title: Noncanonical dendritic cell differentiation and survival driven by a bacteremic pathogen.
abstract: Maintenance of blood DC homeostasis is essential to preventing autoimmunity while controlling chronic infection. However, the ability of bacteremic pathogens to directly regulate blood DC homeostasis has not been defined. One such bacteremic pathogen, Porphyromonas gingivalis, is shown by our group to survive within mDCs under aerobic conditions and therein, metastasize from its oral mucosal niche. This is accompanied by expansion of the blood mDC pool in vivo, independently of canonical DC poietins. We presently know little of how this bacteremic pathogen causes blood DC expansion and the pathophysiological significance. This work shows that optimum differentiation of MoDCs from primary human monocytes, with or without GM-CSF/IL-4, is dependent on infection with P. gingivalis strains expressing the DC-SIGN ligand mfa-1. DC differentiation is lost when DC-SIGN is blocked with its ligand HIV gp120 or knocked out by siRNA gene silencing. Thus, we have identified a novel, noncanonical pathway of DC differentiation. We term these PDDCs and show that PDDCs are bona fide DCs, based on phenotype and phagocytic activity when immature and the ability to up-regulate accessory molecules and stimulate allo-CD4(+) T cell proliferation when matured. The latter is dependent on the P. gingivalis strain used to initially "educate" PDDCs. Moreover, we show that P. gingivalis-infected, conventional MoDCs become resistant to apoptosis and inflammatory pyroptosis, as determined by levels of Annexin V and caspase-8, -3/7, and -1. Taken together, we provide new insights into how a relatively asymptomatic bacteremia may influence immune homeostasis and promote chronic inflammation.
authors.affiliation: 1.Georgia Regent University Augusta, 1120 15th St., GC-1335, Augusta, GA 30912, USA. chcutler@gru.edu.
authors.forename: Brodie
authors.initials: B
authors.lastname: Miles
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Scisci
authors.forename: Julio
authors.initials: J
authors.lastname: Carrion
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Sabino
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Genco
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cutler
mesh_terms: D000332:Aerobiosis; D017304:Annexin A5 / Q000276:immunology; D017209:Apoptosis; D016470:Bacteremia / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D020169:Caspases / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured / Q000276:immunology / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D036781:Fimbriae Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D010861:Fimbriae, Bacterial / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology; D006706:Homeostasis; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D009000:Monocytes / Q000166:cytology; D009061:Mouth Mucosa / Q000276:immunology / Q000382:microbiology; D010587:Phagocytosis; D016966:Porphyromonas gingivalis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D017304:Annexin A5; D001426:Bacterial Proteins; D020169:Caspases; D015815:Cell Adhesion Molecules; D036781:Fimbriae Proteins; D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C545438:Mfa1 protein, Porphyromonas gingivalis; C063055:fimbrillin; C514793:gp120 protein, Human immunodeficiency virus 1
keywords: T cells; apoptosis; inflammation; periodontal pathogen; porphyromonas gingivalis