The second paper discussing the role of death caspases in cell-intrinsic IFN-beta production and heightened anti-viral state came from Richard Flavell's lab at the Yale University School of Medicine.
Initially, the authors made unexpected observation that mice deficient in death caspases in epithelial and hematopoietic cells (caspase 9 fl/fl Tie2Cre+ and caspase 3 fl/fl + caspase 7KO Tie2CRE+ DKO) showed increase viral resistance both in vivo and in vitro.
They showed that this increased resistance against viral infection was type I IFN dependent since it was abolished on IFN-alpha receptor 1 KO background or when using anti-IFN alpha/beta blocking antibodies.
In vitro experiments with a chemical inhibition of caspase pathway confirmed that IFN-beta was induced in cells when pro-apoptotic stimulus was coupled with caspase inhibition. Similar observations were made when using caspase 9 KO or caspases 3/7 DKO primary (MEF) cells.
Here too, the authors found that IFN-beta response were abolished on cGAS and STING knockout backgrounds suggesting the role of endogenous DNA recognition.
Finally, the authors found IFN-beta response was abolished when cells were depleted of mitochondrial DNA (mtDNA).
In summary, the authors proposed that in conditions when caspase-dependent programmed cell death is interrupted (in viral infection [or tumors?], for example), infected cell can secrete IFN-beta as a endogenous danger signal and alert neighboring cells for viral presence and confer paracrine anti-viral resistance.
Still, there are few results from these two papers that require additional explanation: (1) both groups have reported that death caspase deficient mice have high levels of serum IFN-beta but do not show any obvious immunopathology; (2) neither group have examined the impact of caspase deficiency on programmed cell death using physiological stimuli, like FasL, TRAIL, etc; (3) does IFN-beta, spontaneously secreted from caspase-deficient cells, activates tissue resident dendritic cells?