Contribution of monocytes and macrophages to the local tissue inflammation & cytokine storm in COVID-19.

The COVID -19 -, SARS - and MERS -related coronaviruses share many genomic and structural similarities. However, the SARS -CoV -2 is less pathogenic than SARS -CoV and MERS -CoV. Despite some differences in the cytokine patterns, it seems that the cytokine storm plays a crucial role in the pathogenesis of COVID - 19 -, SARS - and MERS. Monocytes and macrophages may be infected by SARS - CoV -2 through ACE2 -dependent and ACE2 -independent pathways. SARS -CoV -2 can effectively suppress the anti -viral IFN response in monocytes and macrophages. Since macrophages and dendritic cells (DCs ) act as antigen presenting cells (APCs ), the infection of these cells by SARS -CoV -2 impair s the adaptive immune responses against the virus. Upon infection, monocytes migrate to the tissue s where they become infected resident macrophages, allowing viruses to spread through all organs and tissues. The SARS -CoV - 2 -infected monocytes and macrophages can produce large amounts of numerous types of pro - inflammatory cytokines and chemokines, which contribute to local tissue inflammation and a dangerous systemic inflammatory response called cytokine storm. Both local tissue inflammation and the cytokine storm play a fundamental role in the development COVID -19 -related complications, such as acute respiratory distress syndrome (ARDS), which is a main cause of death in COVID - 19 patients. Here, we describe the monocytes and macrophage responses during Journal Pre-proof Journal Pre-proof - 3 - Jafarzadeh A. et al. severe coronavirus infections, while highlighting potential therapeutic interventions to attenuate macrophage -related inflammatory reactions in possible approaches for COVID -19 treatment.

In mucosal respiratory infections, alveolar macrophages serve as the first anti -viral defense through production type I IFNs. Monocytes/macrophages are the principal leukocytes attracted to the alveolar space in the initial response to respiratory viral infection. Monocytes and macrophages may be directly infected by SARS -CoV -2 through ACE2 -dependent process or indirectly infected via ACE2 -independent pathways using L -SIGN, DC -SIGN, CD147, ADE, and phagocytosis of virus - containing apoptotic bodies.

SARS -CoV -2 can effectively suppress the anti -viral IFN response in monocytes and macrophages. As DCs, monocytes, and macrophages can act as APCs, the SARS -CoV -2 infection of these cells impairs the anti -viral adaptive immune responses. Upon infection, monocytes migrate to tissues where they become infected resident macrophages, allowing viruses to spread through all organs and tissues. Both infected - and uninfected macrophages can be found in the lungs of patients with COVID -19. Monocytes and macrophages can communicate with other cell types via direct cell -cell contacts, leading to the virus dissemination. The SARS -CoV - 2 -infected monocytes and macrophages can produce large amounts of numerous types of pro -inflammatory cytokines and chemokines , which contribute to the local tissue inflammation and Journal Pre-proof Journal Pre-proof - 32 - Jafarzadeh A. et al. dangerous systemic inflammatory response as named cytokine storm.

Low expression of ACE2 by monocytes/macrophages of COVID -19 patients may also promote pathological reactions due to pro -inflammatory properties of angiotensin II and dysfunction of the renin -angiotensin system (RAS). Both local tissue inflammation and cytokine storm play a fundamental role in the development of COVID -19 -related complications, such ARDS, which is the main cause of death in SARS -CoV - 2 -infected patients (Figure 3B) . Although the modulation of macrophage activation may be considered as a promising therapeutic approach for COVID -19, a better understanding of macrophage polarization and heterogeneity during COVID -19 is required. Moreover, the patterns of the macrophage polarization may vary during the different stages of the COVID -19 and need to be clarified in future researches. Various types of macrophages can perform a decisive role in the outcome of the COVID -19. Since macrophage polarization is a reversible process, it is necessary to clarify the factors affecting macrophage plasticity during COVID -19 and how to manipulate macrophage plasticity in a favourable direction. Moreover, macrophages from different organs may express different markers. The better understanding of which subsets of monocytes/macrophages drive disease pathology is important for the development of proper therapeutic interventions [103].

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