Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1
The Journal of Clinical Investigation
|June 16, 2015
Summary
Macrophages engulfing apoptotic cells rapidly increase expression of cholesterol transporter ABCA1 via a pathway involving BAI1, ELMO1, and Rac1, independent of LXR signaling. This process impacts cardiovascular health.
Area of Science:
- Cell Biology
- Immunology
- Cardiovascular Research
Background:
- Macrophages clear millions of apoptotic cells daily, accumulating significant cholesterol.
- The ATP-binding cassette transporter A1 (ABCA1) is crucial for cholesterol efflux from macrophages and cardiovascular disease protection.
- The link between apoptotic cell clearance and macrophage ABCA1 expression remains unclear.
Purpose of the Study:
- To elucidate the signaling pathway linking apoptotic cell clearance to macrophage ABCA1 expression.
- To investigate the role of brain-specific angiogenesis inhibitor 1 (BAI1) in this process.
- To determine if this pathway is independent of liver X receptor (LXR) signaling.
Main Methods:
- Identification of a plasma membrane-initiated signaling pathway.
- Utilizing primary macrophages from wild-type and knockout mice (lacking BAI1, ELMO1, or Rac1).
- Assessing ABCA1 mRNA and protein levels following apoptotic cell engulfment.
- Examining high-fat diet-induced effects in BAI1-deficient mice.
- Analyzing macrophages from transgenic mice with overexpressed BAI1.
Main Results:
- A novel pathway was identified where apoptotic cell clearance rapidly upregulates ABCA1 mRNA and protein.
- This pathway involves the phagocytic receptor BAI1, and intracellular intermediates ELMO1 and Rac1.
- ABCA1 induction occurred independently of the LXR sterol-sensing pathway.
- BAI1 deficiency in mice on a high-fat diet led to increased apoptotic cells in aortic roots and altered lipid profiles.
- Macrophages with transgenic BAI1 overexpression exhibited enhanced ABCA1 induction upon apoptotic cell exposure.
Conclusions:
- Apoptotic cell engulfment triggers a membrane-initiated signaling pathway that enhances ABCA1 expression in macrophages.
- This pathway, involving BAI1, ELMO1, and Rac1, is critical for regulating cholesterol efflux during phagocytosis.
- The findings reveal a novel mechanism with functional consequences for cardiovascular health.
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