This is a review paper written by a group from University of Bonn, Germany about monocytes and macrophages in COVID-19. Here is my summary of outlines discussed in the review paper.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335157/
Every day, the lung inhales thousands of liters of air containing high amounts of pathogens including viruses, bacteria, and fungi. To prevent infection and its resulting complications for the organism, a tight control by the immune system is needed. In the lung, macrophages are the most abundant immune cell type under homeostatic conditions. Based on their exact location, they can be separated in at least two different populations; the interstitial macrophages (IMs) and alveolar macrophages (AMs). AMs are the first defenders against pathogens entering the respiratory system. They originate from the yolk sac and populate the lung early after birth. AMs have proliferative capacity, thus can persist over the lifespan by self-renewal and are independent of replacement from the bone marrow.
Upon viral infection, AMs are responsible for early pathogen recognition, initiation and resolution of inflammation, as well as repair of tissue damage. AMs produce high levels of cellular mediators, including IL-1β, CCL3, CCL7 and CCL2, also known as monocyte chemotactic protein 1 (MCP1), which rapidly recruits CCR2-expressing bone marrow-derived monocytes into the lung. This is a necessary defense response, since viruses can either reduce the numbers of resident AMs dramatically or impair their phenotype. Furthermore, AMs are the main producers of type I IFN to trigger an antiviral response.
COVID-19 is characterized by a systemic increase of numerous cytokines, including IL-1α, IL-1β, IL-6, IL-7, tumor necrosis factor (TNF), type I and II IFN, and the inflammatory chemokines CCL2, CCL3 and CXCL10. Although the increased systemic cytokine response in COVID-19 is undisputed, the term “cytokine storm” in COVID-19 pathophysiology is a topic of debate, as TNF, IL-6, and IL-8 concentrations in COVID-19 are less strong compared to sepsis, acute respiratory distress syndrome unrelated to COVID-19, trauma, cardiac arrest, and cytokine release syndrome (CRS).
The systemic cytokine profile observed in patients suffering from severe COVID-19 does resemble those observed in macrophage activation syndrome (MAS), which led early on to the working hypothesis that dysregulated activation of mononuclear phagocytes (MNPs) compartment contributes to COVID-19-associated hyperinflammation.
SARS-CoV-2 infection of lung-resident MNPs might result either from phagocytosis of infected alveolar epithelial cells followed by viral escape from the lysosome or by direct infection. The induction of cytokine production in MNPs in COVID-19 can either be triggered via recognition of damage-associated molecular patterns (DAMPs) released from epithelial cells affected by SARS-CoV-2 by pattern recognition receptors (PRRs) or by direct recognition of viral pathogen-associated molecular patterns (PAMPs) via specific Toll-like receptors. Furthermore, C-type lectin receptors, including DC-SIGN, L-SIGN, etc., as well as Tweety family member 2 have been identified to interact with the SARS-CoV-2 spike protein inducing proinflammatory responses. It seems that AMs act as a Trojan horse, transferring the virus to adjacent lung regions, thereby slowly propagating SARS-CoV-2 infection and spreading hyperinflammation across the lung.
Most prominently and consistent across all studies, reduced HLA-DR expression on monocytes was reported in patients suffering from severe COVID-19. Decreased HLA-DR expression appeared to be strongly associated with COVID-19 disease severity. Downregulation of HLA-DR is a molecular feature often described for monocytic myeloid-derived suppressor cells (MDSC) which are observed in late-stage cancers and sepsis, and featured by immunosuppressive functions. In COVID-19, such HLA-DRlo monocytes are attracted to the lung by pro-inflammatory chemokines, resulting in a continuous accumulation of hyperactivated MNPs producing more pro-inflammatory mediators recruiting more inflammatory cells, including cytotoxic T cells and neutrophils, thus further exacerbating inflammation and tissue damage.