The Clinical Course of Experimental Autoimmune Encephalomyelitis is Associated with a Profound and Sustained Transcriptional Activation of the Genes Encoding Toll‐like Receptor 2 and CD14 in the Mouse CNS

Abstract

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune demyelinating disease commonly used to model the pathogenetic mechanisms involved in multiple sclerosis (MS). In this study, we examined the effects of immunization with the myelin oligodendrocyte glycoprotein MOG35–55 on the expression of molecules of the innate immune system, namely toll‐like receptor 2 (TLR2) and CD14. Expression of the mRNA encoding TLR2 increased in the choroid plexus, the leptomeninges and within few isolated cells in the CNS parenchyma 4 to 8 days after immunization with MOG. At day 10, the signal spread across the meninges, few perivas‐cular regions and over isolated groups of parenchy‐mal cells. Three weeks after the MOG treatment, at which time animals showed severe clinical symptoms, a robust expression of both TLR2 and CD14 transcripts occurred in barrier‐associated structures, as well as parenchymal elements of the spinal cord, and within numerous regions of the brain including, the medulla, cerebellum and the cortex. Dual labeling provided the anatomical evidence that microglia/macrophages were positive for TLR2 in the brain of EAE mice. The regions that exhibited chronic expression of TLR2 and CD14 were also associated with an increase in NF‐KB activity and transcriptional activation of genes encoding numerous proinflammatory molecules. The present data provide evidence that receptors of the pathogen‐associated molecular patterns are strongly induced in the CNS of EAE mice, further reinforcing the concept that the innate immune system plays a determinant role in this autoimmune demyelinating disease.

hsp70-Dependent Antiviral Immunity against Cytopathic Neuronal Infection by Vesicular Stomatitis Virus

“…The probable link between hsp70 in the virus-infected cell and IFN induction is the ability of VSV to induce extracellular release of hsp70. hsp70 is a ligand for TLR2 and TLR4, which are primarily expressed on macrophages in the brain (12,13). Macrophage responses to TLR2 and TLR4 ligands include production of IFN-␤ (41,42), and the ability of hsp70 to directly induce IFN-␤ in a TLR2/4-dependent manner has recently been shown in both mouse microglial cell lines and in primary cultures of mouse bone marrow-derived macrophages (11).…”

“…In vitro studies show that MeV infection causes an early release of hsp70 from viable neuronal cells, consistent with exosomal secretion or microvesicular shedding, and the extracellular hsp70 serves as a potent stimulus for IFN-␤ expression in mouse macrophages, including microglia (11). Induction of IFN-␤ by hsp70 is mediated by Toll-like receptors 2 and 4 (TLR2 and TLR4, respectively), which in the brain are expressed predominantly on macrophages (12,13). In vivo, selective neuronal expression of hsp70 enhances the IFN-␤ response to intracranial MeV inoculation, reducing mortality in H-2 d congenic C57BL/6 mice (11).…”

Glial toll-like receptor signaling in central nervous system infection and autoimmunity

“…This unique localization allows the CNS to recognize pathogens which are present in the periphery as well as those which have directly invaded the CNS. The levels of TLRs in the CNS can be upregulated by viral and bacterial infection, treatment with TLR stimuli, or CNS autoimmunity (Bsibsi et al, 2002;Zekki et al, 2002), providing a mechanism for amplification of inflammatory responses to pathogens infecting the CNS. These stimuli upregulate multiple TLRs in a coordinated fashion, not only the TLR involved in recognition of a particular pathogen or class of pathogens.…”

Streptococcus pneumoniaeInfection Aggravates Experimental Autoimmune Encephalomyelitis via Toll-Like Receptor 2

“…TLR2 mRNA is upregulated during the course of EAE. Expression of the mRNA encoding TLR2 starts to increase 4 to 8 days after immunization with MOG and reaches its maximum at 3 weeks (50).…”