MIWI2, a P element-induced wimpy testes (PIWI) argonaute protein known for suppressing retrotransposons during male gonadogenesis, has an unexplored role in mammalian somatic cells. We identify MIWI2 multiciliated (M2MC) cells as a rare subset of airway multiciliated cells and investigate MIWI2's function in antiviral host defense. We analyzed transcriptomes from Miwi2 heterozygous (Miwi2 +/tom) and deficient (Miwi2 tom/tom) mice following influenza A infection. During infection, Miwi2 deficiency was associated with reduced mitochondrial and ribosomal gene expression in M2MC cells, increased mitochondrial reactive oxygen species (ROS) production and ADP/ATP ratios in multiciliated cells, and enhanced viral clearance and recovery. Additionally, Miwi2-expressing cells exhibited reduced levels of small RNAs derived from nuclear mitochondrial DNA. These findings reveal a previously unrecognized role for Miwi2 in regulating small non-coding RNAs and mitochondrial oxidant production in somatic cells, indicating a function beyond its established germline activities. Our study identifies Miwi2/Piwil4 as a potential factor influencing susceptibility to severe respiratory infections.
© 2025 The Author(s).

Ischemic stroke recovery involves dynamic interactions between the central nervous system and infiltrating immune cells. Peripheral immune cells compete with resident microglia for spatial niches in the brain, but how modulating this balance affects recovery remains unclear. Here, we use PLX5622 to create spatial niches for peripheral immune cells, altering the competition between infiltrating immune cells and resident microglia in male mice following transient middle cerebral artery occlusion (tMCAO). We find that early-phase microglia attenuation promotes long-term functional recovery. This intervention amplifies a subset of monocyte-derived macrophages (RAMf) with reparative properties, characterized by high expression of GPNMB and CD63, enhanced lipid metabolism, and pro-angiogenic activity. Transplantation of RAMf into stroke-affected mice improves white matter integrity and vascular repair. We identify Mafb as the transcription factor regulating the reparative phenotype of RAMf. These findings highlight strategies to optimize immune cell dynamics for post-stroke rehabilitation.
© 2025. The Author(s).

β-arrestin 2 (ARRB2) is involved in the desensitization and trafficking of G protein-coupled receptors (GPCRs) and plays a critical role in cell proliferation, apoptosis, chemotaxis, and immune response modulation. The role of ARRB2 in the pathogenesis of multiple myeloma (MM) has not been elucidated. This study addressed this question by evaluating the expression of ARRB2 in bone marrow (BM) samples from newly diagnosed MM patients and deriving correlations with key clinical outcomes. In light of recent trends towards the use of immune checkpoint inhibitors across malignancies, the effect of ARRB2 in the regulation of the PD-1/PD-L1 axis was also investigated. The expression of ARRB2 was significantly higher in MM patients resistant to proteosome inhibitor (bortezomib) treatment compared to those who responded. Higher ARRB2 expression in the BM of newly diagnosed MM patients was associated with inferior progression-free survival and overall survival. PD-1 expression was downregulated in CD3 T cells isolated from ARRB2 knockout (KO) mice. Furthermore, knockdown of ARRB2 with siRNA reduced PD-1 expression in murine CD3 T cells and PD-L1 expression in murine myeloid-derived suppressor cells. These findings suggest an important role of ARRB2 in MM pathogenesis, potentially mediated via modulation of immune checkpoints in the tumor microenvironment. Our study provides new evidence that ARRB2 may have non-canonical functions independent of GPCRs with relevance to the understanding of MM pathobiology as well as immunotherapy and checkpoint inhibitor escape/resistance more broadly.

Background:Echinococcus granulosus represents a significant threat to animal husbandry and human health, but its consequences are often underestimated. Vaccination can prevent E. granulosus infection. We investigated the immune protective effect induced by the recombinant protein P29 of E. granulosus (rEg.P29) peptide vaccine. Methods: The CD4+ T-, CD8+ T-, Treg-, and CD8+CD107a+ T-cell proportions in the spleen and peripheral blood of infected mice were analyzed using flow cytometry. Additionally, we measured the proportions of IFN-γ and IL-2 secreted by memory T cells, CD19+CD138-B cells, CD19+CD138+ plasmablasts, CD19-CD138+ plasma cells, and CD19+IgD-IgG+ and CD19+IgD-IgA+ memory B cells. Results: No significant differences were noted in CD4+ T-, CD8+ T-, and CD8+CD107a+ Treg-cell percentages among the experimental groups. However, IFN-γ, IL-2, and TNF-α levels and vaccine-specific antibody concentrations in the plasma were significantly elevated in the rEg.P29T+B + CpG + infection and rEg.P29 + CpG + infection groups compared to those in the PBS + infection and CpG + infection groups. Similarly, CD19-CD138+ plasma cell and CD19+IgD-IgG+ and CD19+IgD-IgA+ memory B-cell populations, along with specific antibodies, were significantly higher in these groups. Especially, the average cyst burden in the rEg.P29T+B + CpG + infection and rEg.P29 + CpG + infection groups was significantly reduced compared to that in the PBS + infection and CpG + infection groups. Conclusions: Synthetic peptide vaccines targeting rEg.P29 can effectively inhibit cysts, offering a novel strategy for the development of vaccines against E. granulosus. These findings provide a foundation for further research on the immunogenicity and protective efficacy of rEg.P29-based vaccines.

Hepatocellular carcinoma (HCC) mainly depends on liver fibrosis/cirrhosis, which is regulated by tumor cells and the tumor microenvironment (TME), and is a crucial factor in tumor progression. This study aimed to identify abnormally expressed miR-500a-3p in the hepatitis-cirrhosis-HCC pathway and explored the roles of miR-500a-3p in HCC progression. A clinical cohort of patients with HCC is studied retrospectively. Subsequently, the role of miR-500a-3p transported by HCC exosomes in hepatic stellate cell (HSC) activation, hepatoma growth and invasion, and immune cell differentiation is determined by in vitro and in vivo experiments. In clinical tissues, miR-500a-3p is significantly enriched in HCC and cirrhosis tissues, and co-expression of the immune marker CD4 or PD-L1 significantly correlates with low survival rates in patients. Extracellular miR-500a-3p is taken up by HSC and PBMC, which promotes the secretion of the cytokines TGF-β1 and IL-10, increases PD-L1 expression in HSC, and stabilizes PD-1 expression in PBMC to affect the TME. Moreover, miR-500a-3p is associated with CD4+ T-cell exhaustion and Treg differentiation and is significantly associated with increased tumorigenicity in in situ mouse HCC models. Mechanistically, HCC-derived exosomal miR-500a-3p directly influences SOCS2 to regulate the JAK3/STAT5A/STAT5B signaling pathway. MiR-500a-3p promotes the growth and migration of HCC through the SOCS2/JAK3/STAT5A/STAT5B axis.
© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.