Endothelial HSPA12B regulates myocardial monocyte infiltration and inflammatory activity after myocardial infarction
Yana Wang1, Min Fan1,2, Linjian Chen1
1Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States.
Insights
Endothelial cell-specific heat shock protein A12B (eHSPA12B) regulates immune cell responses after myocardial infarction (MI). eHSPA12B controls monocyte infiltration and macrophage activation, improving cardiac function post-MI.
Area of Science:
- Cardiovascular Biology
- Immunology
- Cell Biology
Background:
- Cardiac macrophages are crucial for inflammation and tissue repair after myocardial infarction (MI).
- Endothelial cell-specific heat shock protein A12B (eHSPA12B) is a known vascular regulator, but its role in post-MI immune responses is unclear.
Purpose of the Study:
- To investigate the role of eHSPA12B in regulating monocyte infiltration and immune cell activation following MI.
- To elucidate the underlying mechanisms of eHSPA12B-mediated immune modulation in the context of cardiac injury.
Main Methods:
- Utilized endothelial cell-specific Hspa12b knockout (eHspa12b-/-) and wild-type (WT) mice to model MI.
- Assessed cardiac function, monocyte infiltration, and macrophage phenotypes via flow cytometry, ELISA, and Western blotting.
- Investigated the role of endothelial cell-derived exosomes carrying HSPA12B in modulating macrophage polarization and TLR4/MyD88 signaling.
Main Results:
- eHspa12b-/- mice showed impaired cardiac function and increased monocyte infiltration post-MI compared to WT controls.
- HSPA12B secreted by endothelial cells via exosomes promoted a pro-regenerative macrophage phenotype.
- HSPA12B-containing exosomes induced macrophage polarization by promoting TLR4 and MyD88 degradation.
Conclusions:
- Endothelial HSPA12B plays a significant immunomodulatory role in controlling monocyte infiltration and immune activation after MI.
- Targeting eHSPA12B presents a potential therapeutic strategy for improving cardiac repair and function following myocardial infarction.
Introduction:
Cardiac macrophages are essential mediators of inflammation and tissue remodeling following myocardial infarction (MI). Endothelial cell-specific heat shock protein A12B (eHSPA12B) has emerged as a key vascular regulator, but its role in modulating immune cell responses after MI remains unknown. This study investigates whether eHSPA12B regulates monocyte infiltration following MI injury.
Methods:
We used endothelial cell-specific Hspa12b knockout (eHspa12b -/-) and wild-type (WT) mice to assess cardiac function and monocyte infiltration following MI. Cardiac resident macrophages and infiltrating monocytes were examined by flow cytometry 3 days post-MI. Plasma levels of pro-inflammatory cytokines were evaluated by ELISA following MI. To investigate the mechanism by which Hspa12b regulates immune response of macrophages, endothelial cells were transduced with adenovirus expressing HSPA12B followed by hypoxia challenge. In a separate experiment, endothelial cell-derived exosomes were prepared. Macrophages, Raw 264.7 or bone marrow derived macrophages (BMDMs) were incubated with endothelial cell conditioned medium or endothelial cell-derived exosomes. Macrophage phenotypes were examined by immunofluorescence staining, ELISA and qPCR. Protein degradation of toll-like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MyD88) in macrophages was assessed by immunoprecipitation and Western blotting.
Results:
eHspa12b -/- mice exhibited significantly worsened cardiac function and increased infiltration of monocytes compared to WT controls at 3 days post-MI. Conditioned medium from HSPA12B-overexpressing endothelial cells promoted a pro-regenerative macrophage phenotype, characterized by reduced pro-inflammatory and increased anti-inflammatory cytokine production. HSPA12B was secreted via exosomes from endothelial cells, and these exosomes were sufficient to induce macrophage polarization. Mechanistically, uptake of HSPA12B-containing exosomes promotes the degradation of TLR4 and MyD88 in macrophages.
Discussion:
Endothelial HSPA12B plays a novel immunomodulatory role in controlling monocyte infiltration and immune activation following MI.
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