Abstract
Efferocytosis is a unique phagocytic process for macrophages to remove apoptotic cells in inflammatory loci. This event is maintained by milk fat globule-EGF factor 8 (MFG-E8), but attenuated by high mobility group box 1 (HMGB1). Alcohol abuse causes injury and inflammation in multiple tissues. It alters efferocytosis, but precise molecular mechanisms for this effect remain largely unknown. Here, we showed that acute exposure of macrophages to alcohol (25 mmol/L) inhibited MFG-E8 gene expression and impaired efferocytosis. The effect was mimicked by hydrogen peroxide. Moreover, N-acetylcysteine (NAC), a potent antioxidant, blocked acute alcohol effect on inhibition of macrophage MFG-E8 gene expression and efferocytosis. In addition, recombinant MFG-E8 rescued the activity of alcohol-treated macrophages in efferocytosis. Together, the data suggest that acute alcohol exposure impairs macrophage efferocytosis via inhibition of MFG-E8 gene expression through a reactive oxygen species dependent mechanism. Alcohol has been found to suppress or exacerbate immune cell activities depending on the length of alcohol exposure. Thus, we further examined the role of chronic alcohol exposure on macrophage efferocytosis. Interestingly, treatment of macrophages with alcohol for seven days in vitro enhanced MFG-E8 gene expression and efferocytosis. However, chronic feeding of mice with alcohol caused increase in HMGB1 levels in serum. Furthermore, HMGB1 diminished efferocytosis by macrophages that were treated chronically with alcohol, suggesting that HMGB1 might attenuate the direct effect of chronic alcohol on macrophage efferocytosis in vivo. Therefore, we speculated that the balance between MFG-E8 and HMGB1 levels determines pathophysiological effects of chronic alcohol exposure on macrophage efferocytosis in vivo.
Highlights
Many cells undergo apoptosis at sites of inflammation
In summary, we examined the effect of alcohol exposure on macrophage efferocytosis and explored the role of milk fat globule-EGF factor 8 (MFG-E8) and high mobility group box 1 (HMGB1) in the regulation of macrophage efferocytosis by alcohol treatment in the present study
We showed that acute and chronic alcohol exposures exhibit opposite effects in vitro on macrophage MFG-E8 gene expression as well as HMGB1 production (Table 1)
Summary
Apoptotic cells are timely removed by phagocytes such as macrophages through a phagocytic process known as efferocytosis [1,2]. Removal of apoptotic cells by phagocytes limits inflammatory responses and accelerates resolution of inflammation. Efferocytosis is a dynamic process which consists of recognition and engulfment of apoptotic cells by phagocytes [6]. Recognition of dying cells is an early step of efferocytosis that is mediated by a group of bridging molecules and efferocytic receptors [7]. It triggers distinctive signal events in phagocytes and induces cytoskeletal rearrangement as well as uptake of apoptotic cells. Rac and RhoA, two small Rho GTPases, have been demonstrated to play opposing roles in regulating engulfment of apoptotic cells: Rac enhances, while RhoA and Rho kinase (ROCK, a downstream effector of RhoA) inhibit the process [6]
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