Abstract
Monocytes are crucial immune cells involved in regulation of inflammation either directly or via differentiation into macrophages in tissues. However, many aspects of how their function is controlled in health and disease are not understood. Here we show that human blood monocytes activate high levels of the cytokine TGFβ, a pathway that is not evident in mouse monocytes. Human CD14+, but not CD16+, monocytes activate TGFβ via expression of the integrin αvβ8 and matrix metalloproteinase 14, which dampens their production of TNFα in response to LPS. Additionally, when monocytes differentiate into macrophages, integrin expression and TGFβ-activating ability are maintained in anti-inflammatory macrophages but down-regulated in pro-inflammatory macrophages. In the healthy human intestine, integrin αvβ8 is highly expressed on mature tissue macrophages, with these cells and their integrin expression being significantly reduced in active inflammatory bowel disease. Thus, our data suggest that integrin αvβ8-mediated TGFβ activation plays a key role in regulation of monocyte inflammatory responses and intestinal macrophage homeostasis.
Highlights
Monocytes are short-lived bone marrow–derived immune cells that play an important role in orchestrating inflammation and promoting tolerance (Jakubzick et al, 2017)
We show that human monocytes and macrophages are key activators of latent TGFβ, with such pathways not present in mice. This ability to activate TGFβ is dependent on expression of an integrin, αvβ8, with this activation important in dampening pro-inflammatory cytokine production by monocytes. We find that this pathway is highly expressed on human intestinal macrophages, which are reduced in inflammatory bowel disease (IBD) and replaced by incoming pro-inflammatory monocytes/macrophages that lack expression of αvβ8
The failure to detect TGFβ activation by mouse monocytes was not due to an inability of the reporter cells to respond to murine TGFβ, as a near identical response was observed in the presence of recombinant active mouse and human TGFβ1 (Fig. S1 A)
Summary
Monocytes are short-lived bone marrow–derived immune cells that play an important role in orchestrating inflammation and promoting tolerance (Jakubzick et al, 2017). Human CD14+ monocytes activate TGFβ via expression of the integrin αvβ8 Monocytes represent the major mononuclear phagocyte cell population in the periphery with a crucial role in mediating inflammatory responses via regulation of adaptive immunity and maturation into tissue macrophages.
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