Selective expression and cellular localization of pro-inflammatory chemokine ligand/receptor pairs in the sciatic nerves of a severe murine experimental autoimmune neuritis model of Guillain-Barré syndrome.
OBJECTIVE
To determine if specific pro-inflammatory chemokine ligand/receptor pairs expressed in the peripheral nerves of Guillain-Barré syndrome patients are expressed in a severe murine experimental autoimmune neuritis (sm-EAN) model and to determine their cellular localization as a prerequisite to designing potentially therapeutic interventions in vivo.


METHODS
Sm-EAN was induced in 8-12-week-old female SJL/J mice using bovine peripheral nerve myelin emulsified in complete Freund adjuvant with pertussis toxin and recombinant mouse interleukin-12 acting as co-adjuvants, with appropriate controls. Mice were evaluated for neuromuscular weakness and weighed daily. Dorsal caudal tail and sciatic nerve motor electrophysiological studies were performed at expected maximal severity. Sciatic nerves were harvested and specific chemokine ligand/receptor expression was determined using real-time quantitative reverse transcriptase polymerase chain reaction and indirect fluorescent immunohistochemistry.


RESULTS
CCL2/CCR2, CXCL10/CXCR3 and CCL5/CCR1, CCR5 expression was significantly increased in the sciatic nerves of sm-EAN mice compared with controls. CCL2 was expressed on Schwann cells with CCR2 expressed on F4/80+ macrophages and CD3+ T cells. CXCL10 was expressed on endoneurial endothelial cells and within the endoneurial interstitium, with CXCR3 expressed on CD3+ T-lymphocytes. CCL5 co-localized to axons, with CCR1 and CCR5 expression on F4/80+ macrophages and rare CD3+ T cells.


CONCLUSIONS
This study suggests that CCL2 expressed by Schwann cells and CXCL10 expressed by endoneurial endothelial cells may induce F4/80+ macrophage and CD3+ T cell-mediated inflammation and demyelination in sm-EAN. CCL2-CCR2 and CXCL10-CXCR3 signalling pathways are potential targets for therapeutic intervention in peripheral nerve inflammation.
Xia
R H
RH
Neuromuscular Immunopathology Research Laboratory, Department of Neurology, Baylor College of Medicine, Houston, Texas 77030-3411, USA.
Yosef
N
N
Ubogu
E E
EE
D000818:Animals; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism; D018946:Chemokine CCL5 / Q000276:immunology / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020275:Guillain-Barre Syndrome / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D009431:Neural Conduction / Q000276:immunology; D009444:Neuritis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D010525:Peripheral Nerves / Q000166:cytology / Q000276:immunology; D054389:Receptors, CCR1 / Q000276:immunology / Q000378:metabolism; D054390:Receptors, CCR2 / Q000276:immunology / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000276:immunology / Q000378:metabolism; D012583:Schwann Cells / Q000276:immunology; D012584:Sciatic Nerve / Q000166:cytology / Q000276:immunology; D020426:Sciatic Neuropathy / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology
C491768:Ccl2 protein, mouse; C503460:Ccl5 protein, mouse; C515301:Ccr1 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D054367:Receptors, CXCR3