TLR7 and TLR9 Trigger Distinct Neuroinflammatory Responses in the CNS

Abstract

Toll-like receptors (TLRs) 7 and 9 recognize nucleic acid determinants from viruses and bacteria and elicit the production of type I interferons and proinflammatory cytokines. TLR7 and TLR9 are similar regarding localization and signal transduction mechanisms. However, stimulation of these receptors has differing effects in modulating viral pathogenesis and in direct toxicity in the central nervous system (CNS). In the present study, we examined the potential of the TLR7 agonist imiquimod and the TLR9 agonist cytosine-phosphateguanosine oligodeoxynucleotide (CpG-ODN) to induce neuroinflammation after intracerebroventricular inoculation. CpG-ODN induced a more robust inflammatory response than did imiquimod after inoculation into the CNS, with higher levels of several proinflammatory cytokines and chemokines. The increase in cytokines and chemokines correlated with breakdown of the bloodcerebrospinal fluid barrier and recruitment of peripheral cells to the CNS in CpG-ODN-inoculated mice. In contrast, TLR7 agonists induced a strong interferon ␤ response in the CNS but only low levels of other cytokines. The difference in response to these agonists was not due to differences in distribution or longevity of the agonists but rather was correlated with cytokine production by choroid plexus cells. These results indicate that despite the high similarity of TLR7 and TLR9 in binding nucleic acids and inducing similar downstream signaling, the neuroinflammation response induced by these receptors differs dramatically due, at least in part, to activation of cells in the choroid plexus.

Toll-like receptor 7 suppresses virus replication in neurons but does not affect viral pathogenesis in a mouse model of Langat virus infection

“…Possibly, TLR7 signalling may inhibit the signalling pathways of other virus-recognizing PRRs. We have shown previously that TLR7 inhibits TLR9-mediated neuroinflammatory responses (Butchi et al, , 2011, although the mechanism of inhibition is unknown. As other PRRs, including TLR3, RIG-I and MDA-5, can recognize flavivirus infection (Daffis et al, 2008;Fredericksen et al, 2008), it is possible that TLR7 signalling limits the response of these PRRs.…”

“…infection or transmission of the virus by mosquito bite (Town et al, 2009;Welte et al, 2009). TLR7 is present on numerous cell types in the CNS, and direct ligand inoculation into brain tissue induces a strong localized type I IFN response (Butchi et al, , 2011, indicating that TLR7 may be a contributing factor in the development of local antiviral responses in the brain.…”

Interferon Alpha Subtype-Specific Suppression of HIV-1 InfectionIn Vivo

“…Data were normalized against the mock-treated control for each donor, set as 100%. Normalized data from all 6 donors were averaged, and the 50% inhibitory concentration (IC 50 (46,47) normalized to the body surface area (48).…”

“…RNA was isolated from 5 ϫ 10 6 splenocytes using the ZR-Duet DNA/RNA MiniPrep kit (Zymo Research, Irvine, CA). Real-time PCR analysis of mRNA expression was completed as previously described (50). Primers were tested on controls to ensure amplification of a single product.…”

“…The data were normalized against mock infection for each donor. The dose-response curves were generated using a one-phase decay equation that was also used to evaluate the IC 50 .…”