Neuroprotection and remyelination after autoimmune demyelination in mice that inducibly overexpress CXCL1

Kakuri M. Omari, Sarah E. Lutz, Laura Santambrogio, Sergio A. Lira, Cedric S. Raine

Research output: Contribution to journalArticle

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Abstract

In rodents, the chemokine CXCL1 both induces the proliferation and inhibits the migration of oligodendrocyte precursor cells. We previously reported that in multiple sclerosis, the same chemokine is expressed by hypertrophic astrocytes, which associate with oligodendrocytes that express the receptor CXCR2. To investigate whether chemokines influence repair after autoimmune demyelination, we generated GFAP-rtTA x β-Gal-TRE-CXCL1 double-transgenic (Tg) mice that inducibly overexpress CXCL1 under the control of the astrocyte-specific gene, glial fibrillary acidic protein. Experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, was induced in these animals (and controls) by the subcutaneous injection of myelin oligodendrocyte glycoprotein, and after disease onset, CXCL1 production was initiated by the intraperitoneal injection of doxycycline. Double-Tg animals displayed a milder course of disease compared with both single (CXCL1 or glial fibrillary acidic protein)-Tg and wild-type controls. Pathologies were similar in all groups during the acute stage of disease. During the chronic disease phase, both inflammation and demyelination were diminished in double-Tg mice and Wallerian degeneration was markedly decreased. Remyelination was strikingly more prominent in double-Tg mice, together with an apparent increased number of oligodendrocytes. Moreover, cell proliferation, indicated by BrdU incorporation within the central nervous system, was more widespread in the white matter of double-Tg animals. These findings suggest a neuroprotective role for CXCL1 during the course of autoimmune demyelination.

Original languageEnglish (US)
Pages (from-to)164-176
Number of pages13
JournalAmerican Journal of Pathology
Volume174
Issue number1
DOIs
StatePublished - Jan 2009

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Oligodendroglia
Demyelinating Diseases
Transgenic Mice
Genetically Modified Animals
Glial Fibrillary Acidic Protein
Chemokines
Astrocytes
Multiple Sclerosis
Chemokine CXCL1
Interleukin-8B Receptors
Myelin-Oligodendrocyte Glycoprotein
Wallerian Degeneration
Autoimmune Experimental Encephalomyelitis
Doxycycline
Acute Disease
Bromodeoxyuridine
Subcutaneous Injections
Intraperitoneal Injections
Rodentia
Chronic Disease

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Neuroprotection and remyelination after autoimmune demyelination in mice that inducibly overexpress CXCL1. / Omari, Kakuri M.; Lutz, Sarah E.; Santambrogio, Laura; Lira, Sergio A.; Raine, Cedric S.

In: American Journal of Pathology, Vol. 174, No. 1, 01.2009, p. 164-176.

Research output: Contribution to journalArticle

Omari, Kakuri M. ; Lutz, Sarah E. ; Santambrogio, Laura ; Lira, Sergio A. ; Raine, Cedric S. / Neuroprotection and remyelination after autoimmune demyelination in mice that inducibly overexpress CXCL1. In: American Journal of Pathology. 2009 ; Vol. 174, No. 1. pp. 164-176.
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