RNASeq_Results.xlsx (2.47 MB)
RNASeq_Results.xlsx
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.