Abstract 11755: Efferocytic Regulator Rab11FIP1 Alleviates Inflammation and Cardiac Remodeling After Myocardial Infarction

Abstract

Introduction: Defective efferocytosis drives cardiac dysfunction after myocardial infarction (MI); however, the underlying molecular mechanisms and regulators of macrophage efferocytosis remain unknown. Hypothesis: This study aimed to explore the modulator and its mechanisms of the continued clearance and degradation of phagolysosomal cargo during MI. Methods: Leveraging macrophage RAB11FIP1 knockout model, flow cytometry and PET-CT technologies, we examined the functional significance of RAB11FIP1 after MI. Moreover, a nanoliposome-linked ssDNA aptamer contained modified RAB11FIP1 mRNA was designed. Results: By comparing the transcriptomic signatures of our scRNA-seq data, we identified RAB11FIP1 was the most sensitively efferocytic gene among all phagosome-related signatures. RAB11FIP1 deficiency resulted in a considerable exacerbation in cardiac function, the accumulation of apoptotic cardiomyocytes and a reduced efferocytosis. RAB11FIP1-loss also led to increased infiltration of CCR2+ macrophages and neutrophils with upregulation of proinflammatory mediators, IL-1β, TNF-α, Ccl2 after MI. In mechanistic studies, RAB11FIP1 defect disabled the recycling of efferocytic receptor, Mertk, further impaired continued macrophages efferocytosis. Moreover, the scRNA-seq data revealed that the regulon activity of XBP1, which acted as the key ER-stress executor, was significantly activated in RAB11FIP1-null hearts, then, the activated XBP1 governed the transcriptional expression of pro-inflammatory mediators after MI. Finally, we constructed a nanoliposome-linked ssDNA aptamer to specifically target macrophages. RAB11FIP1-expressing phagocytes display a striking increase in efferocytosis and decline in inflammation, cardiac remodeling after MI. Conclusions: Collectively, these findings advance the relationship of RAB11FIP1 between macrophage efferocytosis, ER-stress response and the cardiac inflammation.