Differential Requirement for the IKKβ/NF-κB Signaling Module in Regulating TLR- versus RLR-Induced Type 1 IFN Expression in Dendritic Cells

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.

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