Biology subjects

Siebeler, R.

Publications and source records attributed to Siebeler, R..

3 recordsLinked to original sources

bioRxiv2026

Increasing plasma bile salt levels with Bulevirtide alleviates DSS-induced colitis and LPS-induced inflammation

Background & AimsBulevirtide, a viral entry inhibitor used to treat chronic hepatitis delta virus (HDV) infection, targets the hepatic bile salt transporter Na+-Taurocholate Co-transporting Polypeptide (NTCP). As Bulevirtide displays preclinical potential to mitigate cholestatic liver injury, NTCP inhibition is currently explored as treatment for primary sclerosing cholangitis (PSC), a condition frequently associated with colitis. Here, we investigated the immunomodulatory effects of Bulevirtide in lipopolysaccharide (LPS)-induced inflammation and dextran sodium sulfate (DSS)-induced colitis in mice. MethodsThe immunomodulatory properties of the bile salt taurochenodeoxycholic acid (TCDC) were investigated in LPS-challenged mouse bone marrow-derived macrophages (BMDM) and human BLaER1 macrophages. The therapeutic efficacy of Bulevirtide against LPS-induced inflammation and DSS-induced colitis was evaluated in Slco1a/1b-/- FVB and C57BL/6J mice, which recapitulate human bile salt dynamics. ResultsIn BMDMs, TCDC reduced pro-inflammatory tumor necrosis factor alpha (TNF), increased anti-inflammatory interleukin (IL)-10, and suppressed inflammasome activation, as evidenced by reduced IL-1{beta}, IL-18 and cleaved-IL-1{beta} levels. Consistently, TCDC also reduced TNF and IL1B expression in human BLaER1 macrophages. In both FVB and C57BL/6J Slco1a/1b-/- mice, Bulevirtide increased plasma bile salt levels at least 30-fold. This systemic elevation of bile salts reduced plasma TNF and increased IL-10 in LPS-treated mice. Moreover, Bulevirtide attenuated DSS-induced colitis, evidenced by reduced disease scores and reduced intestinal Tnf expression. ConclusionThese findings highlight the anti-inflammatory effects of bile salts in preclinical models of colitis and support NTCP inhibition as a future therapeutic strategy to ameliorate both cholestasis and colitis in PSC. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/719641v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@38efbeorg.highwire.dtl.DTLVardef@3e09borg.highwire.dtl.DTLVardef@8f1262org.highwire.dtl.DTLVardef@100179c_HPS_FORMAT_FIGEXP M_FIG C_FIG SynopsisInhibition of the Na+-Taurocholate Co-transporting Polypeptide using Bulevirtide induces systemic bile salt elevation and mitigates acute inflammation and colitis in mice. These findings support clinical evaluation of Bulevirtide in primary sclerosing cholangitis with protective effects against cholestasis and colitis.

immunology↗

bioRxiv2025

A CROP-seq screen of histone modifying enzymes reveals histone demethylase Kdm5c regulates inflammatory macrophage activation.

BackgroundMacrophages adopt activation states along a spectrum from pro- to anti-inflammatory, enabling appropriate responses to pathogens and environmental cues. Dysregulated inflammatory macrophage activation contributes to diseases including sepsis, rheumatoid arthritis, cancer, and atherosclerosis. Epigenetic processes such as DNA methylation and histone modification prime macrophages for activation, and several histone modifying enzymes (HMEs) have been implicated in this regulation. ObjectiveTo systematically identify histone modifying enzymes that regulate inflammatory macrophage activation. MethodsWe performed a CRISPR knockout screen with single-cell RNA-seq readout (CROP-seq) targeting 92 macrophage-expressed HMEs in immortalized LPS-activated mouse bone marrow-derived macrophages (BMDMs). The resulting single-cell transcriptomes were analyzed to identify significant perturbations. Kdm5c was selected for experimental validation in mouse BMDMs, and its expression pattern was compared with macrophage subsets from human atherosclerotic plaques using scRNA-seq data. ResultsThe CROP-seq screen identified Prmt6, Carm1, Kat2b, and Kdm5c as top regulators of inflammatory macrophage activation. Validation in a KO cell line revealed loss of Kdm5c suppressed inflammatory tone at baseline but led to an exaggerated transcriptional response to LPS stimulation, indicating a role for Kdm5c in balancing tonic and inducible activation. A weighted gene module derived from Kdm5c-deficient macrophages was enriched in inflammatory macrophages in human atherosclerotic plaques. ConclusionOur findings demonstrate the value of CROP-seq screening to dissect the epigenetic control of macrophage activation. We also identify Kdm5c-mediated histone demethylation as a key mechanism modulating inflammatory macrophage activation.

molecular biology↗

bioRxiv2025

Uncovering an unconventional JAK1/2-STAT3 branch in macrophage IFNγ signaling

Interferon-{gamma} (IFN{gamma}) is a key cytokine in immune activation, especially anti-viral responses and driver of macrophage activation. It classically signals via JAK1/2-mediated STAT1 homodimers. Here, we identify an alternative, non-canonical signaling component in which IFN{gamma} simultaneously also activates STAT3. Our results show that IFN{gamma} activates STAT3 rapidly and directly through JAK1 and JAK2. We provide the first evidence that STAT3 can form heterodimers with STAT1 in this context and demonstrate that STAT3 is co-recruited to a subset of IFN{gamma}-induced, STAT1-bound regulatory elements. While IFN{gamma} directly activates STAT3, our results reveal that its contribution to gene regulation is limited, indicating that STAT1 easily substitutes the STAT1-STAT3 heterodimer for STAT1 homodimers when STAT3 is absent. These findings uncover STAT3 as a new unconventional player in macrophage IFN{gamma} signaling, underscoring the complex and context-dependent nature of cytokine signaling networks.

immunology↗