title: TLR4 contributes to disease-inducing mechanisms resulting in central nervous system autoimmune disease.
abstract: Environmental factors strongly influence the development of autoimmune diseases, including multiple sclerosis. Despite this clear association, the mechanisms through which environment mediates its effects on disease are poorly understood. Pertussis toxin (PTX) functions as a surrogate for environmental factors to induce animal models of autoimmunity, such as experimental autoimmune encephalomyelitis. Although very little is known about the molecular mechanisms behind its function in disease development, PTX has been hypothesized to facilitate immune cell entry to the CNS by increasing permeability across the blood-brain barrier. Using intravital microscopy of the murine cerebromicrovasculature, we demonstrate that PTX alone induces the recruitment of leukocytes and of active T cells to the CNS. P-selectin expression was induced by PTX, and leukocyte/endothelial interactions could be blocked with a P-selectin-blocking Ab. P-selectin blockade also prevented PTX-induced increase in permeability across the blood-brain barrier. Therefore, permeability is a secondary result of recruitment, rather than the primary mechanism by which PTX induces disease. Most importantly, we show that PTX induces intracellular signals through TLR4, a receptor intimately associated with innate immune mechanisms. We demonstrate that PTX-induced leukocyte recruitment is dependent on TLR4 and give evidence that the disease-inducing mechanisms initiated by PTX are also at least partly dependent on TLR4. We propose that this innate immune pathway is a novel mechanism through which environment can initiate autoimmune disease of the CNS.
authors.affiliation: Immunology Research Group, Department of Physiology and Biophysics, University of Calgary, Alberta, Canada.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kerfoot
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Long
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hickey
authors.forename: Graciela
authors.initials: G
authors.lastname: Andonegui
authors.forename: Benoit M
authors.initials: BM
authors.lastname: Lapointe
authors.forename: Renata C O
authors.initials: RC
authors.lastname: Zanardo
authors.forename: Claudine
authors.initials: C
authors.lastname: Bonder
authors.forename: Will G
authors.initials: WG
authors.lastname: James
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Robbins
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology; D001921:Brain / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D002199:Capillary Permeability / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology; D007113:Immunity, Innate / Q000235:genetics; D007275:Injections, Intravenous; D007424:Intracellular Fluid / Q000276:immunology / Q000502:physiology; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D037342:Pertussis Toxin / Q000008:administration & dosage / Q000276:immunology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D051197:Toll-Like Receptor 4
chemical_list: D018950:Lipopolysaccharide Receptors; D019007:P-Selectin; D011956:Receptors, Cell Surface; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D037342:Pertussis Toxin