Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice

IFN regulatory factor 3 ( IRF3) is a transcription regulator of cellular responses in many cell typesthat is known to be essential for innate immunity. To confirm IRF3’s broad role in immunity and to more fully discern its role in various cellular subsets, we engineered Irf3- floxedmice to allow for the cell type-specific ablation of Irf3. Analysis of these mice confirmed the general requirement of IRF3for the evocationof type I IFN responses in vitro and in vivo. Furthermore, immune cell ontogeny and frequencies of immune cell typeswere unaffected when Irf3was selectively inactivated in either T cells or B cells in the mice. Interestingly, in a model of lipopolysaccharide-induced septic shock, selective Irf3deficiency in myeloid cells led to reduced levels of type I IFN in the sera and increased survival of these mice, indicating the myeloid-specific, pathogenic role of the Toll-like receptor 4– IRF3type I IFN axis in this model of sepsis. Thus, Irf3- floxedmice can serve as useful tool for further exploring the cell type-specific functions of this transcription factor.