title: Identification of a TLR-independent pathway for Borrelia burgdorferi-induced expression of matrix metalloproteinases and inflammatory mediators through binding to integrin alpha 3 beta 1.
abstract: Borrelia burgdorferi stimulates a robust inflammatory response at sites of localization. Binding of borrelial lipoproteins to TLR-2 is one pathway important in the host response to B. burgdorferi. However, while TLR-2 is clearly important in control of infection, inflammation is actually worsened in the absence of TLR-2 or the shared TLR adapter molecule, MyD88, suggesting that there are alternative pathways regulating inflammation. Integrins are cell surface receptors that play an important role in cell to cell communications and that can activate inflammatory signaling pathways. In this study, we report for the first time that B. burgdorferi binds to integrin alpha(3)beta(1) and that binding of B. burgdorferi to this integrin results in induction of proinflammatory cytokines, chemokines, and end-effector molecules such as matrix metalloproteinases in primary human chondrocyte cells. Expression of these same molecules is not affected by the absence of MyD88 in murine articular cartilage, suggesting that the two pathways act independently in activating host inflammatory responses to B. burgdorferi. B. burgdorferi-induced alpha(3) signaling is mediated by JNK, but not p38 MAPK. In summary, we have identified a new host receptor for B. burgdorferi, integrin alpha(3)beta(1); binding of B. burgdorferi to integrin alpha(3)beta(1) results in the release of inflammatory mediators and is proposed as a TLR-independent pathway for activation of the innate immune response by the organism.
authors.affiliation: Tufts-New England Medical Center, Tufts University School of Medicine, Tupper Research Institute, Division of Geographic Medicine and Infectious Diseases, Boston, MA 02111.
authors.forename: Aruna K
authors.initials: AK
authors.lastname: Behera
authors.forename: Ethan
authors.initials: E
authors.lastname: Hildebrand
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Jenifer
authors.initials: J
authors.lastname: Coburn
authors.forename: Linden T
authors.initials: LT
authors.lastname: Hu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001422:Bacterial Adhesion / Q000276:immunology; D001899:Borrelia Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D025065:Borrelia burgdorferi / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis / Q000502:physiology; D019902:Chondrocytes / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D039201:Integrin alpha3beta1 / Q000378:metabolism / Q000502:physiology*; D039641:Integrin beta Chains / Q000378:metabolism* / Q000502:physiology; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D039201:Integrin alpha3beta1; D039641:Integrin beta Chains; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1