Macrophage SLC9A1 Links Endocytic Trafficking to Innate Immune Activation in Myocardial Injury

Area of Science:

• Cardiovascular Biology
• Immunology
• Cell Biology

Background:

• Excessive innate immune activation contributes to adverse cardiac remodeling following myocardial infarction (MI).
• The mechanisms by which macrophages detect ischemic danger signals and initiate inflammation are not fully understood.
• Macrophage-mediated inflammatory responses are critical in the progression of heart disease post-MI.

Purpose of the Study:

• To investigate the role of macropinocytosis in post-ischemic inflammation after MI.
• To determine if the Na⁺/H⁺ exchanger SLC9A1 links membrane ion transport to innate immune activation in the injured heart.
• To explore SLC9A1 as a potential therapeutic target for mitigating inflammation in ischemic heart disease.

Main Methods:

• Pharmacologic inhibition of macropinocytosis using 5-(N-ethyl-N-isopropyl)amiloride (EIPA).
• Generation of monocyte- and macrophage-specific Slc9a1 knockout mice.
• Assessment of cardiac function and remodeling post-MI.
• Single-cell RNA sequencing to analyze gene expression in infarct-associated macrophages.
• Investigation of Poly(I:C) uptake and inflammatory signaling pathways.

Main Results:

• Macropinocytosis was significantly activated in macrophages within the injured heart post-MI.
• EIPA treatment improved cardiac function and reduced adverse cardiac remodeling after MI.
• Genetic deletion of Slc9a1 in macrophages mimicked the cardioprotective effects of EIPA.
• Slc9a1 knockout suppressed interferon-stimulated gene programs in macrophages and reduced inflammatory signaling.
• SLC9A1 was found to promote endocytic uptake and enhance endosome-dependent inflammatory responses.

Conclusions:

• Macrophage macropinocytosis acts as a key regulator of innate immune activation subsequent to myocardial infarction.
• SLC9A1 serves as a critical link between membrane ion transport and inflammatory signaling in the injured heart.
• Targeting SLC9A1-dependent membrane trafficking pathways presents a promising therapeutic strategy for managing maladaptive inflammation in ischemic heart disease.