Ethanol exposure suppresses microglia pro-inflammatory response induced by SARS-CoV2-spike protein

In the central nervous system (CNS), microglial cells regulate the immune response by mediating neuroinflammation. Alcohol abuse leads to neuroinflammation and neurodegeneration in CNS. In the context of COVID-19, neuroinflammation and glial reactivity are mediated by the infection of human glial cells by SARS-CoV-2, which recognizes the angiotensin-converting enzyme 2 (ACE2) and other proteins, such as transmembrane serine protease 2 (TMPRSS2), through its surface Spike-1 protein. Although several risk factors for COVID-19 progression have been described, it remains unknown how alcohol consumption affects SARS-CoV-2 Spike protein-induced microglial reactivity. In this study, murine microglial cultures (BV-2) were exposed to ethanol alone and subsequently challenged with the Spike protein. Immunofluorescence analysis revealed that ethanol treatment (1%) did not affect the levels of the reactivity-related proteins C3 and CD86 or the phagocytic potential of microglial cells, although it reduced the number of cells exhibiting an amoeboid morphology. However, ethanol treatment prevented the Spike protein-induced increase in C3 levels, amoeboid cell numbers, and phagocytic activity. Furthermore, chronic in vivo exposure to ethanol decreased ACE2 and TMPRSS2 levels in the cerebral cortex of mice, whereas treatment with higher ethanol concentrations in vitro decreased only TMPRSS2 levels. These data suggest that ethanol exposure suppresses the ability of microglia to respond to the pro-inflammatory effects induced by the Spike protein. This impairment may contribute to the loss of microglial function in regulating the immune response and neuroinflammation in the CNS in the context of COVID-19.