The integrin αvβ8 promotes activation of TGFβ by human peripheral monocyte and intestinal macrophage populations

Abstract

Abstract Transforming growth factor beta (TGFβ) plays a key role in maintaining immune homeostasis, both preventing inflammation and promoting tissue repair. The cytokine is secreted as an inactive complex, with the function of TGFβ tightly regulated at the level of its activation. Our previous work in mice has demonstrated a crucial role for an integrin, αvβ8, in activation of TGFβ in the immune system. This pathway appears especially important in the intestine, with important functions in regulating T-cell response via integrin αvβ8 expression in dendritic cells and regulatory T-cells. However, how TGFβ is activated to regulate the human immune system is poorly understood. Here, we show that, in humans, integrin αvβ8 is highly expressed on blood monocytes, which promotes activation of TGFβ by these cells. When monocytes are differentiated to macrophages, high integrin β8 expression and TGFβ-activating function is observed on the more tolerogenic (M2-like) macrophages versus inflammatory (M1-like) macrophages. In both monocytes and macrophages, expression of β8 is upregulated by specific bacterial TLR ligands, suggesting that stimulation of the cells may promote their ability to activate TGFβ. In addition to peripheral immune cells, intestinal lamina propria mononuclear cells express high levels of integrin αvβ8, with increased levels seen in patients with inflammatory bowel disease. Highest levels of integrin αvβ8 are seen on a population of CD14+CD33+CD64+ cells, corresponding to intestinal macrophages. Thus, our data suggest that expression of integrin αvβ8 on monocytes may play an important role in the induction and function of anti-inflammatory macrophages in the intestine via TGFβ activation.