Extracellularly Delivered Single-Stranded Viral RNA Causes Neurodegeneration Dependent on TLR7

Abstract

Innate immune receptors represent an evolutionarily ancient system that allows organisms to detect and rapidly respond to pathogen- and host-derived factors. TLRs are predominantly expressed in immune cells and mediate such a response. Although this class of pattern recognition receptors is involved in CNS disorders, the knowledge of ligands leading to activation of TLRs and to subsequent CNS damage is limited. We report in this study that ssRNA causes neurodegeneration and neuroinflammation dependent on TLR7 in the CNS. TLR7 is not only expressed in microglia, the major immune cells of the brain, but also in neurons of the CNS. Extracellularly delivered ssRNA40, an oligoribonucleotide derived from HIV and an established ligand of TLR7, induces neuronal cell death dependent on TLR7 and the central adapter molecule MyD88 in vitro. Activation of caspase-3 is involved in neuronal damage mediated by TLR7. This cell-autonomous neuronal cell death induced by ssRNA40 is amplified in the presence of microglia that mount an inflammatory response to ssRNA40 through TLR7. Intrathecal administration of ssRNA40 causes widespread neurodegeneration in wild-type but not in TLR7−/− mice, confirming that neuronal cell death induced by ssRNA40 through TLR7 occurs in vivo. Our results point to a possible mechanism through which extracellularly delivered ssRNA contributes to CNS damage and determine an obligatory role for TLR7 in this pathway.

Molecular Regulation of Cell Fate in Cerebral Ischemia: Role of the Inflammasome and Connected Pathways

“…Release of oxidized mitochondrial DNA into the cytosol was shown to directly activate the NLPR3 inflammasome, a process which is regulated by autophagy. 135,136 Extracellularly delivered viral RNA was shown to cause neurodegeneration upon activation of TLR7, 137 and there are data on significant induction of retrotransponson mRNA in experimental stroke, [138][139][140][141] which is localized in neurons, and which activates a caspase-independent and p53-dependent death pathway via mitochondrial and lysosomal damage. 142 The fact that retrotransposons account for around 45% of the mammalian genome supports the significance of these findings, 140 but it remains yet unknown to what degree they contribute to neuroinflammation after stroke.…”

Innate immune responses regulate morphogenesis and degeneration: roles of Toll-like receptors and Sarm1 in neurons

“…Thus, they concluded that the negative effect of R848 is mediated via TLR8 but not TLR7 [31] . However, their results are in conflict to many recent studies from various laboratories regarding the expression of TLR7 in neurons [10,11,20,32] , as evidenced by the results of in situ hybridization, quantitative polymerase chain reaction (Q-PCR), and immunostaining using TLR7 antibodies [10,11,20,32] . Actually, the expression level of TLR7 in neurons is even higher than that of TLR8 [11] .…”

“…In cultured dorsal root ganglion, cortical, and hippocampal neurons, treatment with poly I:C, a synthetic dsRNA, induces growth-cone collapse and inhibits neurite outgrowth [30] . The effect of poly I:C is mediated via TLR3 because neurons lacking functional TLR3 do [30,61] TLR7 ssRNA CL075, Loxoribine, R848 [11,20,21,32] let-7, miR-21, miR-29a [20,21,32] TLR8 R848 [31] ?…”

“…The studies contributed by Dr. Seija Lehnardt's laboratory unexpectedly revealed that TLR7 recognizes the miRNA let-7, consequently resulting in neurodegeneration [20,32] . They reported that let-7 released from dying cells activates TLR7 expression in neurons, triggering neuronal death in vitro and in vivo [20,32] . Similar to the findings regarding neuronal morphogenesis, MyD88 is required for the function of TLR7 in neurodegeneration, as MyD88 knockout neurons do not respond to let-7 [20] .…”

Role of MicroRNA in Visceral Pain

“…96 Besides the role of intracellular miRNAs as the posttranscriptional regulator of gene expression, the role of extracellular miRNAs as signal regulators for membrane receptors activation have recently been established. 97 The extracellular miRNA-let-7 is identified as an activator of Toll like receptor (TLR)-7 in both immune cells and neurons. In line with this finding, an unconventional role of extracellular miRNAs for rapid excitation of nociceptor neurons via TLR7 has been proposed.…”