title: A role for CXCL12 (SDF-1alpha) in the pathogenesis of multiple sclerosis: regulation of CXCL12 expression in astrocytes by soluble myelin basic protein.
abstract: The pathogenic mechanisms that contribute to multiple sclerosis (MS) include leukocyte chemotaxis into the central nervous system (CNS) and the production of inflammatory mediators, resulting in oligodendrocyte damage, demyelination, and neuronal injury. Thus, factors that regulate leukocyte entry may contribute to early events in MS, as well as to later stages of lesion pathogenesis. CXCL12 (SDF-1alpha), a chemokine essential in CNS development and a chemoattractant for resting and activated T cells, as well as monocytes, is constitutively expressed at low levels in the CNS and has been implicated in T cell and monocyte baseline trafficking. To determine whether CXCL12 is increased in MS, immunohistochemical analyses of lesions of chronic active and chronic silent MS were performed. CXCL12 protein was detected on endothelial cells (EC) in blood vessels within normal human brain sections and on a small number of astrocytes within the brain parenchyma. In active MS lesions, CXCL12 levels were high on astrocytes throughout lesion areas and on some monocytes/macrophages within vessels and perivascular cuffs, with lesser staining on EC. In silent MS lesions, CXCL12 staining was less than that observed in active MS lesions, and also was detected on EC and astrocytes, particularly hypertrophic astrocytes near the lesion edge. Experiments in vitro demonstrated that IL-1beta and myelin basic protein (MBP) induced CXCL12 in astrocytes by signaling pathways involving ERK and PI3-K. Human umbilical vein EC did not produce CXCL12 after treatment with MBP or IL-1beta. However, these EC cultures expressed CXCR4, the receptor for CXCL12, suggesting that this chemokine may activate EC to produce other mediators involved in MS. In agreement, EC treatment with CXCL12 was found to upregulate CCL2 (MCP-1) and CXCL8 (IL-8) by PI3-K and p38-dependent mechanisms. Our findings suggest that increased CXCL12 may initiate and augment the inflammatory response during MS.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, United States.
authors.forename: Tina M
authors.initials: TM
authors.lastname: Calderon
authors.forename: Eliseo A
authors.initials: EA
authors.lastname: Eugenin
authors.forename: Lillie
authors.initials: L
authors.lastname: Lopez
authors.forename: Sridhar Sampath
authors.initials: SS
authors.lastname: Kumar
authors.forename: Joseph
authors.initials: J
authors.lastname: Hesselgesser
authors.forename: Cedric S
authors.initials: CS
authors.lastname: Raine
authors.forename: Joan W
authors.initials: JW
authors.lastname: Berman
mesh_terms: D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001369:Axons / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018932:Chemokine CCL2 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D042783:Endothelial Cells / Q000276:immunology; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004676:Myelin Basic Protein / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D009186:Myelin Sheath / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014855:Wallerian Degeneration / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: C111835:CCL2 protein, human; C515255:CXCL12 protein, human; D018932:Chemokine CCL2; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D007375:Interleukin-1; D016209:Interleukin-8; D004676:Myelin Basic Protein; D019718:Receptors, CXCR4