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 (M¿) 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 M¿ polarization in
T2D hearts. Finally, we have made a novel finding that extracellular membrane vesicles (EVs) released by probiotic
bacteria can promote M¿ 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 M¿ efferocytosis during
acute cardiac I/R? 2) can elevation of Lcn10 in M¿s and/or administration of recombinant Lcn10 protein (rLcn10)
drive M¿s 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 M¿ function or phenotype for repairing I/R or T2D hearts?
The proposed work represents a paradigm shift in M¿ biology by defining the roles of three novel modulators
(Sectm1a, Lcn10, and bacterial EVs) in the regulation of M¿ function and polarization. We will utilize multiple genetic
mouse models (M¿-specific transgenic, global knockout, and intercross models) and an adoptive M¿ 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 M¿
research forward, and offer new therapeutic options for reducing sterile inflammation-caused heart injury, with the
hope of improving heart failure patient survival.