Macrophage coordination of the interferon lambda immune response

Lambda interferons (IFN-λs) are a major component of the innate immune
defense to viruses, bacteria and fungi. In human liver, IFN-λ not only
drives antiviral responses, but also promotes inflammation and fibrosis in
viral and non-viral diseases. Here we demonstrate that macrophages are
primary responders to IFN-λ, uniquely positioned to bridge the gap between
IFN-λ producing cells and lymphocyte populations that are not
intrinsically responsive to IFN-λ. While CD14+ monocytes do not express
the IFN-λ receptor, IFNLR1, sensitivity is quickly gained upon
differentiation to macrophages in vitro. IFN-λ stimulates macrophage
cytotoxicity and phagocytosis as well as the secretion of pro-inflammatory
cytokines and interferon stimulated genes that mediate immune cell
chemotaxis and effector functions. In particular, IFN-λ induced CCR5 and
CXCR3 chemokines, stimulating T and NK cell migration, as well as
subsequent NK cell cytotoxicity. Using immunofluorescence and cell sorting
techniques, we confirmed that human liver macrophages expressing CD14 and
CD68 are highly responsive to IFN-λ ex vivo. Together, these data
highlight a novel role for macrophages in shaping IFN-λ dependent immune
responses both directly through pro-inflammatory activity and indirectly
by recruiting and activating IFN-λ unresponsive lymphocytes.