title: Differential requirement for the IKKβ/NF-κB signaling module in regulating TLR- versus RLR-induced type 1 IFN expression in dendritic cells.
abstract: Host innate-immune responses are tailored by cell type to control and eradicate specific infectious agents. For example, an acute RNA virus infection can result in high-level expression of type 1 IFNs by both conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs), but whereas cDCs preferentially use RIG-I-like receptor (RLR) signaling to produce type 1 IFNs, pDCs predominantly use TLRs to induce these cytokines. We previously found that the IκB kinase β (IKKβ)/NF-κB pathway regulates early IFN-β expression, but not the magnitude of type 1 IFN expression following RLR engagement. In this study, we use IKKβ inhibition and mice deficient in IKKβ or canonical NF-κB subunits (p50, RelA/p65, and cRel) to demonstrate that the IKKβ/NF-κB axis is critical for virus-induced type 1 IFN expression in pDCs, but not in cDCs. We also reveal a crucial and more general requirement for IKKβ/NF-κB in TLR- but not RLR-induced expression of type 1 IFNs and inflammatory cytokines. Together, these findings reveal a previously unappreciated specificity of the IKKβ/NF-κB signaling axis in regulation of antimicrobial responses by different classes of pattern recognition receptors, and therefore by individual cell types reliant on particular pattern recognition receptors for their innate-immune transcriptional responses.
authors: Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612;
authors: Xingyu
authors: X
authors: Wang
authors: Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612;
authors: Junmei
authors: J
authors: Wang
authors: Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612;
authors: Hong
authors: H
authors: Zheng
authors: Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612;
authors: Mengyu
authors: M
authors: Xie
authors: Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612; Cancer Biology Ph.D. Program, Department of Oncologic Sciences, University of South Florida, Tampa, FL 33612;
authors: Emily L
authors: EL
authors: Hopewell
authors: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Randy A
authors: RA
authors: Albrecht
authors: Fox Chase Cancer Center, Philadelphia, PA 19111; and.
authors: Shoko
authors: S
authors: Nogusa
authors: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors: Adolfo
authors: A
authors: García-Sastre
authors: Fox Chase Cancer Center, Philadelphia, PA 19111; and.
authors: Siddharth
authors: S
authors: Balachandran
authors: Department of Immunology, Moffitt Cancer Center, Tampa, FL 33612; amer.beg@moffitt.org.
authors: Amer A
authors: AA
authors: Beg
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology*; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology*; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology*; D000097905:Roundabout Proteins
chemical_list: D051550:I-kappa B Kinase; D007370:Interferon Type I; D008565:Membrane Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins