Monocytes and Macrophages in COVID-19

Abstract

COVID-19 is a contagious viral disease caused by SARS-CoV-2 that led to an ongoing pandemic with massive global health and socioeconomic consequences. The disease is characterized primarily, but not exclusively, by respiratory clinical manifestations ranging from mild common cold symptoms, including cough and fever, to severe respiratory distress and multi-organ failure. Macrophages, a heterogeneous group of yolk-sac derived, tissue-resident mononuclear phagocytes of complex ontogeny present in all mammalian organs, play critical roles in developmental, homeostatic and host defense processes with tissue-dependent plasticity. In case of infection, they are responsible for early pathogen recognition, initiation and resolution of inflammation, as well as repair of tissue damage. Monocytes, bone-marrow derived blood-resident phagocytes, are recruited under pathological conditions such as viral infections to the affected tissue to defend the organism against invading pathogens and to aid in efficient resolution of inflammation. Given their pivotal function in host defense and the potential danger posed by their dysregulated hyperinflammation, understanding monocyte and macrophage phenotypes in COVID-19 is key for tackling the disease’s pathological mechanisms. Here, we outline current knowledge on monocytes and macrophages in homeostasis and viral infections and summarize concepts and key findings on their role in COVID-19. While monocytes in the blood of patients with moderate COVID-19 present with an inflammatory, interferon-stimulated gene (ISG)-driven phenotype, cellular dysfunction epitomized by loss of HLA-DR expression and induction of S100 alarmin expression is their dominant feature in severe disease. Pulmonary macrophages in COVID-19 derived from infiltrating inflammatory monocytes are in a hyperactivated state resulting in a detrimental loop of pro-inflammatory cytokine release and recruitment of cytotoxic effector cells thereby exacerbating tissue damage at the site of infection.

Alterations in Circulating Monocytes Predict COVID-19 Severity and Include Chromatin Modifications Still Detectable Six Months after Recovery

“…We first set out to characterize the changes of circulating monocytes at the early phase of acute SARS-CoV-2 infection, and how these monocytes returned to homeostasis after recovery. We confirmed that in comparison to HC, in early acute COVID-19 non-classical monocytes were reduced while classical and intermediate monocytes predominated and showed downregulation of HLA-DR surface expression [ 10 , 12 , 13 , 14 , 15 , 33 , 34 ]. In patients who had overcome the disease 6 months previously, the monocyte distribution resembled more closely that of HC and monocytes showed a high expression of HLA-DR and CD86, which suggested a recovery of antigen presentation and co-stimulation capacity.…”

Heparin-Functionalized Adsorbents Eliminate Central Effectors of Immunothrombosis, including Platelet Factor 4, High-Mobility Group Box 1 Protein and Histones

“…As evident as it may seem, the concept of focusing on the elimination of pathogens from the circulation by using heparin-immobilized adsorbents appears challenging, based on the following considerations: first, a multitude of pathogens can cause blood stream infection, and their affinity for heparin varies over a wide range; second, pathogen loads of typically 1-10 colony-forming units per mL have been reported in sepsis [61], and it is difficult to conceive that a specific elimination of pathogens from whole blood can occur at such low abundance; third, intracellular pathogens would not be amenable for adsorption, while in fact both bacterial and viral pathogens can persist in immune cells [62], and macrophages have been reported to act as vectors of infection that contribute to the dissemination of SARS-CoV-2 [63,64].…”

Activation of Intracellular Complement in Lungs of Patients With Severe COVID-19 Disease Decreases T-Cell Activity in the Lungs

“…These cells are known to form the mononuclear phagocyte (MNP) system, which sense and phagocytose pathogens, mediate leukocyte recruitment, initiate and shape immune responses and regulate inflammation (17). It has been suggested that during COVID-19 these cells release proinflammatory cytokines resulting in erratic infiltration of pro-inflammatory effector cells, which in turn exacerbates tissue damage (17). COVID-19 patients with the severe disease show higher leukocyte and neutrophil counts with lower lymphocyte counts and a high neutrophil-to-lymphocyte ratio, as well as lower percentages of monocytes, eosinophils, and basophils (18).…”

“…In EXP2 we observed increases of dendritic cells, monocytes, and macrophages. These cells are known to form the mononuclear phagocyte (MNP) system, which sense and phagocytose pathogens, mediate leukocyte recruitment, initiate and shape immune responses and regulate inflammation ( 17 ). It has been suggested that during COVID-19 these cells release proinflammatory cytokines resulting in erratic infiltration of pro-inflammatory effector cells, which in turn exacerbates tissue damage ( 17 ).…”