Rescue from acute neuroinflammation by pharmacological chemokine-mediated deviation of leukocytesReport as inadecuate




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Journal of Neuroinflammation

, 9:243

First Online: 25 October 2012Received: 15 May 2012Accepted: 11 October 2012

Abstract

BackgroundNeutrophil influx is an important sign of hyperacute neuroinflammation, whereas the entry of activated lymphocytes into the brain parenchyma is a hallmark of chronic inflammatory processes, as observed in multiple sclerosis MS and its animal models of experimental autoimmune encephalomyelitis EAE. Clinically approved or experimental therapies for neuroinflammation act by blocking leukocyte penetration of the blood brain barrier. However, in view of unsatisfactory results and severe side effects, complementary therapies are needed. We have examined the effect of chlorite-oxidized oxyamylose COAM, a potent antiviral polycarboxylic acid on EAE.

MethodsEAE was induced in SJL-J mice by immunization with spinal cord homogenate SCH or in IFN-γ-deficient BALB-c KO mice with myelin oligodendrocyte glycoprotein peptide MOG35-55. Mice were treated intraperitoneally i.p. with COAM or saline at different time points after immunization. Clinical disease and histopathology were compared between both groups. IFN expression was analyzed in COAM-treated MEF cell cultures and in sera and peritoneal fluids of COAM-treated animals by quantitative PCR, ELISA and a bioassay on L929 cells. Populations of immune cell subsets in the periphery and the central nervous system CNS were quantified at different stages of disease development by flow cytometry and differential cell count analysis. Expression levels of selected chemokine genes in the CNS were determined by quantitative PCR.

ResultsWe discovered that COAM 2 mg i.p. per mouse on days 0 and 7 protects significantly against hyperacute SCH-induced EAE in SJL-J mice and MOG35-55-induced EAE in IFN-γ KO mice. COAM deviated leukocyte trafficking from the CNS into the periphery. In the CNS, COAM reduced four-fold the expression levels of the neutrophil CXC chemokines KC-CXCL1 and MIP-2-CXCL2. Whereas the effects of COAM on circulating blood and splenic leukocytes were limited, significant alterations were observed at the COAM injection site.

ConclusionsThese results demonstrate novel actions of COAM as an anti-inflammatory agent with beneficial effects on EAE through cell deviation. Sequestration of leukocytes in the non-CNS periphery or draining of leukocytes out of the CNS with the use of the chemokine system may thus complement existing treatment options for acute and chronic neuroinflammatory diseases.

KeywordsEncephalitis Leukocytes Chemokines Central nervous system AbbreviationsBBBBlood–brain barrier

CFAComplete Freund’s adjuvant

CNSCentral nervous system

COAMChlorite-oxidized oxyamylose

EAEExperimental autoimmune encephalomyelitis

ELISAEnzyme-linked immunosorbent assay

FCSFetal calf serum

H and EHaematoxylin and eosin

IFAIncomplete Freund’s adjuvant

IFNInterferon

i.p.Intraperitoneally

i.v.Intravenously

mAbMonoclonal antibody

MEFMouse embryonic fibroblasts

MEMModified Eagle’s medium

MOGMyelin oligodendrocyte glycoprotein

MSMultiple sclerosis

PBSPhosphate-buffered saline

SCHSpinal cord homogenate

qPCRQuantitative polymerase chain reaction.

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