2  The mononuclear phagocyte system (MPS)
The MPS is a dispersed organ, present throughout the body, with distinctive properties in every organ [21]. Tissue resident macrophage populations in the adult derive from embryonic progenitors and differ markedly in phenotype from bone marrow-derived monocytes, which are recruited to tissues in response to increased demand, for instance infection and tissue damage [19]. Monocyte- derived macrophages are the main generators of inflammation in COVID-19 [2,17,18,20,[22], [23], [24]]. These mononuclear phagocytes express a broad repertoire of plasma membrane and intracellular receptors, serving as sensors of micro-organisms, dying cells and soluble products, to mediate recognition, signaling, migration and activation [19]. Monocytes and macrophages are professional phagocytes, utilizing Fc, complement, Toll-like and non-opsonic lectin-like and scavenger receptors for ingestion, but are also highly active biosynthetic and secretory cells, contributing to inflammation, innate and adaptive cellular and humoral immunity and antimicrobial defences [21]. While promoting tissue homeostasis and repair, they also induce tissue injury, the proverbial two-edged sword. They interact readily with other cells through contact and soluble mediators including cytokines, chemokines and enzymes that activate plasma coagulation and complement cascades [24]; in addition, they generate reactive oxygen, nitrogen and arachidonate metabolites implicated in host inflammation and resolution [25]. By analogy with lymphocytes, their activation status is characterized for convenience as M1-type (pro-inflammatory) and M2-type (anti-inflammatory, reparative) [7]. Unlike T and B lymphocytes, mononuclear phagocytes are antigen non-specific, and only display a transient form of memory [26], primed to adapt to secondary challenges such as phagocytosis and microbial stimuli by further activation of potent secretory and cytotoxic pathways [7]. The level of activation covers a spectrum of effector mechanisms, constrained by inhibitory cytokines such as IL-10, IL-1 receptor antagonist [27] and transforming growth factor beta TGF-β, and by anti-inflammatory glucocorticoids and prostaglandins.