Harnessing the early post-injury inflammatory responses for cardiac regeneration

Abstract

Cardiac inflammation is considered by many as the main driving force in prolonging the pathological condition in the heart after myocardial infarction. Immediately after cardiac ischemic injury, neutrophils are the first innate immune cells recruited to the ischemic myocardium within the first 24 h. Once they have infiltrated the injured myocardium, neutrophils would then secret proteases that promote cardiac remodeling and chemokines that enhance the recruitment of monocytes from the spleen, in which the recruitment peaks at 72 h after myocardial infarction. Monocytes would transdifferentiate into macrophages after transmigrating into the infarct area. Both neutrophils and monocytes-derived macrophages are known to release proteases and cytokines that are detrimental to the surviving cardiomyocytes. Paradoxically, these inflammatory cells also play critical roles in repairing the injured myocardium. Depletion of either neutrophils or monocytes do not improve overall cardiac function after myocardial infarction. Instead, the left ventricular function is further impaired and cardiac fibrosis persists. Moreover, the inflammatory microenvironment created by the infiltrated neutrophils and monocytes-derived macrophages is essential for the recruitment of cardiac progenitor cells. Recent studies also suggest that treatment with anti-inflammatory drugs may cause cardiac dysfunction after injury. Indeed, clinical studies have shown that traditional ant-inflammatory strategies are ineffective to improve cardiac function after infarction. Thus, the focus should be on how to harness these inflammatory events to either improve the efficacy of the delivered drugs or to favor the recruitment of cardiac progenitor cells.

Keywords: Heart regeneration; Inflammation; Macrophage.

Fig. 1

Platelet-like proteoliposomes enhance the targeting specificity for infarcted heart through biomimicking platelet interactions with circulating monocytes. (1) Platelets adhere to the surface of recruited monocytes during the development of MI. (2) Accordingly, platelet-monocyte aggregates will undergo extravasation. (3) It is hypothesized that platelet-like proteoliposomes (PLPs) will interact with monocytes in a similar way to platelets. (4) Once crossing the endothelium, the PLPs are expected to be phagocytized by monocyte-derived macrophages

Fig. 2

Effects of prostaglandin E₂ on macrophages, cardiomyocytes and cardiac progenitor cells after myocardial infarction. Ly6C^high monocytes undergo maturation to generate M1 macrophages during the phase 1 of inflammation in the infarct area and perform phagocytosis to clean cell debris and produce pro-inflammatory cytokines TNFα, IL1β, IL6 and IL10. Maturation of M1 macrophages is inhibited by PGE₂ via the EP2/cAMP/PKA pathway. Ly6C^low monocytes undergo M2 macrophage polarization during the phase 2 of inflammation which is promoted by PGE₂ through the EP(2/4)/cAMP/CREB/CRTC(2/3)/KLF4 pathway