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.
Highlights
Neutrophil 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)
Neuroinflammation is a common denominator in a wide variety of diseases of the central nervous system (CNS), ranging from various forms of acute infectious or vascular meningoencephalitis to chronic inflammation associated with multiple sclerosis (MS) or neurodegenerative diseases
chlorite-oxidized oxyamylose (COAM) protects against hyperacute and chronic EAE without inducing interferon-β Monophasic hyperacute EAE in SJL/J mice was induced by immunization with syngeneic spinal cord homogenate (SCH) in Complete Freund’s Adjuvant (CFA) and mice were treated by injection of COAM (2 mg i.p.) at various time points
Summary
Neutrophil 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). Hyperacute experimental autoimmune encephalomyelitis (EAE), named as such to distinguish it from T cell-mediated forms of EAE, is induced by immunization of mice with spinal cord homogenates, has an important neutrophil component [1] and is an appropriate model for the study of neuroinflammation in acute encephalitis. Neuroinflammation occurs upon migration of leukocytes through the endothelial and parenchymal layers of the BBB in order to gain access to the CNS parenchyma [5] and as a result of chemokine-governed attraction of specific leukocytes to the CNS [6]. Current ways to prevent leukocyte entry into the CNS include treatment with IFN-α/β or antiadhesive agents that prevent binding of leukocytes to CNS endothelium [7,8]
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