Theiler's virus infection induces TLR3‐dependent upregulation of TLR2 critical for proinflammatory cytokine production

Abstract

Theiler's murine encephalomyelitis virus (TMEV) infection directly induces many proinflammatory genes, including type I interferon (IFN) and a variety of cytokine genes. These virus-induced cytokines are a critical factor in developing TMEV-induced demyelinating disease. We have previously reported that the major activation signal for the cytokine genes is mediated via TLR3. In this study, we describe that TLR2 is upregulated via TLR3 signal and cooperatively participates in the expression of IL-6, IL-1β, CCL2, and CCL5 genes following TMEV infection. The expression of these genes was significantly impaired in both TLR2-deficient and TLR3-deficient primary astrocytes. However, the induction of type I IFNs was not affected by TLR2-deficiency in the primary cells. TMEV infection led to TLR2-mediated NF-κB activation, but not IRF3 or IRF7 activation critical for type I IFN production. More importantly, TLR3 was required for TMEV-induced early TLR2 upregulation in primary astrocytes leading to the production of TLR2-dependent cytokines such as IL-6. Interestingly, soluble factor(s) produced via TLR2/3-dependent signals appears to be partially associated with the downstream cytokine production. These results indicate that TMEV utilizes TLR3-induced TLR2 to induce inflammatory cytokines, which are critical to the development of immune-mediated demyelinating disease.

The Level of Viral Infection of Antigen-Presenting Cells Correlates with the Level of Development of Theiler's Murine Encephalomyelitis Virus-Induced Demyelinating Disease

“…Our present study (Fig. 7) showed that the Th17 polarization can be achieved equally well in APCs from susceptible and resistant mice with agonists of multiple TLR receptors (TLR2, -3, -4, and -7), which are either known or suspected to be associated with the innate immune responses following TMEV infection (18,26,(29)(30)(31). Therefore, the potential deficiency of the signal induction in any of these TLRs is unlikely to be associated with the differential Th17 polarization.…”

Activation of Innate Immune Responses in the Central Nervous System during Reovirus Myelitis

“…The overexpression of TLR2 has been shown to increase the release of inflammatory mediators from Theiler's virus-infected astrocytes (71). In this model, TLR2 is required for astrocytes to respond to media from infected astrocytes that had been UV irradiated to kill infectious Theiler's virus, suggesting that TLR2 responds to danger signals released by apoptotic cells (71).…”

Melanoma Differentiation-Associated Gene 5 Is Critical for Protection against Theiler's Virus-Induced Demyelinating Disease

“…NF-B activation following viral infection requires TLR3 and TLR2 (42,43) and is partially dependent on PKR (3,35). However, the induction of type I IFNs and IRF3/IRF7 activation, critical for type I IFN production, are not fully dependent on the presence of TLRs (43). These data indicate that other PRRs are also involved, either cooperatively or independently, in mediating TMEV-induced innate cytokine responses, particularly the production of type I IFNs.…”

“…TMEV-induced cytokine gene expression, as well as viral replication, is dependent on the NF-B pathway (19,25,35). NF-B activation following viral infection requires TLR3 and TLR2 (42,43) and is partially dependent on PKR (3,35). However, the induction of type I IFNs and IRF3/IRF7 activation, critical for type I IFN production, are not fully dependent on the presence of TLRs (43).…”