Immune cell Dilemma in Ischemic Cardiomyopathy: To Heal or Not to Heal

Abstract

Inflammation is a double-edged sword for sterile tissue injury such as in myocardial infarction (MI). After ischemic injury, inflammatory immune responses activate repair processes, clear tissue-debris, form a stable scar and initiate angiogenesis in the myocardium for efficient wound-healing. However, incomplete immune resolution or sustained low-grade inflammation lead to ischemic cardiomyopathy (IC) characterized by maladaptive tissue remodeling and left-ventricular dilatation. It is clear that a delicate balance of cytokines, chemokines, prostaglandins, resolvins, and the innate and adaptive immune systems is critical for adequate healing as both insufficient- or overt-activation of inflammatory responses can either enhance rupture incidence or exacerbate cardiac dysfunction in the long-term. Among all the players, immune cells are the most critical as they are not only a source for all of the inflammatory protein mediators, but are also a target. However, phenotypic complexities associated with different immune subtypes, their interdependence, phasic-activations and varied functionalities often make it difficult to segregate the effects of one immune cell from another. In this review, we briefly summarize the role of several innate and adaptive immune cells to acquaint readers with complex immune-networks that dictate the extent of wound-healing post-MI and maladaptive remodeling during IC.

Keywords: Heart Failure; Immune Cells; Inflammation; Ischemic Cardiomyopathy; Myocardial Infarction.

Figure 1:

Schematic showing several key players of the innate and adaptive immune system known to play an important role in wound-healing post-myocardial infarction (MI), and mediating left-ventricular remodeling during ischemic cardiomyopathy (IC) in preclinical studies. Both innate and adaptive immune cells function in an interdependent complex network where one cell-type regulates and influences the behavior of others to achieve an overall goal of wound-healing, scar formation and ultimately immune resolution post-MI. However, the same network of immune cells responds differently to sustained low-grade inflammation and undergo a phenotypic change to mediate maladaptive tissue-remodeling during IC. If one player is more pathological/critical than the others is not known. Some of the components were designed using ‘Biorender’.

Figure 2:

Different phases of immune activation post-MI are temporally regulated to induce intense pro-inflammation from 0-72 h post-injury to clear the damaged cells followed by scar-formation and somewhat immune-resolution from 4-14 days. While the first phase is predominated by the phagocytic and pro-inflammatory cells, 2^nd phase is dictated by anti-inflammatory and pro-fibrotic cells. Phase-1 specific chemokines are CXCR2/KC, CXCR4/SDF1α, CCR1/MIP1α, CCR2/MCP1, CXCL1, CXCL12, CXCL13, and CXCL9 whereas cytokines are TNFα, IFNγ, IL-6, and IL-1β. In contrast, phase-II specific chemokines are CCR2/MCP1, CXCR2/CXCR4/MIF, CCR1/MIP1α, CCR5/RANTES, CX3CR1/Fractalkine, CXCL2, CXCL5, CXCL8, and CXCL12, and cytokines are IL-10, TGFβ, CTGF, IL-4, IL-13, IL-6 and eotaxin. Ischemic cardiomyopathy (IC) is associated with low-grade inflammation that over a period of months to years (post-MI) lead to extensive extracellular matrix remodeling, inhibit angiogenesis, and promote LV-remodeling. Both pro- and anti-inflammatory immune responses have been found to be active during this phase suggesting disparate local networks of functionally-similar immune cells. This phase is also associated with several chemokines (CX3CR1/Fractalkine, CXCR4/SDF1α, CCR2/MCP1, CXCL1, CXCL2, CXCL5, and CXCL8) and cytokines (TNFα, IFNγ, TGFβ, IL-10, IL-12, IL-6, and eotaxin). Some of the components were designed using ‘Biorender’.