Deleterious Anti-Inflammatory Macrophage Recruitment in Early Post-Infarction Phase
Alexandre Paccalet, Sally Badawi, Bruno Pillot, Lionel Augeul, Laura Mechtouff, Zeina Harhous, Yves Gouriou, M. Paillard, Marine Breuilly, Camille Amaz, Yvonne Varillon, Simon Leboube, Camille Brun, Cyril Prieur, Gilles Rioufol, Nathan Mewton, Michel Ovize, Gabriel Bidaux, Thomas Bochaton, Claire Crola Da Silva
Abstract
• MCP-1 and IL-6 blood levels peak at 24 hours in STEMI patients and are associated with an increased risk of MACE. • Blood levels of MCP-1 and IL-6 peak at 3 hours in a mouse model of STEMI. The mRNA level of both cytokines was increased in the ischemic heart, suggesting a local production. • Cardiac myocytes produce MCP-1 and IL-6 that play a synergistic role in macrophage recruitment and polarization via STAT3 signaling pathway. • Use of anti–IL-6 and anti–MCP-1 neutralizing antibodies mix or a inhibitor of STAT3 pathway (STATTIC) at the onset of reperfusion reduces infarct size in a mouse model of STEMI. • This study highlights the potential deleterious role of anti-inflammatory macrophages recruitment during the early phase of myocardial infarction. Using a translational approach with an ST-segment myocardial infarction (STEMI) cohort and mouse model of myocardial infarction, we highlighted the role of the secreted IL-6 and MCP-1 cytokines and the STAT3 pathway in heart macrophage recruitment and activation. Cardiac myocytes secrete IL-6 and MCP-1 in response to hypoxic stress, leading to a recruitment and/or polarization of anti-inflammatory macrophages via the STAT3 pathway. In our preclinical model of myocardial infarction, neutralization of IL-6 and MCP-1 or STAT3 pathway reduced infarct size. Together, our data demonstrate that anti-inflammatory macrophages can be deleterious in the acute phase of STEMI.