Cell reports最新文献

Malignancies can compromise systemic innate immunity, but the underlying mechanisms are largely unknown. Here, we find that tumor-derived small extracellular vesicles (sEVs; TEVs) deliver PD-L1 to host macrophages, thereby impeding antibacterial immunity. Mice implanted with Rab27a-knockdown tumors are more resistant to bacterial infection than wild-type controls. Injection of TEVs into mice impairs macrophage-mediated bacterial clearance, increases systemic bacterial dissemination, and enhances sepsis score in a PD-L1-dependent manner. Mechanistically, TEV-packaged PD-L1 inhibits Bruton's tyrosine kinase/PLCγ2 signaling-mediated cytoskeleton reorganization and reactive oxygen species generation, impacting bacterial phagocytosis and killing by macrophages. Neutralizing PD-L1 markedly normalizes macrophage-mediated bacterial clearance in tumor-bearing mice. Importantly, circulating sEV PD-L1 levels in patients with tumors can predict bacterial infection susceptibility, while patients with tumors treated with αPD-1 exhibit fewer postoperative infections. These findings identify a mechanism by which cancer cells dampen host innate immunity-mediated bacterial clearance and suggest targeting TEV-packaged PD-L1 to reduce bacterial infection susceptibility in tumor-bearing conditions.

Cytochrome b5 (CYB5) is a hemoprotein crucial for electron transfer to oxygenases. Although microsomal CYB5A is required for sterol C4-demethylation in vitro, cholesterol biosynthesis remains intact in Cyb5a knockout mice. Here, we show that knockout of mitochondrial CYB5B, rather than CYB5A, blocks cholesterol biosynthesis at the sterol-C4 oxidation step in HeLa cells, causing an accumulation of testis meiosis-activating sterol (T-MAS) and dihydro-T-MAS. Surprisingly, liver-specific Cyb5b knockout (L-Cyb5b^-/-) mice exhibit normal cholesterol metabolism. Further knockdown of Cyb5a in L-Cyb5b^-/- (L-Cyb5b^-/-/short hairpin [sh]Cyb5a) mice leads to a marked accumulation of T-MAS and dihydro-T-MAS, indicating that either CYB5A or CYB5B is required for sterol C4-demethylation. The L-Cyb5b^-/-/shCyb5a mice are largely normal, with lower sterol regulatory element-binding protein (SREBP)-target gene expression during refeeding and higher liver triglyceride levels while fasting, as T-MAS and dihydro-T-MAS inhibit the SREBP pathway and activate the PPARγ pathway. In summary, CYB5A and CYB5B compensate for sterol C4-demethylation, and T-MAS and dihydro-T-MAS can modulate the SREBP and PPARγ pathways.

Using high-resolution quantitative mass spectrometry, we present comprehensive human and mouse microglia proteomic datasets consisting of over 11,000 proteins across six microglia groups. Microglia share a core protein signature of over 5,600 proteins, yet fundamental differences are observed between species and culture conditions. Mouse microglia demonstrate proteome differences in inflammation- and Alzheimer's disease-associated proteins. We identify differences in the protein content of ex vivo and in vitro cells and significant proteome differences associated with protein synthesis, metabolism, microglia marker expression, and environmental sensors. Culturing microglia induces rapidly increased growth, protein content, and inflammatory protein expression. These changes are restored by engrafting in vitro cells into the brain, with xenografted human embryonic stem cell (hESC)-derived microglia closely resembling microglia from the human brain. These data provide an important resource for the field and highlight important considerations needed when using model systems to study human physiology and pathology of microglia.

Low doses of general anesthetics like ketamine and dexmedetomidine have anxiolytic properties independent of their sedative effects, but the underlying mechanisms remain unclear. We discovered a population of GABAergic neurons in the oval division of the bed nucleus of the stria terminalis that are activated by multiple anesthetics and the anxiolytic drug diazepam (ovBNST_GA). The majority of ovBNST_GA neurons express neurotensin receptor 1 (Ntsr1) and form circuits with brain regions known to regulate anxiety and stress responses. Optogenetic activation of ovBNST_GA or ovBNST^Ntsr1 neurons significantly attenuated anxiety-like behaviors in both naive animals and mice with inflammatory pain, while inhibition of these cells elevated anxiety. Activation of these neurons decreased heart rate and increased heart rate variability, suggesting that they reduce anxiety by modulating autonomic responses. Our study identifies ovBNST_GA/ovBNST^Ntsr1 neurons as a common neural substrate mediating the anxiolytic effect of low-dose anesthetics and a potential therapeutic target for treating anxiety-related disorders.

Innate immune responses can be triggered upon detection of pathogen- or damage-associated molecular patterns by host receptors that are often present on the surface of immune cells. While invertebrates like Caenorhabditis elegans lack professional immune cells, they still mount pathogen-specific responses. However, the identity of host receptors in the nematode remains poorly understood. Here, we show that C-type lectin receptors mediate species-specific recognition of divergent oomycetes in C. elegans. A CLEC-27/CLEC-35 pair is essential for recognition of the oomycete Myzocytiopsis humicola, while a CLEC-26/CLEC-36 pair is required for detection of Haptoglossa zoospora. Both clec pairs are transcriptionally regulated through a shared promoter by the conserved PRD-like homeodomain transcription factor CEH-37/OTX2 and act in sensory neurons and the anterior intestine to trigger a protective immune response in the epidermis. This system enables redundant tissue sensing of oomycete threats through canonical CLEC receptors and host defense via cross-tissue communication.

Bone marrow endothelial cells (BM-ECs) are the essential components of the BM niche and support the function of hematopoietic stem cells (HSCs). However, conditioning for HSC transplantation causes damage to the recipients' BM-ECs and may lead to transplantation-related morbidity. Here, we investigated the cellular and clonal mechanisms of BM-EC regeneration after irradiative conditioning. Using single-cell RNA sequencing, imaging, and flow cytometry, we revealed how the heterogeneous pool of BM-ECs changes during regeneration from irradiation stress. Next, we developed a single-cell in vitro clonogenic assay and demonstrated that all EC fractions hold a high potential to reenter the cell cycle and form vessel-like structures. Finally, we used Rainbow mice and a machine-learning-based model to show that the regeneration of BM-ECs after irradiation is mostly polyclonal and driven by the broad fraction of BM-ECs; however, the cell output among clones varies at later stages of regeneration.

Camellia oleifera is an economically important woody oil plant. Complex ploidy and lack of genomic information have seriously hindered the molecular breeding of C. oleifera. Here, we present an 11.43-Gb haplotype-resolved, chromosome-level genome assembly of tetraploid C. oleifera (COL-tetra). Methods employed in this study support the conclusion that COL-tetra is an autotetraploid and probably originates from genome doubling of the diploid C. brevistyla. In addition, DNA methylation plays a significant role in imbalanced allelic expression and seed development. Genetic divergence analyses reveal significant differentiation signals for flowering time between spring-flowering and autumn-flowering oil Camellia species, which probably account for reproductive isolation between species with distinct flowering times. Strong introgression signals are detected between COL-tetra and C. sasanqua and between C. vietnamensis and COL-hexa, which might affect the development of agronomic traits and environmental adaptability. This study provides valuable insights into the evolution, agronomic trait development, and genetic architecture of oil Camellia plants.

The seamless transition through stages of pluripotency relies on a balance between transcription factor networks and epigenetic mechanisms. Here, we reveal the crucial role of the transgene activation suppressor (TASOR), a component of the human silencing hub (HUSH) complex, in maintaining cell viability during the transition from naive to primed pluripotency. TASOR loss in naive pluripotent stem cells (PSCs) triggers replication stress, disrupts H3K9me3 heterochromatin, and impairs silencing of LINE-1 (L1) transposable elements, with more severe effects in primed PSCs. Notably, the survival of Tasor knockout PSCs during this transition can be restored by inhibiting caspase or deleting the mitochondrial antiviral signaling protein (MAVS). This suggests that unscheduled L1 expression activates an innate immune response, leading to cell death specifically in cells exiting naive pluripotency. Our findings highlight the importance of epigenetic programs established in naive pluripotency for normal development.

Ferroptosis is an iron-dependent cell death that occurs due to the peroxidation of phospholipids in the cell membrane. In this study, we find that the protein level of NSUN2 is significantly decreased in hepatocyte ferroptosis. This is attributed to STUB1-mediated ubiquitination of NSUN2 at lysines 457 and 654, promoting NSUN2 degradation in ferroptosis. Selenoprotein glutathione peroxidase 4 (GPX4) is a prominent suppressor of ferroptosis. We find that downregulation of NSUN2 diminishes m⁵C methylation of Gpx4 mRNA 3' UTR. The reduction of NSUN2-mediated Gpx4 mRNA m⁵C methylation abrogates the interaction between SBP2 and the selenocysteine insertion sequence (SECIS) and leads to inhibition of GPX4 protein expression. Lower GPX4 expression promotes hepatocyte ferroptosis in vivo and in vitro, which is reversed by restoration of NSUN2. These findings shed light on the mechanism of NSUN2 degradation and also indicate that the STUB1-NSUN2-GPX4 axis plays a regulatory role in hepatocyte ferroptosis.

The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to promote T cells with anti-tumor capabilities. Here, we compared mutant neoantigen (neoAg) peptide-based vaccines with ICT in preclinical models. NeoAg vaccines induce the most robust expansion of proliferating and stem-like PD-1⁺TCF-1⁺ neoAg-specific CD8 T cells in tumors. Anti-CTLA-4 and/or anti-PD-1 ICT promotes intratumoral TCF-1^- neoAg-specific CD8 T cells, although their phenotype depends in part on the specific ICT used. Anti-CTLA-4 also prompts substantial changes to CD4 T cells, including induction of ICOS⁺Bhlhe40⁺ T helper 1 (Th1)-like cells. Although neoAg vaccines or ICTs expand iNOS⁺ macrophages, neoAg vaccines maintain CX3CR1⁺CD206⁺ macrophages expressing the TREM2 receptor, unlike ICT, which suppresses them. TREM2 blockade enhances neoAg vaccine efficacy and is associated with fewer CX3CR1⁺CD206⁺ macrophages and induction of neoAg-specific CD8 T cells. Our findings highlight different mechanisms underlying neoAg vaccines and different forms of ICT and identify combinatorial therapies to enhance neoAg vaccine efficacy.