Novel regulators of macrophage function to repair sterile inflammation-induced heart injury

项目总结

Project Summary The heart is a unique organ from an immunological perspective, as it exhibits extremely low tolerance to damage and inflammation. Growing evidence from basic and clinical research suggests that sterile inflammation, triggered by either acute myocardial ischemia/reperfusion (I/R) or chronic metabolic disorders (i.e., type-2 diabetes), plays a critical role in the development of heart failure, a leading cause of death worldwide. Unfortunately, clinical trials attempting to modulate inflammation in heart failure have been either disappointing or inconsistent and none are yet clinically applicable. This sobering fact reinforces the urgent need to explore new mediators of cardiac inflammation and to better understand their underlying molecular/cellular mechanisms. The studies supported by NIGMS in the principal investigator’s laboratory over the past 5 years have identified several novel mediators and their associated signaling pathways to control immune dysfunction in inflammation-triggered heart injury. First, we discovered that secreted and transmembrane 1a (Sectm1a), a protein highly expressed in immune cells of myeloid lineage, is essential for macrophage (MФ) efferocytosis to clear dead cells from I/R hearts and thereby, restoring cardiac function. Second, using type-2 diabetic (T2D) mice as a chronic low-grade inflammation model, we identified that loss of lipocalin 10 (Lcn10), a poorly characterized member of the lipocalin superfamily, could cause an imbalanced MФ polarization in T2D hearts. Finally, we have made a novel finding that extracellular membrane vesicles (EVs) released by probiotic bacteria can promote MФ efferocytosis, but the underlying mechanism is unclear. Together, these diverse and compelling data provide a strong basis to address three critical knowledge gaps in the study of sterile inflammation-triggered heart injury, which will be examined by three different projects of this MIRA application: 1) what are exact roles and underlying mechanisms of endogenous and exogenous Sectm1a in MФ efferocytosis during acute cardiac I/R? 2) can elevation of Lcn10 in MФs and/or administration of recombinant Lcn10 protein (rLcn10) drive MФs to an anti-inflammatory phenotype for improving cardiac function in T2D mice? and 3) can a probiotic bacterial EV-based nano-drug be developed to modulate MФ function or phenotype for repairing I/R or T2D hearts? The proposed work represents a paradigm shift in MФ biology by defining the roles of three novel modulators (Sectm1a, Lcn10, and bacterial EVs) in the regulation of MФ function and polarization. We will utilize multiple genetic mouse models (MФ-specific transgenic, global knockout, and intercross models) and an adoptive MФ transfer model to determine cardiac outcomes in two sterile inflammation conditions (acute myocardial I/R-induced robust and chronic T2D-triggered low-grade inflammation). These projects, if completed, will significantly push the field of MФ research forward, and offer new therapeutic options for reducing sterile inflammation-caused heart injury, with the hope of improving heart failure patient survival.