Overreactive macrophages in SARS-CoV-2 infection: The effects of ACEI

Among various factors influencing the course of SARS-CoV-2 infection in humans, macrophage overactivation is considered the main cause of the cytokine storm that leads to severe complications of COVID-19. Moreover, the increased expression of angiotensin converting enzyme 2 (ACE2), an obligatory entry receptor of the coronavirus, caused by treatment with ACE inhibitors (ACEI) lowered overall confidence in the safety of these drugs. However, analysis of the course of coronavirus infection in patients treated with ACEI does not support these concerns. Instead, the beneficial effect of ACEI on macrophages has increasingly been emphasized. This includes their anti-inflammatory activation and the consequent reduction in the risk of severe disease and life-threatening complications. Herein, we summarize the current knowledge and understanding of the dual role of macrophages in SARS-CoV-2 infection, with a special focus on the postulated mechanisms underlying the beneficial effects of macrophage targeting by ACEI. These seem to involve the stimulation of macrophage angiotensin II type 2 and Mas receptors by angiotensin 1-7, intensively produced due to the up-regulation of ACE2 expression on macrophages, as well as the direct inhibition of macrophage hyper-responsiveness by ACEI. The impact of ACEI on macrophages may also lead to the activation of an effective antiviral response due to the increased expression of ACE2.