Trained Innate Immune Tolerance in the Heart: TLR4’s Role in Stress-Induced Cardiomyopathy

Abstract

Background:The cardiomyopathy caused by stress (SIC) such as Takotsubo syndrome is an acute yet reversible left ventricular dysfunction resulting in acute caused by emotional or physiological stress. There is an increasing amount of evidence that innate pathways influence myocardial susceptibility and recovery in SIC. One of the important pattern-recognition receptors, TLR4 (toll-like receptor), controls the inflammation signaling and can mediate some form of its creation -trained immunity, or -trained tolerance, where an immune response to initial stimuli reprograms innate cells to respond differently to subsequent stress. Nevertheless, the contribution of TLR4-mediated tolerance to cardiomyocyte and cardiac macrophage tolerance to SIC is not well comprehended.

Objective:To explore the purpose of TLR4 in trained innate immune tolerance in the heart and also to understand the functional role of TLR4 in modulating inflammatory response, myocardial infarction, and ventricular function in experimental cardiomyopathy caused by stress.

Methods:Acute catecholamine challenge in Murine models of SIC was used to establish them. Two groups of mice with wild-type and TLR4-deficient (TLR4−/−) received a controlled preconditioning stimulus of low dose to trigger the action of innate immune training prior to high dose exposure to stress. Echocardiography was used to determine cardiac performance. Transcription of inflammatory cytokines, macrophage phenotypes and histopathologic injury of myocardial tissue were examined. TLR4-dependent signaling and epigenetic signals of trained tolerance such as the deposition of H3K27ac and H3K4me1 were assessed using ex vivo cardiomyocyte cultures.

Results:In preconditioning, a tolerant innate immune state was achieved in wild-type mice, which included suppressed NF-KB, less IL-1 0 and TNF -alpha expression, and less myocardial necrosis after the stress. This effect of protection was not present in TLR4−/− mice, which exhibited enhanced levels of inflation and increased ventricular dysfunction. TLR4-dependent cardiac macrophage epigenetic reprogramming with subsequent cardiomyocyte mitochondrial integrity preservation under catecholamine challenge were associated with trained tolerance.

Conclusion:TLR4 is at the forefront in bringing about trained innate immune tolerance within the heart in cardiomyopathy under stress induced conditions. Reprogramming of maladaptive inflammation by TLR4 reduces myocardial injury and stress functional resilience. The present research shows TLR4-mediated innate immune training as a promising therapeutic control of preventing or alleviating SIC.