiments and human tissue to investigate the source of IL-6 following myocardial infarction. The authors showed that cardiac fibroblasts produced IL-6 after coronary ligation in mice and proposed the existence of a pathway involving adenosine signaling via the adenosine A2b receptor. The findings underscore the complexity of IL-6 biology in ischemic heart disease and identify an adenosine/IL-6 pathway that warrants consideration for targeting as a modulator of cardiovascular risk.

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Conflict of interest statement

Conflict of interest: PL consults or is involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Moderna, Novo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron. PL is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, Soley Therapeutics, and XBiotech Inc. PL receives research funding from Novartis, Novo Nordisk, and Genentech, is on the board of directors of XBiotech, and has a financial interest in XBiotech, TenSixteen Bio, Soley Therapeutics, and iRhythm. PL holds the following patents: “Treatment of brain ischemia-reperfusion injury” (patent no. 5409-0001) and “Use of canakinumab” (patent no. 20200239564).

Figures

Figure 1
Figure 1. IL-6 is a multifaceted mediator of cardiovascular disease.
Hypoxia in the ischemic region during an acute coronary syndrome leads to release of the nucleotide AMP. T cell–produced CD73 hydrolyzes this nucleotide to adenosine, which in turn engages the A2bR, which is predominantly expressed in the ischemic myocardium by cardiac fibroblasts. The cardiac fibroblasts respond by releasing IL-6. IL-1, also activated within the ischemic region, can impinge on cardiomyocytes, endothelial cells, and smooth muscle cells, as well as on resident macrophages, to augment local IL-6 production. IL-6 and IL-1 can mediate fever, a common concomitant of acute coronary syndromes. IL-6 can also stimulate hematopoiesis, contributing to the leukocytosis that can accompany acute coronary syndromes. Additionally, IL-6 can activate leukocytes and adipose tissue to augment local and systemic inflammation. In hepatocytes, IL-6 unleashes the acute-phase response, heightening the production of fibrinogen, the precursor of thrombi, and of plasminogen activator 1 (PAI-1), which inhibits endogenous fibrinolysis. A role for cardiac fibroblasts in producing IL-6 and orchestrating an inflammatory response during acute coronary syndrome extends our understanding of the complex circuits of inflammatory signaling following myocardial ischemic injury.
See this image and copyright information in PMC

Comment on

  • IL-6 in the infarcted heart is preferentially formed by fibroblasts and is modulated by purinergic signaling doi: 10.1172/JCI163799

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