Acute alcohol exposure impairs macrophage function on clearance of apoptotic cells via inhibition of MFG‐E8 gene expression through a H2O2 dependent mechanism

Abstract

Alcohol is found to inhibit macrophage (MΦ) function on clearance of apoptotic cells. Milk fat globule‐EGF factor 8 (MFG‐E8) is an important molecule for MΦ to identify apoptotic cells. We hypothesized that alcohol impacts MΦ function on clearance of apoptotic cells through alteration of MFG‐E8 levels in MΦ. To this end, we treated mouse MΦ with alcohol (25 mM) for 18 h and processed the cells for determining MFG‐E8 expression, activity of MFG‐E8 gene promoter, and ability of the cells to clearance of apoptotic cells. We found that acute alcohol exposure resulted in repression of MΦ activity on clearance of apoptotic cells. This effect was associated with down‐regulation of MFG‐E8 gene expression as well as reduction of its promoter activity. Recombinant MFG‐E8 (10 nM) rescued alcohol‐treated MΦ from clearance of apoptotic cells, suggesting that down‐regulation of MFG‐E8 contributes to alcohol effect on impairment of MΦ functions on clearance of apoptotic cells. In addition, we revealed that H2O2 mimics alcohol effect on MFG‐E8 gene expression and phagocytosis of apoptotic cells. Antioxidant NAC (10mM) attenuated the alcohol action. Collectively, our data suggest that acute alcohol exposure impairs macrophage function on clearance of apoptotic cells via inhibition of MFG‐E8 gene expression through a H2O2 dependent mechanism. This effect may play an important role in pathogenesis of alcohol‐induced tissue injury. (Supported by NIH R21AA020494 & R01DK064240).