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2’-O-Methyl-guanosine 3-base RNA fragments mediate essential natural TLR7/8 antagonism

ABSTRACT: Daily phagocytic clearance of billions of apoptotic cells is fundamental to the maintenance of homeostasis and is normally immune silent. Toll-like receptors (TLR) 7 and 8 are phagosomal innate immune sensors known to instigate inflammation in response to guanosine, uridine, and ~2-3 base long degradation products from endosomal RNAs. Exactly how TLR7 and TLR8 evade activation by degradation products from host-RNAs is currently unknown. The activity of the mouse TLR7 inhibitory sequence GGC-v1 was tested on primary bone marrow-derived macrophages (BMDMs) derived from Tlr7Y264H gain-of-function mutant mice. This Tlr7Y264H gain of function mutation results in constitutive engagement of TLR7 through an increased affinity for guanosine. Overnight treatment of Tlr7Y264H mutant BMDMs with GGC-v1 or the small molecule TLR7/8 inhibitor Enpatoran led to significant down regulation of 20 out of the 22 genes regulated by GGC-v1 that were also down-regulated by Enpatoran, indicating that TLR7 sensing was effectively dampened.

ORGANISM(S): Mus musculus

PROVIDER: GSE291606 | GEO | 2025/12/09

REPOSITORIES: GEO

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Project description:Endometritis, a prevalent reproductive system disease with high incidence, leads to reproductive dysfunction and potential miscarriage in both humans and animals, impacting human health and the dairy industry, resulting in significant economic loss. Gut microbiota plays an important role in the pathogenesis of endometritis. However, the specific microbial and metabolic mediators participating in the pathogenesis remain to be identified. In this study, we found that the concentration of itaconate in the feces of mice increased after endometritis induced by Escherichia coli (E. coli) infection, suggesting a potential association between itaconate and inflammatory processes. Here, we investigated the specific role of dimethyl itaconate (DI), a derivative of itaconate with potent anti-inflammatory and immunomodulatory properties on endometritis. Oral administration of DI ameliorated the symptoms of E. coli-induced endometritis in mice. The protective effect was abolished by antibiotic-induced depletion of the gut microbiota, and fecal microbiota transplantation (FMT) from DI-treated mice to recipient mice ameliorated E. coli-induced endometritis. Integrative multiomics revealed that the addition of DI led to an enrichment of Muribaculaceae and the microbial purine metabolite guanosine in the feces. Muribaculum intestinale (DSM 28989), a bacterium of Muribaculaceae or guanosine supplementation alleviated E. coli-induced endometritis in mice. Mechanistically, DI promoted the multiplication of Muribaculaceae, and supplementation of M. intestinale upregulated the level of guanosine in the uterus. Transcriptome data and antibody-neutralizing experiment demonstrated the protective effect of guanosine in E. coli-induced endometritis was mediated by activating the expression of CXCL14 in uterine epithelial cells. In conclusion, our study elucidates the significant role of the gut microbiota and its metabolites in safeguarding the uterus against pathogen infections, providing substantiation for the regulation of distal organ by the gut microbiota, and establishing a basis for preventive measures against related diseases through the gut-X axis.

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2’-O-Methyl-guanosine 3-base RNA fragments mediate essential natural TLR7/8 antagonism

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