Inflammation and neurodegeneration in mouse nervous system : experimental application

Abstract

Experimental autoimmune neuritis (EAN) is a CD4+ T cell mediated inflammatory autoimmune disease of peripheral nervous system (PNS) and shares many of clinical, immunological, electrophysiological and morphological characteristics of human Guillain-Barré syndrome (GBS). Hence, EAN is considered to represent a useful model for studying the pathogenesis and therapy of human GBS.

The role of CC Chemokine receptor 5 (CCR5) has been investigated in CCR5 knockout (CCR5-/-) mice with EAN induced by PNS myelin protein PO peptide 180-199. CCR5-/- mice showed a similar clinical course and severity of EAN as well as the profile of infiltrating inflammatory cells in cauda equina (CE) of mice, and the same levels of spleen mononuclear cell (MNC) response to specific antigen and mitogen when compared with wild-type mice. However, increased IP-10 and MIP-1beta production in inflamed nerves were seen in CCR5-/- EAN mice. These results suggest that CCR5 deficiency does not prevent PO peptide 180-199 immunized mice from EAN. Increased MIP-1beta and IP-10 in inflamed nerves may compensate the CCR5 deficiency and contribute to inflammatory cells infiltrating to the PNS.

To investigate the effects of apolipoprotein E (apoE) on autoimmune mediated inflammatory neuritis, EAN was induced in apoE knockout (apoE-/-) mice. ApoE-/- mice exhibited a greater susceptibility to EAN, increased inflammatory cell infiltrates in the PNS, enhanced antigen-specific proliferation of T cells, up-regulation of Th1 and down-regulation of Th2 auto-reactive responses, as well as enhanced antigen-specific antibody responses as compared with wild-type mice. Enhanced antigen-specific proliferation of T cells in apoE-/- mice is relative to the modified macrophage function. These data provide a strong evidence that apoE acts as an inhibitor of this inflammatory and demyelinating disease by up-regulating Th2 and inhibiting Th1 responses and antigen- specific antibody formation.

Intranasal administration of kainic acid (KA) to C57BL/6 mice resulted in neurodegeneration in area CA3 of hippocampus. Enhanced FAS and glial fibrillary acidic protein (GFAP) expression in hippocampus of mice was detected on day 7 after KA administration by immunohistochemistry and Western blotting. Microglia were markedly activated on day 1 and 3, but less activated on day 5 after KA administration by immunohistochemistry and flow cytometry analysis. These data indicated that KA administration results in an early microglial activation and a prolonged astrogliosis in hippocampus of C57BL/6 mice.

To study the role of apoE in neurodegenerative disorders of central nervous system (CNS), apoE-/- mice received KA intranasally. After KA insult, apoE-/- mice exhibited lower activity, decreased rearing and stronger microglial activation, particularly in the lesioned area, as well as more severe neurodegeneration in the hippocampus. Microglial activation was confirmed by high levels of mean fluorescence intensity (MFI) of CD11b and CD86 expressed on microglia of the hippocampus of apoE-/- mice treated with KA. The percentage of CCR3 positive microglia in the hippocampus of apoE-/- mice was enhanced prominently after KA insult, though the level of RANTES expression did not differ between apoE -/and wild-type mice. Our data suggest that apoE deficiency worsens neurodegeneration and increases microglial activation as well as CCR3 expression in KA induced hippocampal neurodegeneration.

In summary, apoE is involved in the inflammatory pathogenesis of EAN and KA-induced neurodegeneration. CCR5 deficiency in EAN can be compensated by increased MIP-1beta and IP-10 in inflamed nerves. KA administration results in an early microglial activation and a prolonged astrogliosis in C57BL/6 mice.