title: Induction of microRNA-155 is TLR- and type IV secretion system-dependent in macrophages and inhibits DNA-damage induced apoptosis.
abstract: Helicobacter pylori is a gastric pathogen responsible for a high disease burden worldwide. Deregulated inflammatory responses, possibly involving macrophages, are implicated in H. pylori-induced pathology, and microRNAs, such as miR-155, have recently emerged as crucial regulators of innate immunity and inflammatory responses. miR-155 is regulated by Toll-like receptor (TLR) ligands in monocyte-derived cells and has been shown to be induced in macrophages during H. pylori infection. Here, we investigated the regulation of miR-155 expression in primary murine bone marrow-derived macrophages (BMMs) during H. pylori infection and examined the downstream mRNA targets of this microRNA using microarray analysis. We report TLR2/4- and NOD1/2-independent up-regulation of miR-155, which was found to be dependent on the major H. pylori pathogenicity determinant, the type IV secretion system (T4SS). miR-155 expression was dependent on NF-κB signaling but was independent of CagA. Microarray analysis identified known gene targets of miR-155 in BMMs during H. pylori infection that are proapoptotic. We also identified and validated miR-155 binding sites in the 3' UTRs of the targets, Tspan14, Lpin1, and Pmaip1. We observed that H. pylori-infected miR-155(-/-) BMMs were significantly more susceptible to cisplatin DNA damage-induced apoptosis than were wild-type BMMs. Thus, our data suggest a function for the prototypical H. pylori pathogenicity factor, the T4SS, in the up-regulation of miR-155 in BMMs. We propose the antiapoptotic effects of miR-155 could enhance macrophage resistance to apoptosis induced by DNA damage during H. pylori infection.
authors.affiliation: Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin 10117, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Koch
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Mollenkopf
authors.forename: Uwe
authors.initials: U
authors.lastname: Klemm
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Meyer
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics; D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism; D017209:Apoptosis; D001426:Bacterial Proteins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004249:DNA Damage; D005260:Female; D020869:Gene Expression Profiling; D016480:Helicobacter pylori / Q000378:metabolism / Q000472:pathogenicity / Q000502:physiology; D054884:Host-Pathogen Interactions; D008264:Macrophages / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D037521:Virulence Factors
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D035683:MicroRNAs; D053594:Myeloid Differentiation Factor 88; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D037521:Virulence Factors; C532623:Mirn155 microRNA, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C080866:cagA protein, Helicobacter pylori; C506255:Ripk2 protein, mouse