Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1
Insights
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.
Abstract:
Macrophages clear millions of apoptotic cells daily and, during this process, take up large quantities of cholesterol. The membrane transporter ABCA1 is a key player in cholesterol efflux from macrophages and has been shown via human genetic studies to provide protection against cardiovascular disease. How the apoptotic cell clearance process is linked to macrophage ABCA1 expression is not known. Here, we identified a plasma membrane-initiated signaling pathway that drives a rapid upregulation of ABCA1 mRNA and protein. This pathway involves the phagocytic receptor brain-specific angiogenesis inhibitor 1 (BAI1), which recognizes phosphatidylserine on apoptotic cells, and the intracellular signaling intermediates engulfment cell motility 1 (ELMO1) and Rac1, as ABCA1 induction was attenuated in primary macrophages from mice lacking these molecules. Moreover, this apoptotic cell-initiated pathway functioned independently of the liver X receptor (LXR) sterol-sensing machinery that is known to regulate ABCA1 expression and cholesterol efflux. When placed on a high-fat diet, mice lacking BAI1 had increased numbers of apoptotic cells in their aortic roots, which correlated with altered lipid profiles. In contrast, macrophages from engineered mice with transgenic BAI1 overexpression showed greater ABCA1 induction in response to apoptotic cells compared with those from control animals. Collectively, these data identify a membrane-initiated pathway that is triggered by apoptotic cells to enhance ABCA1 within engulfing phagocytes and with functional consequences in vivo.
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