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Innate immune TLR sensors

New role for TLR9

Nature Immunology volume 25, page 719 (2024)Cite this article

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Toll-like receptor 9 (TLR9) is an innate immune sensor that recognizes intracellular double-stranded DNA (dsDNA). In Nature, Jovasevic et al. show that TLR9–NF-κB signaling in specific hippocampal neurons is required for the generation of learning-induced memory formation in mice. Using models of contextual fear conditioning (CFC), the authors show that nuclear non-coding dsDNA fragments appear within hours after stimulation, accumulating at perinuclear regions adjacent to the endoplasmic reticulum. After 96 hours, stimulated hippocampal neurons show increased expression of TLR9 and activated DNA-damage response pathways, as indicated by the appearance of γH2AX histone foci and the DNA repair protein 53BP1. TLR9 signaling is required for genomic DNA repair and memory formation, as conditional depletion or knockdown of hippocampal Tlr9 or Rela blunted DNA repair as well as the memory response. Importantly, neuronal TLR9 expression is required, as conditional Tlr9 deletion in either astrocytes or microglia did not blunt the CFC response; similarly, the cGAS-STING pathway (another intracellular DNA sensor) or type I interferon signaling is not required. Single-nuclei RNA-sequencing analysis also indicated TLR9-dependent upregulation of IL-6 production in response to CFC stimulation, but its role remains unclear. How contextual fear stimulation specifically triggers nuclear dsDNA breaks in hippocampal neurons remains unknown; however, what is clear is that these neurons have co-opted the innate TLR9 DNA-sensing pathway to promote their genomic stability and induce contextual long-term memory responses.

Original reference: Nature 628, 145–153 (2024)

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  1. Nature Immunology https://www.nature.com/ni

    Laurie A. Dempsey

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  1. Laurie A. Dempsey
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Correspondence to Laurie A. Dempsey.

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Dempsey, L.A. New role for TLR9. Nat Immunol 25, 719 (2024). https://doi.org/10.1038/s41590-024-01837-6

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