Neuroprotection and remyelination after autoimmune demyelination in mice that inducibly overexpress CXCL1.
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 beta-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.
Omari
Kakuri M
KM
Department of Pathology (Neuropathology), Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Lutz
Sarah E
SE
Santambrogio
Laura
L
Lira
Sergio A
SA
Raine
Cedric S
CS
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism
D054360:Chemokine CXCL1