Genes and immunity最新文献

Genetic variants of NCF1 that impair the production of reactive oxygen species (ROS) are associated with lupus in humans; however, the underlying mechanism of immune dysregulation remains unclear. To clarify this mechanism, the study tested the hypothesis that retrotransposons contribute to the early onset of lupus by facilitating the expansion and activation of macrophages. Using the ROS-deficient lupus-prone lpr mouse model, we employed bulk RNA sequencing, flow cytometry, and spatially resolved single-cell transcriptome imaging to comprehensively characterize tissue-resident macrophages. The results demonstrated increased expression of the mouse transcript family type D (MTD) retrotransposon in tissue-resident macrophages from the spleen, kidneys, and skull dura of ROS-deficient lpr mice, indicating a link between ROS deficiency, MTD expression, and macrophage expansion. Importantly, this MTD expression decreased following two weeks of mycophenolate mofetil therapy, linking therapy response to retrotransposon activity. Furthermore, the MTD-encoded RNA was used to disrupt the signaling of retrotransposons, leading to regulatory T-cell activation and downregulation of both glomerular macrophage infiltration and serum interleukin-6 secretion in lupus-prone mice. Collectively, these findings suggest that the MTD retrotransposons play a crucial role in driving the early onset of lupus by enhancing macrophage activation, which in turn promotes immune dysregulation.

The severity and prognosis of sepsis patients are directly linked to liver damage. Encouraging Kupffer cell transition from M1 to M2 can notably diminish inflammation and hepatic damage triggered by sepsis. Here, the effect of YTH domain N6-methyladenosine RNA binding protein F1 (YTHDF1) on Kupffer cell polarization in sepsis was evaluated. Histological staining of liver sections was conducted in CLP mice. Macrophage markers (M1:iNOS; M2:Arg1) and hepatocyte apoptosis were measured using flow cytometry. Western blot measured protein levels of YTHDF1, KLF2, VSIG4 and macrophage polarization markers. Interactions between YTHDF1, KLF2 and VSIG4 were explored by ChIP, RIP and dual luciferase reporter assays. We found that, in patients with sepsis-induced liver injury and LPS-stimulated macrophages, KLF2 and VSIG4 expression was reduced. KLF2 upregulation facilitated VSIG4 transcriptional regulation in Kupffer cells, promoting M2 polarization to alleviate hepatocyte injury triggered by LPS. The m6A level of KLF2 was regulated by YTHDF1, influencing KLF2 translation. YTHDF1 elevated KLF2 levels, fostering Kupffer M2 polarization to alleviate hepatocyte injury induced by LPS. YTHDF1 or KLF2 upregulation regulated Kupffer cell polarization, mitigating CLP-induced liver injury in septic mice. In conclusion, YTHDF1 reduced sepsis-induced inflammatory responses and liver damage by enhancing Kupffer cell M2 polarization through KLF2/VSIG4 pathway.

The nucleic acid metabolism process is driven by various carcinogenic factors, providing a material basis and energy guarantee for the malignant phenotype of tumor cells. However, the role of nucleic acid metabolism in triple-negative breast cancer (TNBC) development remains unclear. Here, we examined the expression patterns of nucleic acid metabolism-related genes (NAMRGs) in the transcriptome of 297 TNBC samples derived from three datasets. We used single-cell RNA sequencing analysis and both in vivo and in vitro experiments to verify the correlation between NAMRGs and tumor metastasis and tumor immune matrix microenvironment (TME) characteristics. According to the results, two different molecular subtypes were identified, and the relationships between the molecular subtypes, four genetic subtypes, and four pathological subtypes were established. Changes in nucleic acid metabolism were related to changes in homologous recombination repair defects (HRD), cell infiltration in the TME, and patient prognosis. We also constructed a prediction model, NAM_model, by including four NAMRGs (DPYD, PDE6G, PDE8B, and TYMS) and integrating it with other clinical indicators. This model was a highly accurate prognostic nomogram, which showed that the prognosis of high-risk patients was poor, with NAMRGs associated with TME immune exhaustion. In addition, NAMRGs were significantly correlated with drug sensitivity to chemotherapy and targeted therapy. In vivo and in vitro studies have shown that PDE8B is an oncogene that promotes tumor growth and induces TNBC metastasis by promoting epithelial-mesenchymal transition (EMT), which has not been reported previously. Single-cell RNA sequencing also revealed the unique effects of nucleic acid metabolism and HRD on exhausted CD8⁺ T cells. A comprehensive analysis of NAMRGs revealed the potential impact of nucleic acid metabolism-mediated mechanisms, such as HRD and EMT, on the clinical pathological characteristics, TME characteristics, and prognosis of patients with TNBC. These findings have deepened our understanding of the roles of NAMRGs in TNBC and immunotherapy, which will greatly contribute to patient stratification management and individualized clinical decision-making.

Ischemic brain injury triggers complex immune-inflammatory responses that significantly influence disease progression and patient outcomes. This study investigates the role of heat shock protein A8 (Hspa8) in modulating immune cell dynamics following ischemic brain injury. Using single-cell RNA sequencing, bulk RNA sequencing, flow cytometry, and immunofluorescence, we identified significant alterations in T cells, neutrophils, and monocytes within both peripheral blood and brain tissues. Our findings reveal that Hspa8 plays a pivotal role in regulating neutrophil infiltration and reactive oxygen species (ROS) production. Gene silencing of Hspa8 effectively reduced neutrophil accumulation, decreased ROS levels, and mitigated neurological deficits in both in vitro and in vivo ischemic models. Protein-protein interaction (PPI) network analysis further established Hspa8 as a key regulator in immune cell interactions, highlighting its potential as a therapeutic target. These results provide new insights into the immune mechanisms underlying ischemic brain injury and suggest that targeting Hspa8 may offer a promising strategy for reducing inflammation, improving neurological recovery, and enhancing clinical outcomes in affected patients.