Cell reports最新文献

The gut microbiome produces diverse metabolites shaping immunity, yet their pro-inflammatory potential remains unclear. Using untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomics, we identified hippuric acid-an aromatic, microbe-derived metabolite-as a potent enhancer of inflammatory responses during Escherichia coli infection. Hippuric acid administration heightened inflammation, activated innate immune cells, and reduced survival in infected mice. In vitro, hippuric acid selectively potentiated M1-like (lipopolysaccharide [LPS] or LPS+interferon gamma [IFNγ]) macrophage pro-inflammatory responses but had no effect on M2-like (interleukin [IL]-4) polarization. It enhanced responses to myeloid differentiation primary response 88 (MyD88)-dependent Toll-like receptor (TLR) ligands but not TRIF-, STING-, or NOD2-mediated stimuli. Genetic deletion of MyD88 abolished hippuric-acid-induced pro-inflammatory responses. Transcriptomic and lipidomic analyses revealed increased cholesterol biosynthesis and lipid accumulation, while reducing cellular cholesterol blunted the pro-inflammatory effects of hippuric acid. Notably, hippuric acid also enhanced pro-inflammatory responses in human macrophages, and its elevated levels correlated with sepsis mortality, linking microbial metabolism, lipid remodeling, and innate immunity.

Tumor angiogenesis is driven by pro-angiogenic factors and results in a disorganized tumor vasculature that limits effective perfusion and immune infiltration. The p21-activated kinase 2 (PAK2) regulates endothelial cell (EC) migration, an essential step in angiogenesis, yet its role in tumor angiogenesis remains ill-defined. Here, we show that endothelial-specific deletion of PAK2 in orthotopic tumor mouse models markedly reduces tumor size and angiogenesis. Additionally, loss of endothelial PAK2 normalizes the remaining tumor vasculature and promotes infiltration of dendritic and natural killer cells. Mechanistically, PAK2 regulates chemokine expression, notably CXCL10. PAK2 depletion enhances CXCL10 secretion from ECs, and CXCL10 expression is required for the inhibitory effects of PAK2 silencing on EC sprouting. Moreover, CXCL10 neutralization in mice reverses the vascular and immune changes induced by endothelial PAK2 deletion. Together, these findings identify endothelial PAK2 as a potential target to limit tumor angiogenesis and reprogram ECs to promote immune infiltration through CXCL10 signaling.

Eos, a member of the Ikaros family of transcription factors, is expressed by T regulatory cells (Tregs) and has been postulated to play a role in Treg suppression and maintenance of Treg stability. We demonstrate that expression of Eos was limited to a subpopulation of thymus-derived, activated Tregs and is undetectable in resting or activated T conventional cells. Eos associates with Helios and Foxp3 and binds directly to the CD25 locus at a site identical to the Foxp3-binding site, thereby enhancing CD25 expression. Studies in heterozygous female mice demonstrate that Eos is critical for Treg survival and activation. Eos⁺ Tregs also represent the major population of recirculating thymic Tregs, in which Eos plays a critical role in regulating their migration and suppression of Treg precursors in the thymus by competing for IL-2 and depleting MHC II from thymic dendritic cells.

The vascular dynamics supporting hippocampal spatial navigation during naturalistic behavior remain poorly understood. Here, we used functional ultrasound (fUS) imaging to examine cerebral blood volume (CBV) changes in freely exploring rats. High-resolution imaging during open-field exploration revealed strong correlations between CBV and animal speed across hippocampal-parahippocampal regions. Lagged general linear modeling uncovered hierarchical information flow from the thalamus to the parahippocampal cortex and hippocampal subfields (dentate gyrus, CA1-CA3). This speed-CBV relationship showed sharp spatial specificity to navigation structures. Multivariate decoding demonstrated that CBV signals carry highly accurate encodings of locomotion speed, remaining robust across animals. We also identified slow CBV oscillations aligned with exploratory behavior fluctuations. These findings reveal a hemodynamic signature of speed representation arising from energy demands in continuous attractor networks, where population activity scales quadratically with speed, and establish fUS imaging as a powerful tool for investigating the neurovascular basis of navigation.

Staphylococcus aureus pathogenicity islands (SaPIs) are mobile genetic elements carrying virulence genes that spread upon infection by helper phages that induce their transfer. Staphylococci also carry type II and III CRISPR-Cas systems that mount an adaptive immune response against phages through the acquisition of spacer sequences from viral genomes, directing Cas nucleases to their targets. Whether and how SaPIs and CRISPR interact with each other during helper phage infection is not known. Here we report that, as a result of the packaging of incomplete helper phage genomes into SaPI particles, defective viral DNA delivered into new hosts stimulates spacer acquisition in both CRISPR types. Once immunized, staphylococci target the helper phage and prevent SaPI mobilization. Our work reveals an unexpected synergy between CRISPR-Cas systems and SaPIs that enhances antiphage immunity and could favor the retention of beneficial elements within the population.

Colorectal cancer (CRC) represents a significant menace to human health, but its molecular pathogenesis remains unclear. Herein, we explored the functional role of spindle and nucleolar protein 6 (NOL6) in CRC progression. In this study, we found that NOL6 was significantly overexpressed in CRC tissues and correlated with advanced tumor stages and poor patient prognosis. Mechanistically, NOL6 recruited the deubiquitinating enzyme STAMBP to remove K48-linked polyubiquitin chains from Yin Yang 1 (YY1) at lysine 339, preventing YY1 degradation and enhancing c-Myc transcription. A feedback loop was identified where c-Myc directly bound to the NOL6 promoter, reinforcing NOL6 expression. Additionally, lactylation at lysine 54 (K54) of NOL6 stabilized NOL6 by inhibiting its ubiquitination and proteasomal degradation. Targeting NOL6-K54 lactylation with a cell-penetrating peptide inhibitor (K54-pe4) suppressed CRC cell proliferation and metastases in vivo without apparent toxicity. These findings establish a novel regulatory axis (NOL6-STAMBP-YY1-Myc) strengthened by lactylation, highlighting NOL6 as a potential therapeutic target for CRC.

Lupus nephritis (LN) is a leading cause of mortality in systemic lupus erythematosus. While the dominance of Fcγ receptor (FcγR)-activating IgG subclasses has been observed in both human and murine LN, whether this imbalance is causal or merely correlative remains unresolved. To address this, we generated a murine model that exclusively expresses the activating IgG2c while lacking all other IgG subclasses. Despite preserved B cell receptor diversity and intact humoral immunity, these mice developed rapidly progressive and fatal lupus-like nephritis, with 100% mortality by 30 weeks, characterized by extensive renal inflammation. Genetic ablation of FcγRs or complement C3 rescued this phenotype, establishing both as essential and non-redundant mediators of disease. Supporting clinical relevance, renal biopsies from patients with LN exhibited glomerular immune deposits enriched for FcγR-activating IgG1 and minimal inhibitory IgG4. Together, these results identify IgG subclass dominance as a direct driver of LN and provide a fully penetrant, rapid-onset disease model for therapeutic studies.

The neural crest (NC) is a transient embryonic structure composed of highly migratory multipotent stem cells that generate diverse cell types and orchestrate early neurovascular patterning. It has long been assumed that NC cells are exhausted after development once their progeny fully differentiate. However, through NC lineage tracing, single-cell and spatial transcriptomics, interactome modeling, and in vivo imaging, we identified a population of NC-derived multipotent (not lineage-restricted) cells persisting within the adult mouse leptomeninges. Following ischemic stroke, loss- and gain-of-function analyses revealed that these cells are reactivated and recruited toward injured vascular endothelium via SDF1α-CXCR4 signaling; undergo stromal cell transition within the perivascular niche, regulated by β-catenin and STAT3 pathways; and restore vascular integrity through pleiotrophin-mediated signaling. These findings suggest that the adult leptomeninges harbor a vestigial reservoir of NC-derived multipotent cells-once central to embryogenesis and vasculogenesis-that can be re-invoked to promote neurovascular repair after cerebral injury.

Despite rapid advances in mapping genetic drivers and gene expression changes in hematopoietic stem cells (HSCs), few studies exist at the protein level. We perform a deep, multi-omics characterization (epigenome, transcriptome, and proteome) of HSCs in a mouse model carrying a loss-of-function mutation in Tet2, a driver of increased self-renewal in blood cancers. Using state-of-the-art, multiplexed, low-input mass spectrometry (MS)-based proteomics, we profile TET2-deficient (Tet2^-/-) HSCs, revealing previously unrecognized molecular processes that define the pre-leukemic HSC molecular landscape. Specifically, we obtain more accurate stratification of wild-type and Tet2^-/- HSCs than transcriptomic approaches and identify extracellular matrix (ECM) molecules as being dysregulated upon TET2 loss. HSC expansion assays using ECM-functionalized hydrogels confirm a selective effect on the expansion of Tet2-mutant HSCs. Taken together, our study represents a comprehensive molecular characterization of Tet2-mutant HSCs and identifies a previously unanticipated role of ECM molecules in regulating self-renewal of disease-driving HSCs.