The Good and the Bad: Monocytes' and Macrophages' Diverse Functions in Inflammation

Abstract

Monocytes and macrophages are central players of the innate immune response and play a pivotal role in the regulation of inflammation. Thereby, they actively participate in all phases of the immune response, from initiating inflammation and triggering the adaptive immune response, through to the clearance of cell debris and resolution of inflammation. In this review, we described the mechanisms of monocyte and macrophage adaptation to rapidly changing microenvironmental conditions and discussed different forms of macrophage polarization depending on the environmental cues or pathophysiological condition. Therefore, special focus was placed on the tight regulation of the pro- and anti-inflammatory immune response, and the diverse functions of S100A8/S100A9 proteins and the scavenger receptor CD163 were highlighted, respectively. We paid special attention to the function of pro- and anti-inflammatory macrophages under pathological conditions.

Keywords: CD163; COVID-19; S100A8; S100A9; SIRS; chronic inflammation; inflammation; macrophage plasticity; macrophages; monocytes.

Figure 1

Monocytes and macrophages are a central component of the innate immune system. They are able to switch their phenotype from a homeostatic state to the proinflammatory state to eliminate pathogens and fight the inflammation. During uncomplicated inflammation, a switch from a proinflammatory to an anti-inflammatory phenotype occurs which enables the resolution of inflammation and the re-establishment of homeostasis. This enables the monocytes and macrophages to play diverse roles in the inflammatory response, both encouraging and discouraging this process. Depending on the kind of signal or pathophysiologic condition, monocytes and macrophages can undergo specific phenotypic polarization and thus acquire distinct functional phenotypes.

Figure 2

sCD163 modulates the host defense against staphylococcal infections. During sepsis membrane bound CD163 undergoes ectodomain shedding that leads to the generation of the soluble form of CD163 (sCD163). This process is mediated via cleavage by metalloproteinase TACE/ADAM17. S. aureus adheres to host tissue by binding of fibronectin. Once released, sCD163 also recognizes and binds to fibronectin, which then acts as a bridge between sCD163 and the staphylococci. This binding promotes the effective clearance (enhanced phagocytosis and killing) of S. aureus by professional phagocytes, while dampening the induction of proinflammatory cytokines and subsequently protecting the host from overwhelming inflammation.

Figure 3

S100A8 and S100A9 are well known ligands of TLR4 and induce the expression of proinflammatory cytokines and type I interferons in monocytes and macrophages. Therefore, they function as amplifiers of phagocyte activation during the early hyper-inflammatory state of SIRS. However, long-term stimulation with S100A8/S100A9 has a regulatory role in promoting phagocyte hypo-responsiveness to subsequent inflammatory stimulation. It was shown that prolonged stimulation with low doses of S100A8 and S100A9 leads to an activation of the phosphatidylinositol 3-kinase/AKT/GSK-3β pathway which interferes with the NF-κB–driven expression of proinflammatory cytokines. This inhibition of cytokine production is further enhanced by secondary IL-10 triggered activation of STAT3 and BCL-3.