CCR5 is a required signaling receptor for macrophage expression of inflammatory genes in response to viral double-stranded RNA

Shaheen ZR, Christmann BS, Stafford JD, Moran JM, Buller RM, Corbett JA. CCR5 is a required signaling receptor for macrophage expression of inflammatory genes in response to viral double-stranded RNA. Am J Physiol Regul Integr Comp Physiol 316: R525–R534, 2019. First published February 27, 2019; doi:10.1152/ajpregu. 00019.2019.—Double-stranded (ds) RNA, both synthetic and produced during virus replication, rapidly stimulates MAPK and NF-КB signaling that results in expression of the inflammatory genes inducible nitric oxide synthase, cyclooxygenase 2, and IL-1β by macrophages. Using biochemical and genetic approaches, we have identified the chemokine ligand-binding C-C chemokine receptor type 5 (CCR5) as a cell surface signaling receptor required for macrophage expression of inflammatory genes in response to dsRNA. Activation of macrophages by synthetic dsRNA does not require known dsRNA receptors, as poly(inosinic: cytidylic) acid [poly(I:C)] activates signaling pathways leading to expression of inflammatory genes to similar levels in wild-type and Toll-like receptor 3- or melanoma differentiation antigen 5-deficient macrophages. In contrast, macrophage activation in response to poly(I:C) is attenuated in macrophages isolated from mice lacking CCR5. These findings support a role for CCR5 as a cell surface signaling receptor that participates in activation of inflammatory genes in macrophages in response to the viral dsRNA mimetic poly(inosinic:cytidylic) acid by pathways that are distinct from classical dsRNA receptor-mediated responses.