The following is a summary of “Efferocytic Regulator Rab11FIP1 Alleviates Inflammation and Cardiac Remodeling After Myocardial Infarction,” published in the November 2023 issue of Cardiology by Zhuang et al.
Impaired clearance of dead cells by macrophages (defective efferocytosis) fuels heart dysfunction after a myocardial infarction (MI), but the molecular switches controlling this process are a mystery.
Researchers conducted a retrospective study to explore the modulator and its mechanisms governing the sustained clearance and breakdown of phagolysosomal cargo post-MI.
They utilized a macrophage RAB11FIP1 knockout model and employed flow cytometry and PET-CT technologies to assess the functional significance of RAB11FIP1 after MI. A nanoliposome-linked ssDNA aptamer with modified RAB11FIP1 mRNA was designed.
The results showed that, through comparing transcriptomic signatures in scRNA-seq data, RAB11FIP1 emerged as the most sensitively efferocytic gene within phagosome-related signatures. RAB11FIP1 deficiency significantly worsened cardiac function, leading to the accumulation of apoptotic cardiomyocytes and reduced efferocytosis. After MI, the deficiency increased CCR2+ macrophages, neutrophils, and pro-inflammatory mediators IL-1β, TNF-α, and Ccl2. Mechanistically, the RAB11FIP1 defect impaired the recycling of the efferocytic receptor Mertk, further hindering ongoing macrophage efferocytosis. Additionally, scRNA-seq data revealed that the regulon activity of XBP1, a key ER-stress executor, was significantly activated in RAB11FIP1-null hearts, leading to the transcriptional expression of pro-inflammatory mediators after MI. Finally, a nanoliposome-linked ssDNA aptamer was constructed to specifically target macrophages, resulting in a marked increase in efferocytosis and a decline in inflammation and cardiac remodeling after MI in RAB11FIP1-expressing phagocytes.
Investigators concluded that RAB11FIP1 bridges macrophage engulfment, ER stress, and inflammation after a heart attack.
Source: ahajournals.org/doi/10.1161/circ.148.suppl_1.11755
