Type I Interferon Modulates Monocyte Recruitment and Maturation in Chronic Inflammation

Pui Y. Lee^*, Yi Li^*, Yutaro Kumagai, Yuan Xu^*, Jason S. Weinstein^*, Erinn S. Kellner^*, Dina C. Nacionales^*, Edward J. Butfiloski^*, Nico van Rooijen, Shizuo Akira, Eric S. Sobel^*, Minoru Satoh^* and Westley H. Reeves^*

From the Division of Rheumatology and Clinical Immunology and Center for Autoimmune Disease,^* and the Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida; the Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan; and the Department of Molecular Cell Biology, Free University Medical Center, Amsterdam, The Netherlands

Chronic inflammation is characterized by continuous recruitmentand activation of immune cells such as monocytes in responseto a persistent stimulus. Production of proinflammatory mediatorsby monocytes leads to tissue damage and perpetuates the inflammatoryresponse. However, the mechanism(s) responsible for the sustainedinflux of monocytes in chronic inflammation are not well defined.In chronic peritonitis induced by pristane, the persistent recruitmentof Ly6C^hi inflammatory monocytes into the peritoneum was abolishedin type I interferon (IFN-I) receptor-deficient mice but wasunaffected by the absence of IFN- ${gamma}$ , tumor necrosis factor- ${alpha}$ , interleukin-6,or interleukin-1. IFN-I signaling stimulated the productionof chemokines (CCL2, CCL7, and CCL12) that recruited Ly6C^himonocytes via interactions with the chemokine receptor CCR2.Interestingly, after 2,6,10,14-tetramethylpentadecane treatment,the rapid turnover of inflammatory monocytes in the inflamedperitoneum was associated with a lack of differentiation intoLy6C^lo monocytes/macrophages, a more mature subset with enhancedphagocytic capacity. In contrast, Ly6C^hi monocytes differentiatednormally into Ly6C^lo cells in IFN-I receptor-deficient mice.The effects of IFN-I were specific for monocytes as granulocytemigration was unaffected in the absence of IFN-I signaling.Taken together, our findings reveal a novel role of IFN-I inpromoting the recruitment of inflammatory monocytes via thechemokine receptor CCR2. Continuous monocyte recruitment andthe lack of terminal differentiation induced by IFN-I may helpsustain the chronic inflammatory response.