T cell expansion has a crucial function in both autoimmune and chronic inflammatory diseases, with cycling T cells contributing to the pathogenesis of autoimmune diseases by causing uncontrolled immune responses and tissue damage. Yet the regulatory mechanisms governing T cell expansion remain incompletely understood. Here we show that the enzyme N-acetyltransferase 10 (NAT10) regulates T cell activation and proliferation upon antigen stimulation. T cell-specific NAT10 deficiency in mice reduces the number of mature T cells in peripheral lymphoid organs. Mechanistically, NAT10 acetylates RACK1 at K185, preventing subsequent RACK1 K48-linked ubiquitination and degradation. The increased RACK1 stability alters ribosome formation and cellular metabolism, leading to enhanced supply of energy and biosynthetic precursors and, eventually, T cell proliferation. Our findings thus highlight the essential function of NAT10 in T cell self-renewal and metabolism and elucidate NAT10 mode of action for the potential development of novel therapies for immune-related disorders.
© 2024. The Author(s).

Pericytes and endothelial cells (ECs) constitute the fundamental components of blood vessels. While the role of ECs in tumor angiogenesis and the tumor microenvironment is well appreciated, pericyte function in tumors remains underexplored. In this study, we used pericyte-specific deletion of the nitric oxide (NO) receptor, soluble guanylate cyclase (sGC), to investigate via single-cell RNA sequencing how pericytes influence the vascular niche and the tumor microenvironment. Our findings demonstrate that pericyte sGC deletion disrupts EC-pericyte interactions, impairing Notch-mediated intercellular communication and triggering extensive transcriptomic reprogramming in both pericytes and ECs. These changes further extended their influence to neighboring cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) through paracrine signaling, collectively suppressing tumor growth. Inhibition of pericyte sGC has minimal impact on quiescent vessels but significantly increases the vulnerability of angiogenic tumor vessels to conventional anti-angiogenic therapy. In conclusion, our findings elucidate the role of pericytes in shaping the tumor vascular niche and tumor microenvironment and support pericyte sGC targeting as a promising strategy for improving anti-angiogenic therapy for cancer treatment.
© 2024. The Author(s).

Acute myeloid leukemia (AML) is a malignancy characterized by differentiation arrest of hematopoietic precursor cells. Differentiation therapy is effective for patients with acute promyelocytic leukemia; however, only a few effective differentiation therapies have been established for patients with other AML subtypes. In this study, seven benzimidazole anthelmintics were examined to determine the effects of differentiation on AML cells. The expression of monocyte markers (CD11b and CD14) was elevated after treatment with most benzimidazole anthelmintics. Among these drugs, parbendazole (PBZ) induced AML cell differentiation at low concentration. PBZ induced the monocyte marker expression, KLF4/DPYSL2A gene expression, and apoptosis for 21 AML cell lines with various subtypes and a primary AML sample. Finally, an in vivo analysis using an AML patient-derived xenograft mouse model showed a significant decrease in the chimerism level and prolonged survival in PBZ-treated mice. These findings could lead to a more effective differentiation therapy for AML.
© 2024. The Author(s).

Backgroud: During various stages of fracture healing, macrophages control mesenchymal stem cells' (BMSCs') proliferative behavior and osteogenic differentiation through varying polarization states. BMSCs also regulate their own osteogenic differentiation through the polarization state of macrophages to meet the requirements of tissue repair and osteogenic environment. A crucial role in cell proliferation, differentiation, and death is played by the evolutionarily conserved Notch signaling system. It also plays an important role in the osteogenic differentiation and regulation of macrophage polarization of BMSCs. The NOTCH signaling pathway typically plays a role in information exchange through direct contact between cells. Therefore, the Notch signaling pathway is involved in information exchange during direct contact between macrophages and BMSCs. Methods: A co culture system of mouse monocytic megacytic leukemia cell line (RAW264.7) and BMSC was established. RAW264.7 cells in logarithmic growth phase were divided into M0 group (unpolarized) and M1 group (LPS+INF γ induction), M2 group (IL4+IL13 induction), polarization status was detected by flow cytometry, and then BMSC were added to detect the Notch signaling pathway and the expression levels of RUNX2 gene and protein at different time points in each group. To further validate the role of the NOTCH signaling pathway in osteogenesis, we chose to apply the NOTCH signaling blocker RO4929097 to the co culture system of M2 and BMSC.According to whether blockers were used or not, they were divided into control group, M2 group, M2+blocker group, and blocker group. The transmission of the NOTCH signaling pathway in the interaction between M2 and BMSC as well as the production of Hes1 linked to the osteogenic gene RUNX2 were observed by blocking the NOTCH signaling pathway's conduction. At the same time, we detected the polarization of RAW264.7 cells in Mo and M1 groups to determine whether there was a change in the polarization state of RAW264.7 cells after the addition of BMSC. Results: : PCR and WB results showed that the NOTCH signaling pathway and osteogenic specific RUNX2 related protein and gene expression were basically synchronized: the expression of Jagged1 and Notch1 in M2 group was higher than that in M0 and M1 groups (p<0.05), while the expression level of M0 group was higher than that in M1 group (p<0.05). Hes1, as an associated gene and protein of Notch signaling pathway and Runx2, had the highest expression level with RUNX2 in M2 group (p<0.05), followed by M0, and the lowest in M1 group.This revealed that the Notch signaling pathway is involved in the bone immune regulatory effect between RAW264.7 and BMSC. After administering the NOTCH signaling blocker RO4929097, the M2 group had the highest expression of Notch signaling pathway related protein genes (p<0.05), followed by the control group (<0.05), and the blocker group had the lowest expression level (p<0.05), indicating a higher expression of the NOTCH signaling pathway between M2 cells and BMSC. The M2+blocker group had a higher expression level than the blocker group, suggesting that there are other pathways between M2 and BMSC that affect the conduction of the NOTCH signaling pathway. BMSC and RAW264.7 were co cultured, and flow cytometry analysis showed that the proportion of M2 like cells in the M0 group was higher than that in the M1 group. Conclusion: In the co culture system of macrophages and BMSC,the Notch signaling pathway promotes macrophage polarization towards M2 type, thereby regulating the osteogenic differentiation of BMSC and participating in the bone immune regulation of macrophages and mesenchymal stem cells.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune neuropsychiatric disease. Brain access of anti-NMDAR autoantibody through the blood-brain barrier (BBB) is essential for pathogenesis. Most previous animal models limit the investigation of etiologies of BBB damage in patients.
In this study, we established a novel humanized mouse model of anti-NMDAR encephalitis by intraperitoneal injection of patients' peripheral blood mononuclear cells (PBMCs) into BALB/c Rag2-/-Il2rg-/-SirpαNODFlk2-/- mice.
We found that engraftment of patients' PBMCs not only produced potent anti-GluN1 autoantibodies, but also disrupted BBB integrity to allow brain access of autoantibodies, resulting in a hyperactive locomotor phenotype, anxiety- and depressive-like behaviors, cognitive deficits, as well as functional changes in corresponding brain regions. Transcriptome analysis suggested an exaggerated immune response and impaired neurotransmission in the mouse model and highlighted Il-1β as a hub gene implicated in pathological changes. We further demonstrated that Il-1β was produced by endothelial cells and disrupted BBB by repressing tight junction proteins. Treatment with Anakinra, an Il-1 receptor antagonist, ameliorated BBB damage and neuropsychiatric behaviors.
Our study provided a novel and clinically more relevant humanized mouse model of anti-NMDAR encephalitis and revealed an intrinsic pathogenic property of the patient's lymphocytes.
© 2023. The Author(s).