The DNA-damage response triggered by the caspase-activated DNAse contributes to inflammation and immune response

A DNA-damage response (DDR) occurs upon physical and chemical insults to genomic DNA and drives inflammation. The caspase-activated DNAse (CAD) is a nuclear enzyme that degrades DNA during apoptosis but that can also be activated by sub-lethal signals in the mitochondrial apoptosis pathway. Viral and bacterial agents of disease trigger such sub-lethal signals in infected cells and cause the activation of CAD. We report that activation of CAD causes transient genomic DNA-breaks and a DDR that involves activation of major pro-inflammatory signaling pathways and induction of a gene-expression profile typical of the host response to viral and bacterial infection. Cells deficient in CAD had a reduced inflammatory response to sub-lethal mitochondrial signals and to infection with DNA- and RNA-viruses. CAD-deficient mice infected with influenza A virus showed a reduced inflammatory gene-expression profile in lung tissue, accompanied by an increase in viral titers, changes in pathology and higher weight loss. The results identify CAD as a contributor to host defense to infection and the initiation of the immune response. They further suggest that the induction of genomic DNA-damage is a physiological event in the defense against pathogens. HaCaT iCAD knock out cells (expressing Tir1) reconstituted with a minimal auxin inducible degron (mAID) of human ICAD fused to GFP were stimulated for the indicated time points with auxin (IAA) or DMSO (solvent control) and total RNA was isolated. Four replicates were used for "Sequencing"