title: CCR2 gene deletion and pharmacologic blockade ameliorate a severe murine experimental autoimmune neuritis model of Guillain-Barré syndrome.
abstract: The molecular determinants and signaling pathways responsible for hematogenous leukocyte trafficking during peripheral neuroinflammation are incompletely elucidated. Chemokine ligand/receptor pair CCL2/CCR2 has been pathogenically implicated in the acute inflammatory demyelinating polyradiculoneuropathy variant of Guillain-Barré syndrome (GBS). We evaluated the role of CCR2 in peripheral neuroinflammation utilizing a severe murine experimental autoimmune neuritis (sm-EAN) model. Sm-EAN was induced in 8-12 week old female SJL CCR2 knockout (CCR2KO), heterozygote (CCR2HT) and wild type (CCR2WT) mice, and daily neuromuscular severity scores and weights recorded. In vitro and in vivo splenocyte proliferation and cytokine expression assays, and sciatic nerve Toll-like receptor (TLR) 2, TLR4 and CCL2 expression assays were performed to evaluate systemic and local innate immune activation at disease onset. Motor nerve electrophysiology and sciatic nerve histology were also performed to characterize the inflammatory neuropathy at expected peak severity. To further determine the functional relevance of CCR2 in sm-EAN, 20 mg/kg CCR2 antagonist, RS 102895 was administered daily for 5 days to a cohort of CCR2WT mice following sm-EAN disease onset, with efficacy compared to 400 mg/kg human intravenous immunoglobulin (IVIg). CCR2KO mice were relatively resistant to sm-EAN compared to CCR2WT and CCR2HT mice, associated with attenuated peripheral nerve demyelinating neuritis. Partial CCR2 gene deletion did not confer any protection against sm-EAN. CCR2KO mice demonstrated similar splenocyte activation or proliferation profiles, as well as TLR2, TLR4 and CCL2 expression to CCR2WT or CCR2HT mice, implying a direct role for CCR2 in sm-EAN pathogenesis. CCR2 signaling blockade resulted in rapid, near complete recovery from sm-EAN following disease onset. RS 102895 was significantly more efficacious than IVIg. CCR2 mediates pathogenic hematogenous monocyte trafficking into peripheral nerves, with consequential demyelination in sm-EAN. CCR2 is amenable to pharmacologic blockade, making it a plausible drug target for GBS.
authors.affiliation: Neuromuscular Immunopathology Research Laboratory, Department of Neurology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Furong
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Neuromuscular Immunopathology Research Laboratory, Department of Neurology, Baylor College of Medicine, Houston, Texas, United States of America; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Nejla
authors.initials: N
authors.lastname: Yosef
authors.affiliation: Neuromuscular Immunopathology Research Laboratory, Department of Neurology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Chetan
authors.initials: C
authors.lastname: Lakshmana Reddy
authors.affiliation: Neuromuscular Immunopathology Research Laboratory, Department of Neurology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Ailing
authors.initials: A
authors.lastname: Huang
authors.affiliation: Department of Statistics, Rice University, Houston, Texas, United States of America.
authors.forename: Sharon C
authors.initials: SC
authors.lastname: Chiang
authors.affiliation: Neuromuscular Immunopathology Research Laboratory, Department of Neurology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Hafiza Rahman
authors.initials: HR
authors.lastname: Tithi
authors.affiliation: Neuromuscular Immunopathology Research Laboratory, Department of Neurology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Eroboghene E
authors.initials: EE
authors.lastname: Ubogu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D020275:Guillain-Barre Syndrome / Q000235:genetics / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D009444:Neuritis, Autoimmune, Experimental / Q000235:genetics / Q000628:therapy*; D010525:Peripheral Nerves / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics / Q000502:physiology*; D012584:Sciatic Nerve / Q000378:metabolism
chemical_list: C515335:Ccr2 protein, mouse; D016207:Cytokines; D054390:Receptors, CCR2