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

Abstract

Double-stranded (ds) RNA, both synthetic and produced during virus replication, rapidly stimulates MAPK and NF-κB 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.

Brick plots: an intuitive platform for visualizing multiparametric immunophenotyped cell clusters

“…However, the population in Fig. 3f does not express CD3, and further, it is possible for these markers to be expressed in myeloid populations [13][14][15]. We also verified the existence of this CD25 myeloid population by manual gating (Additional file 3).…”

Longitudinal omics in Syrian hamsters integrated with human data unravel cellular effector responses to moderate COVID-19

“…We then used the predicted cell type of the majority of cells in each cluster to guide cluster annotation, also taking into account cell marker genes published in literature and cell marker databases 87,88 . The following populations were confirmed: Alveolar macrophages (Siglecf + , Marco + ) 89 , interstitial macrophages (C1qb + ) 90 , monocytic macrophages (Ccr2 + , Ccr5 + , Arg1 + ) 91,92 , Treml4 + -monocytes (Treml4 + ) 93 , neutrophils (S100a8 + , Cxcr2 + , Camp + ) 44,94 , myeloid dendritic cells (mDC) (Flt3 + , H2-Ab1 hi , Irf8 lo , Tcf4 lo ) and plasmacytoid dendritic cells (pDC) (Flt3 + , H2-Ab1 hi , Irf8 hi , Tcf4 hi ) 85,95-97 , T / NK / cells (Cd3e + , Cd4 + or Cd8a + , Gzma + , Nkg7 + ) 85,94,98-100 , B cells (Cd79b + , Ms4a1 + ) 44,101 , alveolar epithelial cells type 1 (Rtkn2 + ) 90 , endothelial cells (Pecam1 + ) 89 , ciliated epithelial cells (Foxj1 + )…”

The location of sensing determines the pancreatic β-cell response to the viral mimetic dsRNA

“…The selective recognition of intracellular dsRNA contrasts with the response of macrophages, which have the capacity to respond to both intracellular and extracellular dsRNA (32,60). In macrophages, intracellular dsRNA recognition results in the expression of type 1 IFN and ISG (26,30,32,60), whereas extracellular signaling activated by dsRNA results in macrophage expression of inflammatory genes such as iNOS, IL-1␤, and COX-2 in a manner dependent on CCR5 signaling (46). Whereas ␤ cells fail to respond to extracellular dsRNA, they express iNOS and COX-2 in response to the inflammatory cytokine IL-1␤ (17).…”

“…21). Recently, we have identified CCR5 as the cell surface signaling receptor required for poly(I:C)-induced inflammatory gene expression by macrophages (46). ␤ cells fail to produce nitric oxide in response to poly(I:C) (45) and also do not express CCR5 (expression is restricted to cells of hematopoietic lineage; Fig.…”