A non‐death function of the mitochondrial apoptosis apparatus in immunity

Apoptosis is a frequent form of programmed cell death, but the apoptotic signaling pathway can also be engaged at a low level, in the absence of cell death. We here report that such sub‐lethal engagement of mitochondrial apoptosis signaling causes the secretion of cytokines from human epithelial cells in a process controlled by the Bcl‐2 family of proteins. We further show that sub‐lethal signaling of the mitochondrial apoptosis pathway is initiated by infections with all tested viral, bacterial, and protozoan pathogens and causes damage to the genomic DNA. Epithelial cells infected with these pathogens secreted cytokines, and this cytokine secretion upon microbial infection was substantially reduced if mitochondrial sub‐lethal apoptosis signaling was blocked. In the absence of mitochondrial pro‐apoptotic signaling, the ability of epithelial cells to restrict intracellular bacterial growth was impaired. Triggering of the mitochondrial apoptosis apparatus thus not only causes apoptosis but also has an independent role in immune defense. Synopsis The mitochondrial apoptosis apparatus is activated during infection of epithelial cells with intracellular microbes but at a low level that is insufficient to induce apoptosis. This activation is found to stimulate the infected cell and to contribute to anti‐bacterial, cell‐autonomous immunity. Low‐level, sub‐lethal activation of the mitochondrial apoptosis apparatus (“minority MOMP”) triggers the secretion of cytokines from epithelial cells. Viral, bacterial and parasite infections cause minority MOMP in infected cells, leading to DNA‐damage that depends on the mitochondrial apoptosis pathway. Microbe‐induced minority MOMP contributes to the secretion of cytokines during infection. Cells with defects in mitochondrial apoptosis/minority MOMP are compromised in the containment of intracellular bacteria. Graphical Abstract Different pathogens can trigger sub‐lethal engagement of the mitochondrial apoptosis machinery in epithelial cells, resulting however not in cell death but rather promoting cytokine production and reducing pathogen growth.