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Noncanonical dendritic cell differentiation and survival driven by a bacteremic pathogen

Year: 2013
Type: article
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.
DOI: 10.1189/jlb.0213108
Authors: Brodie Miles, Elizabeth Scisci, Julio Carrion, Gregory J Sabino, Caroline A Genco, Christopher W Cutler
Language: English
Subfield: Immunology
Open Access status: green
Funders: National Institute for Health and Care Research, National Institutes of Health, U.S. Public Health Service, National Institute of Allergy and Infectious Diseases, National Institute of Dental and Craniofacial Research, Office of AIDS Research
Awards: G1958862243, Neutrophil and Dendritic Cell Interactions, Peripheral blood dendritic cells and periodontitis, G3204441492, G337459332, Oral Pathogens and Dendritic Cell Subsets, Role of Innate Immune System in Pathogen Induced Chronic Inflammation, Dendritic Cells Trafficking in Gingival Health and Disease, G4468916223, G8675272695
OpenAlex ID: W2098048264
FWCI: 0.921
Cites: 59
Cited by: 20
Related to: 10