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Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by an overactive immune response, particularly involving excessive production of type I interferons. This overproduction is driven by the phosphorylation of IRF7, a crucial factor in interferon gene activation. Current treatments for SLE are often not very effective and can have serious side effects. Methods: Our study introduces clobenpropit, a histamine analogue, as a potential new therapy targeting the CXCR4 receptor to reduce IRF7 phosphorylation and subsequent interferon production. We employed various laboratory techniques to investigate how clobenpropit interacts with CXCR4 and its effects on immune cells from healthy individuals and SLE patients. Results: Clobenpropit binds effectively to CXCR4, significantly inhibiting IRF7 phosphorylation and reducing interferon production. Additionally, clobenpropit lowered levels of pro-inflammatory cytokines in a mouse model of lupus, demonstrating efficacy comparable to the standard treatment, prednisolone. Discussion: These results suggest that clobenpropit could be a promising new treatment for SLE, offering a targeted approach with potential advantages over current therapies. [ABSTRACT FROM AUTHOR]

IntroductionSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by an overactive immune response, particularly involving excessive production of type I interferons. This overproduction is driven by the phosphorylation of IRF7, a crucial factor in interferon gene activation. Current treatments for SLE are often not very effective and can have serious side effects.MethodsOur study introduces clobenpropit, a histamine analogue, as a potential new therapy targeting the CXCR4 receptor to reduce IRF7 phosphorylation and subsequent interferon production. We employed various laboratory techniques to investigate how clobenpropit interacts with CXCR4 and its effects on immune cells from healthy individuals and SLE patients.ResultsClobenpropit binds effectively to CXCR4, significantly inhibiting IRF7 phosphorylation and reducing interferon production. Additionally, clobenpropit lowered levels of pro-inflammatory cytokines in a mouse model of lupus, demonstrating efficacy comparable to the standard treatment, prednisolone.DiscussionThese results suggest that clobenpropit could be a promising new treatment for SLE, offering a targeted approach with potential advantages over current therapies.

Plasmacytoid dendritic cells (DCs) are reported to induce robust type‐I interferon (IFN) response, whereas cDC1 DCs develop moderate type‐I IFN response upon TLR9 stimulation. It is very interesting to understand how this signaling under TLR9 is tightly regulated for the induction of type‐I IFNs. Here, we report co‐repressor protein NCoR1 as the major factor fine‐tuning the signaling pathways regulating IFN‐β expression under TLR9 in cDC1 DCs. We found that NCoR1 knockdown induced a robust IFN‐β‐mediated antiviral response upon TLR9 activation in cDC1 DCs. At the molecular level, we showed that NCoR1 directly repressed MyD88‐IRF7 signaling axis in cDC1 cells. Therefore, NCoR1 depletion enhanced pIRF7 levels, IFN‐β secretion, and downstream pSTAT1‐pSTAT2 signaling, leading to sustained induction of IFN stimulatory genes. Integrative genomic analysis depicted strong enrichment of an antiviral gene‐module in CpG‐activated NCoR1 knockdown DCs upon TLR9 activation. Moreover, we confirmed our findings in primary DCs derived from splenocytes of WT and NCoR1 DC−/− animals, which showed protection from Sendai and Vesicular Stomatitis viruses upon CpG activation. Ultimately, we identified that NCoR1–HDAC3 complex is involved in repressing the type‐I IFN response in cDC1 DCs. [ABSTRACT FROM AUTHOR]