A role for CXCL12 (SDF-1α) in the pathogenesis of multiple sclerosis: Regulation of CXCL12 expression in astrocytes by soluble myelin basic protein

Tina M. Calderon, Eliseo Eugenin, Lillie Lopez, Sridhar Sampath Kumar, Joseph Hesselgesser, Cedric S. Raine, Joan W. Berman

Research output: Contribution to journalArticle

116 Citations (Scopus)

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-1α), 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-1β 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-1β. 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.

Original languageEnglish (US)
Pages (from-to)27-39
Number of pages13
JournalJournal of Neuroimmunology
Volume177
Issue number1-2
DOIs
StatePublished - Aug 1 2006
Externally publishedYes

Fingerprint

Myelin Basic Protein
Astrocytes
Multiple Sclerosis
Endothelial Cells
Monocytes
Central Nervous System
Interleukin-1
Leukocyte Chemotaxis
Staining and Labeling
CXCR4 Receptors
T-Lymphocytes
Chemokine CXCL12
MAP Kinase Signaling System
Chemotactic Factors
Oligodendroglia
Human Umbilical Vein Endothelial Cells
Brain
Demyelinating Diseases
Interleukin-8
Chemokines

Keywords

  • Chemokines
  • CXCL12
  • MBP
  • Multiple sclerosis
  • Signaling

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Neurology
  • Clinical Neurology

Cite this

A role for CXCL12 (SDF-1α) in the pathogenesis of multiple sclerosis : Regulation of CXCL12 expression in astrocytes by soluble myelin basic protein. / Calderon, Tina M.; Eugenin, Eliseo; Lopez, Lillie; Kumar, Sridhar Sampath; Hesselgesser, Joseph; Raine, Cedric S.; Berman, Joan W.

In: Journal of Neuroimmunology, Vol. 177, No. 1-2, 01.08.2006, p. 27-39.

Research output: Contribution to journalArticle

Calderon, Tina M. ; Eugenin, Eliseo ; Lopez, Lillie ; Kumar, Sridhar Sampath ; Hesselgesser, Joseph ; Raine, Cedric S. ; Berman, Joan W. / A role for CXCL12 (SDF-1α) in the pathogenesis of multiple sclerosis : Regulation of CXCL12 expression in astrocytes by soluble myelin basic protein. In: Journal of Neuroimmunology. 2006 ; Vol. 177, No. 1-2. pp. 27-39.
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AU - Eugenin, Eliseo

AU - Lopez, Lillie

AU - Kumar, Sridhar Sampath

AU - Hesselgesser, Joseph

AU - Raine, Cedric S.

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