Induced CNS expression of CXCL1 augments neurologic disease in a murine model of multiple sclerosis via enhanced neutrophil recruitment.

Abstract

Increasing evidence points to an important role for neutrophils in participating in the pathogenesis of the human demyelinating disease MS and the animal model EAE. Therefore, a better understanding of the signals controlling migration of neutrophils as well as evaluating the role of these cells in demyelination is important to define cellular components that contribute to disease in MS patients. In this study, we examined the functional role of the chemokine CXCL1 in contributing to neuroinflammation and demyelination in EAE. Using transgenic mice in which expression of CXCL1 is under the control of a tetracycline-inducible promoter active within glial fibrillary acidic protein-positive cells, we have shown that sustained CXCL1 expression within the CNS increased the severity of clinical and histologic disease that was independent of an increase in the frequency of encephalitogenic Th1 and Th17 cells. Rather, disease was associated with enhanced recruitment of CD11b+ Ly6G+ neutrophils into the spinal cord. Targeting neutrophils resulted in a reduction in demyelination arguing for a role for these cells in myelin damage. Collectively, these findings emphasize that CXCL1-mediated attraction of neutrophils into the CNS augments demyelination suggesting that this signaling pathway may offer new targets for therapeutic intervention.

• Authors: Jonathan J Grist, Brett S Marro, Dominic D Skinner, Amber R Syage, Colleen Worne, Daniel J Doty, Robert S Fujinami, Thomas E Lane
• Journal: European journal of immunology (Eur J Immunol) Vol. 48 Issue 7 Pg. 1199-1210 (07 2018) ISSN: 1521-4141 [Electronic] Germany
• PMID: 29697856 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Autoantigens
• CD11b Antigen
• Chemokine CXCL1
• Myelin-Oligodendrocyte Glycoprotein
• Peptide Fragments
• myelin oligodendrocyte glycoprotein (35-55)

Topics

• Animals
• Autoantigens (immunology)
• CD11b Antigen (metabolism)
• Cells, Cultured
• Central Nervous System (immunology)
• Chemokine CXCL1 (genetics, metabolism)
• Disease Models, Animal
• Encephalomyelitis, Autoimmune, Experimental (immunology)
• Gene Expression Regulation
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Molecular Targeted Therapy
• Multiple Sclerosis (immunology)
• Myelin-Oligodendrocyte Glycoprotein (immunology)
• Neurogenic Inflammation
• Neutrophil Infiltration
• Neutrophils (immunology)
• Peptide Fragments (immunology)
• Signal Transduction
• Spinal Cord (immunology, pathology)