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.