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Wang X , Wang J , Zheng H , Xie M , Hopewell EL , Albrecht RA , Nogusa S , Garcia-Sastre A , Balachandran S , Beg AA
Differential requirement for the IKKbeta/NF-kappaB signaling module in regulating TLR- versus RLR-induced type 1 IFN expression in dendritic cells
J Immunol. 2014 Sep 1;193(5) :2538-45
AbstractHost 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 IkappaB kinase beta (IKKbeta)/NF-kappaB pathway regulates early IFN-beta expression, but not the magnitude of type 1 IFN expression following RLR engagement. In this study, we use IKKbeta inhibition and mice deficient in IKKbeta or canonical NF-kappaB subunits (p50, RelA/p65, and cRel) to demonstrate that the IKKbeta/NF-kappaB 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 IKKbeta/NF-kappaB in TLR- but not RLR-induced expression of type 1 IFNs and inflammatory cytokines. Together, these findings reveal a previously unappreciated specificity of the IKKbeta/NF-kappaB 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.
Notes1550-6606 Wang, Xingyu Wang, Junmei Zheng, Hong Xie, Mengyu Hopewell, Emily L Albrecht, Randy A Nogusa, Shoko Garcia-Sastre, Adolfo Balachandran, Siddharth Beg, Amer A R01 AI059715/AI/NIAID NIH HHS/United States R21 AI104212/AI/NIAID NIH HHS/United States U01AI095611/AI/NIAID NIH HHS/United States U19AI083025/AI/NIAID NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. United States J Immunol. 2014 Sep 1;193(5):2538-45. doi: 10.4049/jimmunol.1400675. Epub 2014 Jul 23.