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Updated: Jun 21, 2026
Induction of Experimental Autoimmune Encephalomyelitis in Mice and Evaluation of the Disease-dependent Distribution of Immune Cells in Various Tissues
Published on: May 8, 2016
Inhibition of CXCR2 signaling promotes recovery in models of multiple sclerosis
A E Kerstetter1, D A Padovani-Claudio, L Bai
1Department of Neurosciences and Center for Translational Neuroscience, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Abstract:
Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination/remyelination episodes that ultimately fail. Chemokines and their receptors have been implicated in both myelination and remyelination failure. Chemokines regulate migration, proliferation and differentiation of immune and neural cells during development and pathology. Previous studies have demonstrated that the absence of the chemokine receptor CXCR2 results in both disruption of early oligodendrocyte development and long-term structural alterations in myelination. Histological studies suggest that CXCL1, the primary ligand for CXCR2, is upregulated around the peripheral areas of demyelination suggesting that this receptor/ligand combination modulates responses to injury. Here we show that in focal LPC-induced demyelinating lesions, localized inhibition of CXCR2 signaling reduced lesion size and enhanced remyelination while systemic treatments were relatively less effective. Treatment of spinal cord cultures with CXCR2 antagonists reduced CXCL1 induced A2B5+ cell proliferation and increased differentiation of myelin producing cells. More critically, treatment of myelin oligodendrocyte glycoprotein peptide 35-55-induced EAE mice, an animal model of multiple sclerosis, with small molecule antagonists against CXCR2 results in increased functionality, decreased lesion load, and enhanced remyelination. Our findings demonstrate the importance of antagonizing CXCR2 in enhancing myelin repair by reducing lesion load and functionality in models of multiple sclerosis and thus providing a therapeutic target for demyelinating diseases.
Insights
Blocking the chemokine receptor CXCR2 aids myelin repair in multiple sclerosis models. Inhibiting CXCR2 signaling reduces lesion size and improves functionality, offering a potential therapeutic strategy for demyelinating diseases.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Multiple sclerosis (MS) involves damaging demyelination/remyelination cycles.
- Chemokine signaling, particularly involving CXCR2 and its ligand CXCL1, is implicated in oligodendrocyte development and remyelination failure.
- Previous studies show absence of CXCR2 disrupts oligodendrocyte development and myelination.
Purpose of the Study:
- To investigate the therapeutic potential of antagonizing CXCR2 in models of demyelinating diseases.
- To determine if localized or systemic inhibition of CXCR2 signaling impacts lesion size and remyelination.
- To evaluate the effect of CXCR2 antagonists on cell proliferation and differentiation in spinal cord cultures and on disease outcomes in an animal model of MS.
Main Methods:
- Utilized focal lysolecithin (LPC)-induced demyelination models in spinal cord cultures and in vivo.
- Administered localized and systemic CXCR2 signaling inhibitors.
- Treated spinal cord cultures with CXCR2 antagonists to assess effects on A2B5+ cell proliferation and myelin production.
- Used myelin oligodendrocyte glycoprotein peptide 35-55-induced experimental autoimmune encephalomyelitis (EAE) mice, a model for MS, treated with CXCR2 antagonists.
Main Results:
- Localized inhibition of CXCR2 signaling in LPC-induced lesions reduced lesion size and enhanced remyelination.
- Systemic treatments showed less effectiveness compared to localized inhibition.
- CXCR2 antagonists reduced CXCL1-induced A2B5+ cell proliferation and promoted differentiation of myelin-producing cells in vitro.
- Treatment of EAE mice with CXCR2 antagonists led to improved functionality, reduced lesion load, and enhanced remyelination.
Conclusions:
- Antagonizing CXCR2 is a promising therapeutic strategy for enhancing myelin repair in demyelinating diseases like MS.
- Targeting CXCR2 signaling effectively reduces lesion load and improves functional recovery in experimental models.
- This study highlights the critical role of the CXCL1/CXCR2 axis in modulating the response to demyelination and suggests CXCR2 antagonists as potential treatments for MS.
