Transposon-derived decoy fine-tunes IFN responses
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Ginsenoside Rg3 enriches SCFA-producing commensal bacteria to confer protection against enteric viral infection via the cGAS-STING-type I IFN axis
The microbiota-associated factors that influence host susceptibility and immunity to enteric viral infections remain poorly defined. We identified that the herbal monomer ginsenoside Rg3 (Rg3) can shape the gut microbiota composition, enriching robust short-chain fatty acid (SCFA)-producing Blautia spp. Colonization by representative Blautia coccoides and Blautia obeum could protect germ-free or vancomycin (Van)-treated mice from enteric virus infection, inducing type I interferon (IFN-I) responses in macrophages via the MAVS-IRF3-IFNAR signaling pathway. Application of exogenous SCFAs (acetate/propionate) reproduced the protective effect of Rg3 and Blautia spp. in Van-treated mice, enhancing intracellular Ca2+– and MAVS-dependent mtDNA release and activating the cGAS-STING-IFN-I axis by stimulating GPR43 signaling in macrophages. Our findings demonstrate that macrophage sensing of metabolites from specific commensal bacteria can prime the IFN-I signaling that is required for antiviral functions.
IFN-γ reprograms cardiac microvascular endothelial cells to mediate doxorubicin transport and influences the sensitivity of mice to doxorubicin-induced cardiotoxicity
Doxorubicin (DOX) is a first-line chemotherapy agent known for its cardiac toxicity. DOX-induced cardiotoxicity (DIC) severely limits the use for treating malignant tumors and is associated with a poor prognosis. The sensitivity to DIC varies among patients, but the precise mechanisms remain elusive. Here we constructed a mouse model of DIC using DOX to investigate potential mechanisms contributing to the differential susceptibility to DIC. Through surface-enhanced Raman spectroscopy and single-cell RNA sequencing, we explored the mechanisms underlying DIC phenotypic variations. In vitro and in vivo studies with small-molecule drugs were conducted. DIC-insensitive mice displayed preserved ejection fractions, lower DOX levels in cardiac tissues and higher levels in the serum. Single-cell RNA sequencing revealed differences of gene expression in cardiac endothelial cells between DIC-insensitive and DIC-sensitive groups. The expression of IFN-γ pathway-related genes was high in DIC-insensitive mice. IFN-γ administration decreased the DOX distribution in cardiac tissues, whereas PPAR-γ activation increased DIC susceptibility. IFN-γ stimulation upregulated P-glycoprotein expression, leading to increased DOX efflux and DIC insensitivity. Our model provides insights into the mechanisms of DIC sensitivity and potential preventive strategies.
IκBζ controls IL-17-triggered gene expression program in intestinal epithelial cells that restricts colonization of SFB and prevents Th17-associated pathologies
Control of gut microbes is crucial for not only local defense in the intestine but also proper systemic immune responses. Although intestinal epithelial cells (IECs) play important roles in cytokine-mediated control of enterobacteria, the underlying mechanisms are not fully understood. Here we show that deletion of IκBζ in IECs in mice leads to dysbiosis with marked expansion of segmented filamentous bacteria (SFB), thereby enhancing Th17 cell development and exacerbating inflammatory diseases. Mechanistically, the IκBζ deficiency results in decrease in the number of Paneth cells and impairment in expression of IL-17-inducible genes involved in IgA production. The decrease in Paneth cells is caused by aberrant activation of IFN-γ signaling and a failure of IL-17-dependent recovery from IFN-γ-induced damage. Thus, the IL-17R–IκBζ axis in IECs contributes to the maintenance of intestinal homeostasis by serving as a key component in a regulatory loop between the gut microbiota and immune cells.
NF-κB RelB suppresses the inflammatory gene expression programs of dendritic cells by competing with RelA for binding to target gene promoters
A group of autoinflammatory disorders termed relopathies arise as a consequence of NF-κB dysregulation. Genetic loss of the NF-κB subunit RelB in humans and mice leads to autoimmunity and lethal multi-organ inflammatory pathology. Our recent study showed that this inflammatory pathology is independent of type I interferon signaling, and further identified dysregulation of a set of pro-inflammatory NF-κB target genes. However, it remains unknown how the loss of RelB leads to the dysregulation of these NF-κB motif-containing pro-inflammatory genes. Here, we report epigenome profiling studies revealing that RelB is associated with pro-inflammatory genes in dendritic cells. While these genes recruit RelA binding upon exposure to a maturation stimulus, we observed substantially more RelA recruitment in the absence of RelB. For these genes, we found that elevated RelA recruitment is correlated with elevated gene expression. To test whether RelB may compete with RelA for binding to NF-κB-regulated gene promoters via competition for κB sites, we generated a new mouse strain (RelBDB/DB) that harbors targeted point mutations in the RelB DNA binding domain that eliminates high-affinity DNA binding. We found that this targeted mutation in the RelB DNA binding domain is sufficient to drive multi-organ inflammatory pathology. These results provide insights into the biological mechanism of RelB as a suppressor of pro-inflammatory gene expression and autoimmune pathology.
Systemic IFN-I combined with topical TLR7/8 agonists promotes distant tumor suppression by c-Jun-dependent IL-12 expression in dendritic cells
Dendritic cell (DC) activation by pattern recognition receptors like Toll-like-receptors (TLRs) is crucial for cancer immunotherapies. Here, we demonstrate the effectiveness of the TLR7/8 agonist imiquimod (IMQ) in treating both local tumors and distant metastases. Administered orally, IMQ activates plasmacytoid DCs (pDCs) to produce systemic type I interferons (IFN-I) required for TLR7/8 upregulation in DCs and macrophages, sensitizing them to topical IMQ treatment, which is essential for therapeutic efficacy. The mechanism involves c-Jun/AP-1 mediating TLR7/8 signaling in IFN-I-primed DCs, upregulating the pDC-recruiting chemokine CCL2 and the anti-angiogenic cytokine interleukin-12, which suppresses VEGF-A production leading to tumor necrosis and regression. Combining topical and systemic IMQ or IFN-I generates a CD8+ T cell-dependent response at metastatic sites, reinforced by PD-1 blockade, leading to long-lasting memory. Analysis of cohorts of patients with melanoma demonstrates DC-specific TLR7/8 upregulation by IFN-I, supporting the translational potential of combining systemic IFN-I and topical IMQ to improve immunotherapy of topically accessible tumors.
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