Initiation and Progression of Axonopathy in Experimental Autoimmune Encephalomyelitis

Abstract

Axonal loss is the principal cause of chronic disability in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). In C57BL/6 mice with EAE induced by immunization with myelin oligodendrocyte glycoprotein peptide 35-55, the first evidences of axonal damage in spinal cord were in acute subpial and perivascular foci of infiltrating neutrophils and lymphocytes and included intra-axonal accumulations of the endovesicular Toll-like receptor TLR8, and the inflammasome protein NAcht leucine-rich repeat protein 1 (NALP1). Later in the course of this illness, focal inflammatory infiltrates disappeared from the spinal cord, but there was persistent activation of spinal cord innate immunity and progressive, bilaterally symmetric loss of small-diameter corticospinal tract axons. These results support the hypothesis that both contact-dependent and paracrine interactions of systemic inflammatory cells with axons and an innate immune-mediated neurodegenerative process contribute to axonal loss in this multiple sclerosis model.

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

“…This infiltration pattern is reminiscent of a short-lived myeloid population, which together with their high number and early course of action relative to BSCB disruption led us to hypothesize that GFP + infiltrates are mainly composed of neutrophils. This hypothesis is supported by earlier studies that showed that neutrophil infiltration increases during EAE onset, remains high at the peak of disease, and dramatically declines thereafter (18,62).…”

Hyaluronan Anchored to Activated CD44 on Central Nervous System Vascular Endothelial Cells Promotes Lymphocyte Extravasation in Experimental Autoimmune Encephalomyelitis

“…However, the causative relationship between PEG-PH20 treatment and reduced axonal damage is unclear due to fewer CD4 ϩ cells in the spinal cord at this time point. A recent EAE study demonstrates foci of infiltrating immune cells correlate with locally impaired axonal transport and markers of axonal damage at disease onset (51). It is likely the increase in spared axons is related to lower levels of inflammation within demyelinating lesions and not directly attributable to the activity of PEG-PH20.…”

Critical role for PDE4 subfamilies in the development of experimental autoimmune encephalomyelitis

“…Therefore the upregulation of PDE4B2 mRNA that we report here, in areas with high amount of cellular infiltrates and around the microvessels, together with the role of cAMP in the antigen presentation process (Fallarino et al, 2010) The amelioration of the clinical signs and delayed onset of EAE described after PDE4 inhibition (Folcik et al, 1999;Martinez et al, 1999;Moore et al, 2006;Sommer et al, 1995) T-cell populations that have a crucial role in the EAE model are Th1-and Th17-positive cells (Komiyama et al, 2006;Tzartos et al, 2008;Zamvil and Steinman 1990). These immune cells infiltrate and attack oligodendrocytes, activate resident microglia and astrocytes, leading to demyelination and axonal damage in the EAE model (Lassmann et al, 2001;Soulika et al, 2009). Another T-cell population, FoxP3 + Treg cells, regulates the immunological response e.g.…”

“…Several days after immunization, immune cells start to infiltrate the CNS and microglial cells are activated, predominantly affecting the spinal cord but also other brain structures like the cerebellum and the optic tract (Brown and Sawchenko 2007). This is followed by axonal damage and demyelination (Soulika et al, 2009).…”