M2 Macrophage‐Derived sEV Regulate Pro‐Inflammatory CCR2⁺ Macrophage Subpopulations to Favor Post‐AMI Cardiac Repair

Abstract

Tissue‐resident cardiac macrophage subsets mediate cardiac tissue inflammation and repair after acute myocardial infarction (AMI). CC chemokine receptor 2 (CCR2)‐expressing macrophages have phenotypical similarities to M1‐polarized macrophages, are pro‐inflammatory, and recruit CCR2+ circulating monocytes to infarcted myocardium. Small extracellular vesicles (sEV) from CCR2̶ macrophages, which phenotypically resemble M2‐polarized macrophages, promote anti‐inflammatory activity and cardiac repair. Here, the authors harvested M2 macrophage‐derived sEV (M2EV) from M2‐polarized bone‐marrow‐derived macrophages for intramyocardial injection and recapitulation of sEV‐mediated anti‐inflammatory activity in ischemic‐reperfusion (I/R) injured hearts. Rats and pigs received sham surgery; I/R without treatment; or I/R with autologous M2EV treatment. M2EV rescued cardiac function and attenuated injury markers, infarct size, and scar size. M2EV inhibited CCR2+ macrophage numbers, reduced monocyte‐derived CCR2+ macrophage recruitment to infarct sites, induced M1‐to‐M2 macrophage switching and promoted neovascularization. Analysis of M2EV microRNA content revealed abundant miR‐181b‐5p, which regulated macrophage glucose uptake, glycolysis, and mitigated mitochondrial reactive oxygen species generation. Functional blockade of miR‐181b‐5p is detrimental to beneficial M2EV actions and resulted in failure to inhibit CCR2+ macrophage numbers and infarct size. Taken together, this investigation showed that M2EV rescued myocardial function, improved myocardial repair, and regulated CCR2+ macrophages via miR‐181b‐5p‐dependent mechanisms, indicating an option for cell‐free therapy for AMI.

Fenofibrate Induces a Resolving Profile in Heart Macrophage Subsets and Attenuates Acute Chagas Myocarditis

“…Concerning this, it has been reported that macrophage polarization to an M2 profile is associated with rescued function and improved heart repair in acute myocardial infarction. 79 In summary, here we show for the first time that in the early stages of experimental Chagas disease, fenofibrate significantly increased the proportion of cardiac MdMΦ and MΦ with a marked restorative profile. These findings were accompanied by switch toward to a noninflammatory microenvironment which correlates with reduced fibrosis and attenuates ventricular function.…”

“…This correlates with the restored cardiac function. Concerning this, it has been reported that macrophage polarization to an M2 profile is associated with rescued function and improved heart repair in acute myocardial infarction …”

CCR2 antagonist attenuates calcium oxalate-induced kidney oxidative stress and inflammation by regulating macrophage activation

“…CCR2-positive (CCR2+) inflammatory monocytes are crucial early response immune cells, and excessive infiltration or accumulation vitiates the remission of inflammation and promotes disease progression [ 15 , 16 ]. CCR2+ monocytes appear pro-inflammatory activity and differentiate into monocyte-derived CCR2+ macrophages with features similar to classically activated macrophages (M1-like macrophages), whereas CCR2-negative (CCR2-) macrophages have phenotypic characteristics similar to alternately activated macrophages (M2-like macrophages) [ 17 ]. CCR2+ monocytes are recruited into the glomerular capillaries and may be precursors of immature macrophages in the nephritic kidney [ 18 ].…”

Melatonin Engineering M2 Macrophage‐Derived Exosomes Mediate Endoplasmic Reticulum Stress and Immune Reprogramming for Periodontitis Therapy

“…Exosomes are naturally occurring nanosized membrane vesicles encased by phospholipid bilayers ranging in size from 30 to 150 nm. [12] As a unique class of natural nanomaterials, exosomes can act as mediators of genetic information, carry and deliver biological signals to neighboring and distant cells, regulate the physiological and pathological state of recipient cells, and participate in the progression of various diseases. [13] The endogenous and heterogeneous nature of exosomes gives them a broad and unique advantage over synthetic carriers such as liposomes and nanoparticles in the diagnosis and treatment of periodontitis.…”