Interferon lambda drives a pro-inflammatory phenotype in macrophages

Interferon lambdas (IFNLs) are potent antiviral cytokines that are widely implicated in many chronic inflammatory diseases. While IFNLs are best known for their role in clearance of hepatitis C virus infection, there is substantial data supporting their role in acute viral infections such as influenza and viral gastroenteritis, as well as chronic autoimmune and liver disease. Numerous tissues have reported IFNL expression, but there remains controversy over which PBMC subsets are responsive to IFNL and thus contribute to inflammatory activity in chronic diseases. Upon examining IFNL sensitivity in vitro, we demonstrate macrophages but not monocytes are more responsive to IFNL3 than myeloid and plasmacytoid dendritic cells; the only other leukocyte populations with a significant IFNL response. To investigate the role of IFNLs on macrophage maturation and function, human monocytes from healthy subjects were differentiated using either GM- CSF (M1 skewed) or M-CSF (M2 skewed), alone or in combination with IFNL3. M1 macrophages expressed more IFNL receptor (IFNLR1) and were more responsive to IFNL3, supporting their role as pro-inflammatory cytokines. Moreover, IFNL3 increased the expression of numerous inflammatory/chemotactic cytokines and activation markers as measured by qPCR and flow cytometry respectively. Functionally, macrophages differentiated in the presence of IFNL3 were more phagocytic towards apoptotic cells and more chemo-attractant towards CD3, NK and NKT cells. Lastly, we demonstrated an accumulation of IFNLR1 expressing macrophages in numerous chronic inflammatory conditions, supporting their potential to drive a pro-inflammatory state. Our data suggests that IFNL contributes to chronic inflammation by driving a pro-inflammatory macrophage phenotype.