Cardiac Macrophage Plasticity in Sepsis-induced Cardiomyopathy - Project Summary
Sepsis is a leading cause of death in critical care units. Our long-term research goal is to
understand the mechanisms of sepsis-induced multi-organ failure and to identify
potential new therapeutic opportunities for this devastating clinical condition. Studies
proposed in this application are designed to elucidate novel pathological functions of an
immunometabolism regulator, growth hormone secretagogue receptor (GHS-R), in
sepsis-induced cardiomyopathy using preclinical models.
Recent studies revealed that macrophages localized in the heart are originated from
different sources. With diversified functions ranging from reparative to inflammatory, the
dynamics of changing these macrophage subsets forms a diagram of cardiac
macrophage plasticity. Our ongoing investigation have obtained exciting preliminary
evidence showing that GHS-R is a critical cellular switch that reprograms macrophage
polarization to an inflammatory state. Furthermore, in a newly generated genetic mouse
model, our data showed that ablation of myeloid linage macrophage-specific GHS-R
attenuated systemic inflammation and improved heart function in response to
endotoxemia challenge, which benefits were well associated with responses in
metabolism, mitochondria, and autophagy in the heart. In this exploratory project, we will
use in vitro and in vivo approaches to test the hypothesis that macrophage GHS-R
reprograms cardiac macrophage plasticity and stimulates inflammation during sepsis
(aim 1). We will further address whether macrophage GHS-R stimulates mitochondrial
deficiencies, metabolic perturbations, and maladaptive autophagy in the heart during
sepsis (aim 2). Together, this investigation is expected not only to advance the
fundamental understanding of sepsis pathology but also to evaluate whether targeting
GHS-R signal improves cardiac outcomes in sepsis, laying a scientific foundation for
future development of novel therapies.
