Type I interferons regulate inflammatory cell trafficking and macrophage inflammatory protein 1α delivery to the liver

Macrophage inflammatory protein 1 (MIP-1, CCL3) is critical for liver NK cell inflammation and delivery of IFN- to mediate downstream protective responses against murine cytomegalovirus (MCMV) infections.This system was used to evaluate the upstream contribution of the type 1 IFNs, IFN-/, in promotion of MIP-1 production.Mice deficient in IFN-/ functions, as a result of mutation in the receptor for these cytokines (IFN-/R -), were profoundly deficient in MIP-1 expression and accumulation of NK cells and macrophages in the liver and had increased sensitivity to MCMV infection.The cytokines themselves were responsible for the immunoregulatory effects, since administration of recombinant IFN- (rIFN-) to immunocompetent mice also induced these changes.IFN-/ was required for NK cell accumulation during infection, and MIP-1 was required for NK cell accumulation in response to administered rIFN-.In vivo trafficking assays demonstrated a requirement for IFN-/R signaling for leukocyte localization in, and delivery of MIP-1-producing macrophages to, the liver.These results extend characterization of the cytokine and chemokine cascade required for protection against viral infections in tissues by defining IFN-/-dependent mechanisms promoting MIP-1 production and the resulting hepatic accumulation of NK cells.