title: Secondary lymphoid organ homing phenotype of human myeloid dendritic cells disrupted by an intracellular oral pathogen.
abstract: Several intracellular pathogens, including a key etiological agent of chronic periodontitis, Porphyromonas gingivalis, infect blood myeloid dendritic cells (mDCs). This infection results in pathogen dissemination to distant inflammatory sites (i.e., pathogen trafficking). The alteration in chemokine-chemokine receptor expression that contributes to this pathogen trafficking function, particularly toward sites of neovascularization in humans, is unclear. To investigate this, we utilized human monocyte-derived DCs (MoDCs) and primary endothelial cells in vitro, combined with ex vivo-isolated blood mDCs and serum from chronic periodontitis subjects and healthy controls. Our results, using conditional fimbria mutants of P. gingivalis, show that P. gingivalis infection of MoDCs induces an angiogenic migratory profile. This profile is enhanced by expression of DC-SIGN on MoDCs and minor mfa-1 fimbriae on P. gingivalis and is evidenced by robust upregulation of CXCR4, but not secondary lymphoid organ (SLO)-homing CCR7. This disruption of SLO-homing capacity in response to respective chemokines closely matches surface expression of CXCR4 and CCR7 and is consistent with directed MoDC migration through an endothelial monolayer. Ex vivo-isolated mDCs from the blood of chronic periodontitis subjects, but not healthy controls, expressed a similar migratory profile; moreover, sera from chronic periodontitis subjects expressed elevated levels of CXCL12. Overall, we conclude that P. gingivalis actively "commandeers" DCs by reprogramming the chemokine receptor profile, thus disrupting SLO homing, while driving migration toward inflammatory vascular sites.
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Brodie
authors.initials: B
authors.lastname: Miles
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Zakhary
authors.forename: Ahmed
authors.initials: A
authors.lastname: El-Awady
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Scisci
authors.forename: Julio
authors.initials: J
authors.lastname: Carrion
authors.forename: John C
authors.initials: JC
authors.lastname: O'Neill
authors.forename: Aaron
authors.initials: A
authors.lastname: Rawlings
authors.forename: J Kobi
authors.initials: JK
authors.lastname: Stern
authors.forename: Cristiano
authors.initials: C
authors.lastname: Susin
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cutler
mesh_terms: D016866:Bacteroidaceae Infections / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12 / Q000378:metabolism; D002633:Chemotaxis / Q000502:physiology; D055113:Chronic Periodontitis / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D042783:Endothelial Cells / Q000378:metabolism; D010861:Fimbriae, Bacterial / Q000235:genetics / Q000502:physiology; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D009389:Neovascularization, Pathologic / Q000382:microbiology; D010641:Phenotype; D016966:Porphyromonas gingivalis / Q000502:physiology*; D054400:Receptors, CCR7 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D054377:Chemokine CXCL12; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C515370:CCR7 protein, human; C515255:CXCL12 protein, human