title: MMP-independent role of TIMP-1 at the blood brain barrier during viral encephalomyelitis.
abstract: Infection of the CNS (central nervous system) with a sublethal neurotropic coronavirus (JHMV) induces a vigorous inflammatory response. CD4⁺ and CD8⁺ T cells are essential to control infectious virus but at the cost of tissue damage. An enigma in understanding the contribution of T cell subsets in pathogenesis resides in their distinct migration pattern across the BBB (blood brain barrier). CD4⁺ T cells transiently accumulate within the perivascular space, whereas CD8⁺ T cells migrate directly into the CNS parenchyma. As MMPs (matrix metalloproteinases) facilitate migration across the glia limitans, specific expression of the TIMP (tissue inhibitor of MMPs)-1 by CD4⁺ T cells present in the perivascular cuffs suggested that TIMP-1 is responsible for stalling CD4⁺ T cell migration into the CNS parenchyma. Using TIMP-1 deficient mice, the present data demonstrate an increase rather than a decrease in CD4⁺ T cell accumulation within the perivascular space during JHMV infection. Whereas virus control was not affected by perivascular retention of CD4⁺ T cells, disease severity was decreased and associated with reduced IFNγ (interferon γ) production. Moreover, decreased CD4⁺ T cell recruitment into the CNS parenchyma of TIMP-1 deficient mice was not associated with impaired T cell recruiting chemokines or MMP expression, and no compensation by other TIMP molecules was identified. These data suggest an MMP-independent role of TIMP-1 in regulating CD4⁺ T cell access into the CNS parenchyma during acute JHMV encephalitis.
authors.affiliation: *Department of Neurosciences NC-30, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, U.S.A.
authors.forename: Carine
authors.initials: C
authors.lastname: Savarin
authors.affiliation: *Department of Neurosciences NC-30, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, U.S.A.
authors.forename: Cornelia C
authors.initials: CC
authors.lastname: Bergmann
authors.affiliation: †Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, U.S.A.
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
authors.affiliation: *Department of Neurosciences NC-30, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, U.S.A.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Stohlman
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000503:physiopathology / Q000821:virology; D001921:Brain / Q000473:pathology / Q000821:virology; D018946:Chemokine CCL5 / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000378:metabolism; D017934:Coronavirus / Q000502:physiology; D018352:Coronavirus Infections / Q000150:complications; D004195:Disease Models, Animal; D004679:Encephalomyelitis / Q000209:etiology / Q000473:pathology* / Q000821:virology*; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000172:deficiency* / Q000235:genetics
chemical_list: D015703:Antigens, CD; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D012333:RNA, Messenger; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D020782:Matrix Metalloproteinases