Efficient Clearance of Early Apoptotic Cells by Human Macrophages Requires M2c Polarization and MerTK Induction

Abstract

Mer tyrosine kinase (MerTK) is a major macrophage apoptotic cell (AC) receptor. Its functional impairment promotes autoimmunity and atherosclerosis, while overexpression correlates with poor prognosis in cancer. However, little is known about mechanisms regulating MerTK expression in humans. We found that MerTK expression is heterogenous among macrophage subsets, being mostly restricted to anti-inflammatory “M2c” (CD14+CD16+CD163+CD204+CD206+CD209−) cells, differentiated by M-CSF or glucocorticoids. Small numbers of MerTK+ “M2c-like” cells are also detectable among circulating CD14brightCD16+ monocytes. MerTK expression levels adapt to changing immunological environment, being suppressed in M1 and “M2a” macrophages, and in dendritic cells. Remarkably, while glucocorticoid-induced differentiation is IL-10-independent, M-CSF-driven M2c polarization and related MerTK up-regulation require IL-10. However, neither IL-10 alone nor TGFβ are sufficient to fully differentiate M2c (CD16+CD163+MerTK+) macrophages. M-CSF and IL-10, both released by T lymphocytes, may thus be required together to promote regulatory T cell-mediated induction of anti-inflammatory monocytes-macrophages. MerTK enables M2c macrophages to clear early ACs more efficiently than other macrophage subsets, and mediates AC clearance by CD14brightCD16+ monocytes. Moreover, M2c cells release Gas6, which in turn amplifies IL-10 secretion via MerTK. IL-10-dependent induction of the Gas6/MerTK pathway may, therefore, constitute a positive loop for M2c macrophage homeostasis and a critical checkpoint for maintenance of anti-inflammatory conditions. Our findings give new insight into human macrophage polarization and favor a central role for MerTK in regulation of macrophage functions. Eliciting M2c polarization can have therapeutic utility for diseases such as lupus, in which a defective AC clearance contributes to initiate and perpetuate the pathological process.

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

“…Monocytes conditioned with cmMTB differentiated into cells displaying an equivalent or low- er expression of M1 polarization markers (i.e., CD86, HLA-DR, FCAR and Serpine1) compared with cells differentiated in the presence of cmCTR (Supplementary information, Figure S1A-S1B). By contrast, the expression of markers related to M2 macrophage activation, such as CD16, CD163, MerTK, CD206, AMAC1 and CD200R1 [23][24][25][26][27], was upregulated in cmMTB-conditioned cells ( Figure 1B, Supplementary information, Figure S1B). Similarly, the expression of CCR2 and CCR5 chemokine receptors was higher in the presence of cmMTB, supporting the acquisition of the M2 program (Supplementary information, Figure S1C) [28,29].…”

“…Recent studies by Zizzo et al [25,69] suggested a strict correlation between systemic lupus erythematosus (SLE) disease severity and the activation of an M2-like macrophage characterized by CD163 and MerTK expression during the monocyte-to-macrophage differentiation. Expanding upon our previous observation that the monocyte compartment becomes perturbed in TB patients [18], we now report that the CD163 + MerTK + pSTAT3 + signature accompanies the expansion of the CD16 + monocytes.…”

“…However, there has been no confirmation of these results ever since, and more importantly, there is no actual evaluation available on the effect of anti-TB drugs on sCD163 levels until now. Interestingly, sCD163 is considered as a valuable marker of the activation of an M2-like monocyte-macrophage program and biomarkers of disease activity in SLE [25,40], alluding to a critical biological significance for the presence of this soluble receptor as immune response biomarkers in TB disease.…”

Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer

“…How Axl and Mer are activated in this macrophage population in the context of an inflammatory response remains to be determined, however. The TAM agonists Pros1 and Gas6 are expressed by murine and human macrophages (43,44); thus, it is possible that TAM signaling in macrophages is triggered in an autocrine manner. In addition, we have recently demonstrated that T-cell-derived Pros1 constitutes a relevant in vivo source of this anti-inflammatory TAM ligand (45).…”

A Janus role for MerTK in the outcome of septic shock

“…When expressed by monocytes and granulocytes, these receptors (and in particular MerTK) can also mediate the phagocytosis of apoptotic cells [7], which is fundamental in order to remove dead cells without triggering inflammation. Several data now exist that underline the importance of MerTK activation in the elimination of potential autoantigens derived by apoptotic cells, in the inhibition of the production of proinflammatory cytokines, and in the prevention of the expansion of autoreactive lymphocytes [8][9][10]. The functional impairment of MerTK promotes not only autoimmunity but also atherosclerosis, while its overexpression is linked to poor prognosis in cancer [11].…”