van der Vorst, E. P. C. | bioRxiv Science

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↗

bioRxiv2024

MicroRNA-26b protects against MASH development and can be efficiently targeted with lipid nanoparticles.

Background & AimsThe prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing, urging more research into the underlying mechanisms. MicroRNA-26b (miR-26b) might play a role in several MASH-related pathways. Therefore, we aimed to determine the role of miR-26b in MASH and its therapeutic potential using miR-26b mimic-loaded lipid nanoparticles (LNPs). MethodsApoe-/-Mir26b-/-, Apoe-/-LysMcreMir26bfl/fl mice, and respective controls were fed a western-type diet to induce MASH. Plasma and liver samples were characterized regarding lipid metabolism, hepatic inflammation, and fibrosis. Additionally, miR-26b mimic-loaded LNPs were injected in Apoe-/-Mir26b-/- mice to rescue the phenotype and key results were validated in human precision-cut liver slices. Finally, kinase profiling was used to elucidate underlying mechanisms. ResultsApoe-/-Mir26b-/- mice showed increased hepatic lipid levels, coinciding with increased expression of scavenger receptor a and platelet glycoprotein 4. Similar effects were found in mice lacking myeloid-specific miR-26b. Additionally, hepatic TNF and IL-6 levels and amount of infiltrated macrophages were increased in Apoe-/- Mir26b-/- mice. Moreover, Tgfb expression was increased by the miR-26b deficiency, leading to more hepatic fibrosis. A murine treatment model with miR-26b mimic-loaded LNPs reduced hepatic lipids, rescuing the observed phenotype. Kinase profiling identified increased inflammatory signaling upon miR-26b deficiency, which was rescued by LNP treatment. Finally, miR-26b mimic-loaded LNPs also reduced inflammation in human precision-cut liver slices. ConclusionsOverall, our study demonstrates that the detrimental effects of miR-26b deficiency in MASH can be rescued by LNP treatment. This novel discovery leads to more insight into MASH development, opening doors to potential new treatment options using LNP technology. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/580792v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@b8b5b8org.highwire.dtl.DTLVardef@a26333org.highwire.dtl.DTLVardef@11ed2a0org.highwire.dtl.DTLVardef@963208_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗