Role for CXCR2 and CXCL1 on glia in multiple sclerosis

Omari, Kakuri M.; John, Gareth R.; Lango, Richard; Raine, Cedric S.

doi:10.1002/glia.20246

Cited by 126 publications

(103 citation statements)

References 32 publications

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“…24,55 Similar to our earlier results in human tissue, findings from the current study suggest that CXCL1/CXCR2-mediated signals might influence oligodendrocyte behavior during the course of inflammation in the CNS. Double-Tg, CXCL1, or GFAP single-Tg and wild-type littermate mice all developed EAE when sensitized with MOG peptide, indicating that the two transgenes did not affect disease susceptibility.…”

Section: Discussionsupporting

confidence: 89%

Neuroprotection and Remyelination after Autoimmune Demyelination in Mice that Inducibly Overexpress CXCL1

Omari

Lutz

Santambrogio

et al. 2009

The American Journal of Pathology

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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 ؋ ␤-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.

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Section: Discussionsupporting

confidence: 89%

Neuroprotection and Remyelination after Autoimmune Demyelination in Mice that Inducibly Overexpress CXCL1

Omari

Lutz

Santambrogio

et al. 2009

The American Journal of Pathology

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“…Increased expression of these factors has also been demonstrated in experimental models of remyelination (Hinks and Franklin, 1999). Cytokines (TGF␤1, TNF␣), chemokines (CXCL1), extracellular matrix components (high-molecular-weight glycosaminoglycans), and developmental cues (Jagged1) have also been shown to regulate the behavior of fetal or perinatal OPCs (McKinnon et al, 1993;Wu et al, 2000;Arnett et al, 2001;John et al, 2002;Back et al, 2005), and to be expressed in MS lesions (Cannella and Raine, 1995;John et al, 2002;Back et al, 2005;Omari et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-11 Potentiates Oligodendrocyte Survival and Maturation, and Myelin Formation

Zhang¹,

Taveggia²,

et al. 2006

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Mechanisms that regulate oligodendrocyte survival and myelin formation are an intense focus of research into myelin repair in the lesions of multiple sclerosis (MS). Although demyelination and oligodendrocyte loss are pathological hallmarks of the disease, increased oligodendrocyte numbers and remyelination are frequently observed in early lesions, but these diminish as the disease course progresses. In the current study, we used a microarray-based approach to investigate genes regulating repair in MS lesions, and identified interleukin-11 (IL-11) as an astrocyte-derived factor that potentiates oligodendrocyte survival and maturation, and myelin formation. IL-11 was induced in human astrocyte cultures by the cytokines IL-1␤ and TGF␤1, which are both prominently expressed in MS plaques. In MS tissue samples, IL-11 was expressed by reactive astrocytes, with expression particularly localized at the myelinated border of both active and silent lesions. Its receptor, IL-11R␣, was expressed by oligodendrocytes. In experiments in human cultures in vitro, IL-11R␣ localized to immature oligodendrocytes, and its expression decreased during maturation. In cultures treated with IL-11, we observed a significant increase in oligodendrocyte number, and this was associated with enhanced oligodendrocyte survival and maturation. Importantly, we also found that IL-11 treatment was associated with significantly increased myelin formation in rodent CNS cocultures. These data are the first to implicate IL-11 in oligodendrocyte viability, maturation, and myelination. We suggest that this pathway may represent a potential therapeutic target for oligodendrocyte protection and remyelination in MS.

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“…The interaction between epithelial cancer cells and stromal cells may be especially important in the development of various epithelial cancers, including breast cancer, colon cancer, prostate cancer, and glioma (34)(35)(36)(37), and in aging (3,(38)(39)(40). Some studies have shown that the interaction of ovarian cancer epithelial cells and stromal cells stimulates the progression of ovarian epithelial cancers (41,42).…”

Section: Discussionmentioning

confidence: 99%

The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis

Yang¹,

Rosen²,

Zhang³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

302

257

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Epithelial-stromal interactions play a critical role in tumor initiation and progression; cancer-associated stroma, but not normal stroma, is known to be tumor-promoting. However, the molecular signal used by epithelial cancer cells to reprogram normal stroma to a tumorigenic stroma is not known. Here, we present evidence to suggest that the chemokine growth-regulated oncogene 1 (Gro-1) may be one such signaling molecule. We showed that the expression of Gro-1 is activated by RAS and is vital for cell survival and the malignant transformation of ovarian epithelial cells. Surprisingly, we found that Gro-1 is a potent inducer of senescence in stromal fibroblasts and that this effect depends on functional p53. Senescent fibroblasts induced by Gro-1 can promote tumor growth whereas abrogation of senescence through immortalization results in loss of such tumor promoting activity. We also demonstrated that stromal fibroblasts adjacent to epithelial cancer cells are senescent in human ovarian cancer specimens and in heterografts from RAS-transformed human ovarian epithelial cells and ovarian cancer cells. Moreover, Gro-1 was expressed at significantly higher amounts in ovarian cancer than in normal tissues and was higher in serum samples from women with ovarian cancer than in serum from women without ovarian cancer. These findings provide strong evidence that RAS-induced Gro-1 can reprogram the stromal microenvironment through the induction of senescence of fibroblasts and thus can promote tumorigenesis. Therefore, Gro-1 may be a therapeutic target as well as a diagnostic marker in ovarian cancer.ovarian cancer ͉ Ras ͉ transformation ͉ tumor microenvironment

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Role for CXCR2 and CXCL1 on glia in multiple sclerosis

Cited by 126 publications

References 32 publications

Neuroprotection and Remyelination after Autoimmune Demyelination in Mice that Inducibly Overexpress CXCL1

Neuroprotection and Remyelination after Autoimmune Demyelination in Mice that Inducibly Overexpress CXCL1

Interleukin-11 Potentiates Oligodendrocyte Survival and Maturation, and Myelin Formation

The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis

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