Experimental autoimmune neuritis induces differential microglia activation in the rat spinal cord

doi:10.1016/j.jneuroim.2004.10.027

Journal of Neuroimmunology

Volume 160, Issues 1–2, March 2005, Pages 25-31

https://doi.org/10.1016/j.jneuroim.2004.10.027 Get rights and content

Abstract

The reactive spatial and temporal activation pattern of parenchymal spinal cord microglia was analyzed in rat experimental autoimmune neuritis (EAN). We observed a differential activation of spinal cord microglial cells. A significant increase in ED1⁺ microglia predominantly located in the dorsal horn grey matter of lumbar and thoracic spinal cord levels was observed on Day 12. As revealed by morphological criteria and by staining with further activation markers [allograft inflammatory factor 1 (AIF-1), EMAPII, OX6, P2X₄R], reactive microglia did not reach a macrophage-like state of full activation. On Day 12, a significant proliferative response could be observed, affecting all spinal cord areas and including ED1⁺ microglial cells and a wide range of putative progenitor cells. Thus, in rat EAN, a reactive localized and distinct microglial activation correlating with a generalized proliferative response could be observed.

Introduction

Experimental autoimmune neuritis (EAN) is an acute demyelinating inflammatory disease of the peripheral nervous system (PNS) mediated by autoantigen-specific T cells (Gold et al., 1999, Linington et al., 1984, Mäurer and Gold, 2002, Shin et al., 1989, Spies et al., 1995, Taylor and Pollard, 2003).

Histopathologically, EAN is characterized by perivascular inflammatory lesions and severe demyelination of tissues in the PNS. These changes are entirely restricted to the PNS and do not directly involve the central nervous system (CNS) (Izumo et al., 1985). Therefore, only few studies have been performed concerning the impact of EAN on the CNS (Gehrmann et al., 1992, Gehrmann et al., 1993).

In spinal cord, immune-like glial cells (astrocytes and microglia) are activated in response to a variety of peripheral stimuli, resulting from degeneration of central terminals of dying sensory neurons or through the release of substances by incoming sensory afferents or pain-responsive neurons in the dorsal horn (Watkins and Maier, 2002). It has become evident that microglial cells play a key role in regulating the communication among neuronal and other types of glial cells (Nakamura, 2002). Microglia, expressing numerous receptors for CNS signaling molecules, is very sensitive to changes in the CNS microenvironment and rapidly become activated in virtually all conditions that affect normal neuronal function (Piehl and Lidman, 2001).

This study was performed to examine the reactive spatial and temporal activation pattern of spinal cord microglia in rat EAN.

Section snippets

Animals

Male Lewis rats (8–10 weeks old; 170–200 g, Charles River, Sulzfeld, Germany) were kept under controlled conditions of light and temperature. Food and water were available ad libitum. All rats were cared for in accordance with the published International Health Guidelines under a protocol approved by the University of Tübingen Institutional Animal Care and Use Committee and the Administration District Official Committee.

Experimental approach

Rats were immunized by subcutaneous injection of 50 μg of synthetic

Clinical course of EAN

Rats developed first neurological signs of EAN (reduced tail tonicity, Fig. 1) at Day 9 after immunization. Disease severity was maximal at Days 12–13, with rats showing mild to moderate paralysis of the hind limbs or paraparesis (mean clinical score of 5). Rats recovered fast from disease, and, by Day 19, neurological signs were no longer observed. Clinical scores were concomitant with progression of inflammatory response in peripheral nerves, as demonstrated by immunohistochemistry (data not

Discussion

Our study demonstrates that the peripheral inflammatory processes in EAN are mirrored in a central microglial response predominantly located in the grey matter dorsal horn. Spinal cord microglial activation is accompanied by a short-termed but generalized proliferative response affecting the entire spinal cord area.

Pathological activation of microglia has been reported in a wide range of conditions, such as degenerative lesions, cerebral ischemia, Alzheimer's disease, prion diseases, multiple

Acknowledgements

This work has been supported by a grant of the Deutsche Forschungsgemeinschaft (DFG).

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Experimental autoimmune neuritis induces differential microglia activation in the rat spinal cord

Abstract

Introduction

Section snippets

Animals

Experimental approach

Clinical course of EAN

Discussion

Acknowledgements

Brain Res. Bull.

J. Neuroimmunol.

J. Pharmacol. Sci.

Exp. Neurol.

Cell

J. Neuroimmunol.

Neurosci. Lett.

Exp. Neurol.

J. Neuroimmunol.

Exp. Neurol.

Immune function of microglia

Glia

Increased morphological diversity of microglia in the activated hypothalamic supraoptic nucleus

J. Neurosci.

Rat macrophage lysosomal membrane antigen recognized by monoclonal antibody ED1

Immunology

Deficiency of inducible nitric oxide synthase protects against MPTP toxicity in vivo

J. Neurochem.

Spinal cord microglia in experimental allergic neuritis. Evidence for fast and remote activation

Lab. Invest.

Microglial involvement in experimental autoimmune inflammation of the central and peripheral nervous system

Glia