Mitochondria supply sub-lethal signals for cytokine secretion and DNA-damage in H. pylori infection

Abstract

The bacterium Helicobacter pylori induces gastric inflammation and predisposes to cancer. H. pylori-infected epithelial cells secrete cytokines and chemokines and undergo DNA-damage. We show that the host cell’s mitochondrial apoptosis system contributes to cytokine secretion and DNA-damage in the absence of cell death. H. pylori induced secretion of cytokines/chemokines from epithelial cells, dependent on the mitochondrial apoptosis machinery. A signalling step was identified in the release of mitochondrial Smac/DIABLO, which was required for alternative NF-κB-activation and contributed to chemokine secretion. The bacterial cag-pathogenicity island and bacterial muropeptide triggered mitochondrial host cell signals through the pattern recognition receptor NOD1. H. pylori-induced DNA-damage depended on mitochondrial apoptosis signals and the caspase-activated DNAse. In biopsies from H. pylori-positive patients, we observed a correlation of Smac-levels and inflammation. Non-apoptotic cells in these samples showed evidence of caspase-3-activation, correlating with phosphorylation of the DNA-damage response kinase ATM. Thus, H. pylori activates the mitochondrial apoptosis pathway to a sub-lethal level. During infection, Smac has a cytosolic, pro-inflammatory role in the absence of apoptosis. Further, DNA-damage through sub-lethal mitochondrial signals is likely to contribute to mutagenesis and cancer development.

Mitochondrial control of inflammation

“…Similarly, chronic low-grade inflammation generally contributes to oncogenesis and tumour progression 7 , and at least in some scenarios this is initiated by mitochondrial dysfunction 193 – 196 . Finally, SMAC release upon minority MOMP driven by Helicobacter pylori seems to have a role in both the short-term and the long-term detrimental effects of the infection as it drives pathogenic inflammation as well as DNA damage in the absence of overt RCD, ultimately promoting malignant transformation 197 .…”

Mitochondria and cell death-associated inflammation

“…During minority MOMP caspase activity is generally not high enough to induce cell death, raising the question if there is a threshold for caspase activity in blocking inflammatory signalling pathways. Recently, three separate studies observed increased inflammation upon the induction of minority MOMP [73,106,107]. Pathogenic infections can induce minority MOMP causing caspase-dependent DNA damage and the secretion of pro-inflammatory cytokines [106,107].…”

“…Recently, three separate studies observed increased inflammation upon the induction of minority MOMP [73,106,107]. Pathogenic infections can induce minority MOMP causing caspase-dependent DNA damage and the secretion of pro-inflammatory cytokines [106,107]. Furthermore, induction of type I interferons was observed upon minority MOMP caused by the formation of mtDNA double strand breaks.…”

Decoding immunogenic cell death from a dendritic cell perspective

“…Consistently, blocking caspase activity following mitochondria outer membrane permeabilization (MOMP), the central mechanism of intrinsic apoptosis (see Box 2), stimulates Type I IFN response and NF‐κB activation thus promoting immune responses, without ultimately preventing killing. Notably, inflammation can also ensue under conditions of so‐called minority MOMP, which is insufficient to fully activate caspase signaling 153–155 . Whether the strength of (MOMP‐induced) caspase signaling ultimately determines its contextual role in regulating inflammation during ICD remains speculative.…”

“…Notably, inflammation can also ensue under conditions of so-called minority MOMP, which is insufficient to fully activate caspase signaling. [153][154][155] Whether the strength of (MOMP-induced) caspase signaling ultimately determines its contextual role in regulating inflammation during ICD remains speculative. Furthermore, caspase-8 has a scaffolding function driving the assembly of a complex together with Fas-associated death domain (FADD) and RIPK1 ripoptosome, which promotes NF-κB activation and chemokine production after ER stress-mediated TRAIL stimulation.…”