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

• Published in: Glia 2009-08, Vol.57 (11), p.1216-1226
• Main Authors: So, Eui Young, Kim, Byung S.
• Format: Article
• Language: English
• Subjects: Animals; astrocytes; Astrocytes - immunology; Astrocytes - metabolism; Cardiovirus Infections - immunology; Chemokine CCL2 - metabolism; Chemokine CCL5 - metabolism; CNS inflammation; cytokine gene activation; Cytokines - metabolism; Interferon Regulatory Factor-3 - metabolism; Interferon Regulatory Factor-7 - metabolism; Interferon Type I - metabolism; Interleukin-1beta - metabolism; Interleukin-6 - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B - metabolism; Theiler's encephalomyelitis virus; Theilovirus; TLRs; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 3 - genetics; Toll-Like Receptor 3 - metabolism; Toll-Like Receptor 4 - genetics; Up-Regulation; viral immunity
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.20843

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. © 2009 Wiley‐Liss, Inc.