title: Toll-Like Receptor 2, Toll-Like Receptor 4, Myeloid Differentiation Response Gene 88, and Toll-IL-1 Receptor Domain-Containing Adaptor-Inducing Interferon-γ (TRIF) Selectively Regulate Susceptibility of P0106-125-Induced Murine Experimental Autoimmune Neuritis.
abstract: The functional relevance of the innate immune system has not yet been dissected in P0106-125-induced murine experimental autoimmune neuritis. Therefore, the role of Toll-like receptor (TLR) 2, TLR4, myeloid differentiation response gene 88, and Toll-IL-1 receptor domain-containing adaptor-inducing interferon-γ (TRIF), factors critically involved in the TLR signaling pathway, was studied in experimental autoimmune neuritis. In the absence of TLR2, TLR4, myeloid differentiation response gene 88, or TRIF, the clinical course was significantly attenuated compared to wild-type mice. This could be attributed to impaired NF-κB activation, as shown by the absence of nuclear translocation of RelA with a decreased expression of IL-6, IL-12p40, and IL-17A. Remarkably, P0106-125-immunized TLR20/0mice exhibited a delayed recovery as compared to TLR40/0mice, which was because of an impaired T helper cell 2 polarization. Immunized TLR20/0mice were unable to induce OX40 and OX40L by matrix metalloproteinase-2 on splenic dendritic cells. Subsequently, M2 polarization was impaired and macrophages were unable to sufficiently induce T regulatory cells (Tregs). Thus, in the recovery phase, Tregswere significantly increased in TLR40/0mice as compared to wild-type mice, whereas Tregsin immunized TLR20/0mice were only slightly increased. Our data highlight the relevance of innate immunity and, especially, the tight interaction between the innate and the adaptive immune system, which should be considered for therapeutic approaches of autoimmune diseases.
authors.affiliation: Department of Neuropathology, University Hospital of Cologne, Cologne, Germany. Electronic address: anna.brunn@uk-koeln.de.
authors.forename: Anna
authors.initials: A
authors.lastname: Brunn
authors.affiliation: Department of Neuropathology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Mirna
authors.initials: M
authors.lastname: Mihelcic
authors.affiliation: Department of Neuropathology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Mariana
authors.initials: M
authors.lastname: Carstov
authors.affiliation: Department of Neuropathology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Feind
authors.affiliation: Department of Neuropathology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Eva C
authors.initials: EC
authors.lastname: Wieser
authors.affiliation: Department of Neuropathology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schmidt
authors.affiliation: Institute for Medical Microbiology, Immunology, and Hygiene, Medical Center, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Utermöhlen
authors.affiliation: Department of Neuropathology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Deckert
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D015922:Complement C1q / Q000276:immunology; D018450:Disease Progression; D004198:Disease Susceptibility; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D018655:Lymphocyte Count; D008262:Macrophage Activation; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000294:innervation / Q000473:pathology; D018993:Myelin P0 Protein; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009444:Neuritis, Autoimmune, Experimental / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D053278:OX40 Ligand / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053262:Receptors, OX40 / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D015922:Complement C1q; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007371:Interferon-gamma; D020778:Matrix Metalloproteinase 2; D018993:Myelin P0 Protein; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D053278:OX40 Ligand; D012333:RNA, Messenger; D053262:Receptors, OX40; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse