Journal of Leukocyte Biology最新文献

The monocyte-to-macrophage transition is marked by alterations to both the structure and function of the genome, including changes in histone posttranslational modifications, DNA methylation, 3D nuclear architecture, and expression of lineage specific genes. The nucleosome is the fundamental organizational unit of the eukaryotic genome and underpins both genome structure and function. However, nucleosome dynamics at promoters, which are essential for transcriptional regulation, are understudied in cellular differentiation. We conducted high-resolution chromatin structure profiling at promoters in the THP-1 cell line at 8 different time points spanning phorbol-12-myristate 13-acetate (PMA)-induced monocyte-to-macrophage differentiation. We found that fewer than 10% of nucleosomes within promoters were redistributed during differentiation and only a subset of these were associated with immediate transcriptional alterations. Nucleosomes within the promoters of PMA-responsive genes were strongly positioned prior to differentiation and experienced minimal alterations during differentiation, thus implying the existence of a predifferentiation primed chromatin state. Additionally, we observed pronounced alterations in nucleosome sensitivity to MNase digestion within 1 h of PMA-induced differentiation and the emergence of a highly resistant phenotype in fully differentiated cells. We found that resistance is correlated with active chromatin marks, transcription factor binding, gene expression, and higher-order chromatin structure, demonstrating that it is a useful measure of both genome structure and function. Together, this suggests that, unlike more stable nucleosome distribution, transient sensitivity alterations may underpin new genomic functions in differentiating cells. Our results offer a framework for understanding how chromatin structural alterations potentiate cellular differentiation in a monocyte model and use methodology that is widely applicable to other systems.

Ion channels are integral membrane proteins that facilitate rapid transport of small ions into and out of the cell and between organelles and cytosol. Cytolytic lymphocytes including natural killer (NK) cells principally kill virus-infected and cancer cells by releasing cytolytic granules within the immunological synapse, formed between target and effector cells. This process strongly depends on Ca2+ signaling, which in human NK cells is controlled by the PLCγ/IP3R/CRAC axis. It is believed that CRAC, a Ca2+-selective channel within the cell membrane, is a principal mediator of Ca+ entry in nonexcitable cells including immune cells. However, in addition to CRAC, the activity of other plasma membrane and organellar channels, which are permeable for Ca2+ and Na+, K+, or small anions, also plays important roles in regulating NK cell functions. In this review, we discuss the role of different ion channels in the NK-mediated immune response including members of 4 distinct families of K+-selective channels, transient receptor potential channels, purinergic receptors, and pentameric ligand-gated channels that are located in the plasma membrane and lysosomes of NK cells.

Regulatory B cells, specifically the CD24+CD38+ phenotype, are known for their capacity to reduce inflammation by releasing interleukin 10. However, their potential role in regulating inflammation through macrophage differentiation is not well understood. This study investigates how CD24+CD38+ regulatory B cells modulate the differentiation and function of pro-resolving macrophages through programmed death-ligand 1/programmed death-1 interactions and interleukin 10 secretion. Human CD24+CD38+ B cells were isolated from peripheral blood and co-cultured with THP-1-derived macrophages. Recombinant interleukin 10/ programmed death-ligand 1 and neutralizing antibodies were used to conduct gain and loss-of-function studies. Flow cytometry, quantitative PCR, and mass spectrometry were used to evaluate macrophage polarization, efferocytosis activity, and pro-resolving lipid mediator production. After co-culture, M2 polarization, programmed death-1 expression, and efferocytosis activity were increased significantly. Inhibition of either interleukin 10 or programmed death-ligand 1 pathway reduced M2 macrophage differentiation and functional activity. Co-culture of macrophages with CD24+CD38+ B cells enhanced the production of pro-resolving lipid mediators, particularly 12-HEPE and RvD5 through interleukin 10 secretion and programmed death-ligand 1/programmed death-1 ligation. These findings reveal a novel mechanism by which human CD24+CD38+ regulatory B cells promote macrophage-mediated resolution of inflammation through interleukin 10 secretion and programmed death-ligand 1/programmed death-1 ligation. By exploring how these regulatory pathways influence macrophage biology, we ultimately aim to uncover novel therapeutic targets for enhancing inflammation resolution in chronic inflammatory diseases.

Acute lymphoblastic leukemia is a hematological malignancy characterized by the uncontrolled proliferation of immature lymphoid cells, but the role of circNR3C1 in acute lymphoblastic leukemia is not fully elucidated. In this study, expression levels of circNR3C1, RPS3, ENO1, and MSI2 were assessed in acute lymphoblastic leukemia cell lines and normal bone marrow mononuclear cells using RT-qPCR and Western blotting. Co-immunoprecipitation, RNA immunoprecipitation, RNA pull-down, and protein stability analyses were performed to investigate interactions between circNR3C1, MSI2, ENO1, and RPS3. A xenograft mouse model was utilized to assess the impact of circNR3C1 on tumor growth. The results showed that circNR3C1 expression was significantly upregulated in acute lymphoblastic leukemia cells compared to normal bone marrow mononuclear cells. Knockdown of circNR3C1 suppressed proliferation and induced apoptosis in acute lymphoblastic leukemia cells. CircNR3C1 positively regulated RPS3 expression by enhancing the stability of ENO1 mRNA through interaction with MSI2. ENO1 is bound to RPS3, increasing its protein stability. Overexpression of MSI2 or RPS3 reversed the inhibitory effects of circNR3C1 knockdown on cell proliferation and survival. These findings indicate that circNR3C1 promotes acute lymphoblastic leukemia cell proliferation and inhibits apoptosis by interacting with MSI2 to stabilize ENO1 mRNA, leading to upregulation of ENO1 and RPS3. The circNR3C1/MSI2/ENO1/RPS3 axis represents a novel regulatory pathway contributing to acute lymphoblastic leukemia progression and offers potential therapeutic targets for treatment.

There is limited understanding of the impact of anti-IL5 treatment on nasal polyp tissue biology in chronic rhinosinusitis with nasal polyps (CRSwNP). This study examined nasal polyp tissue cellular proteome and transcriptome responses to anti-IL5 treatment in CRSwNP utilising spatial profiling. GeoMx™ Digital Spatial Profiling (DSP) of 80 proteins and 1,833 mRNA targets in the polyp stroma and the whole transcriptome (18,815 mRNA targets) in polyp epithelia was undertaken on sinonasal biopsies collected from 20 individuals with eosinophilic CRSwNP before and after 16 and 24 weeks of mepolizumab treatment. Anti-IL5 therapy in patients with eosinophilic CRSwNP had significant tissue biological impact. Treatment-related changes in polyp stroma proteins associated with checkpoint inhibition (PD-1), neutrophil degranulation (CD6b, CD44, STING1) and the innate immune system (CD14, CD68, STING, CD163) were identified in a protein interaction network. Transcriptionally, there were significant reductions in gene sets associated with the reactome-terms innate and adaptive immune system, neutrophil degranulation and TGFβ receptor signalling in epithelial to mesenchymal transition within polyp stroma, as well as enhancing antioxidant pathways. In polyp epithelia, increases in gene sets associated with the reactome-terms cilium assembly and keratinisation and a reduction in the regulation of KIT signalling were observed. Spatial profiling demonstrates that the effects of anti-IL5 treatment within nasal polyp tissue extend beyond simple eosinophil reduction to regulation of innate and adaptive immune cells and in improving epithelial barrier biology. The clinical relevance of changes to improved barrier function may relate to quality-of-life metrics observed previously with anti-IL5 treatment.

CD57 is one of the biomarkers for immunosenescence, and its expression increases with age. This study aimed to analyze CD4+ T cell phenotypes and cytokine production (interferon-gamma [IFN-γ] and interleukin [IL]-17) and their association with cardiovascular disease risk factors. Using multicolor flow cytometry, leftover whole blood specimens from 53 older people (≥60 yr) and 42 young individuals (≤35 yr) were analyzed. We found that older individuals had significantly higher percentages of CD4+CD57+ and CD4+ CD28- T cells than the younger group. Notably, CD57 expression was positively correlated with the number of CD4+CD28- T cells. Among the participants, older individuals with ≥1 cardiovascular disease risk factor (dyslipidemia and/or hypertension and/or diabetes mellitus) had the highest median values of CD4+CD57+, CD4+CD28-, and CD4+CD28-CD57+ T cells. Comparing the CD57+ and CD57- populations, the median percentage of IFN-γ and IL-17 from CD4+CD57+ T cells was significantly higher than those from CD4+CD57- T cells. Interestingly, older participants with ≥1 cardiovascular disease risk factor displayed a significantly higher percentage of IFN-γ-producing CD4+CD57+ T cells than older and young individuals without cardiovascular disease risk factors. In conclusion, this work reports prominent CD57 expression on CD4+ T cells and their subsets in older people. Increasing age, along with cardiovascular disease risk factors, may participate to alterations in immune function, reflected by higher levels of IFN-γ- and IL-17-producing CD4+CD57+ T cells, and may be associated with an elevated level of chronic low-grade inflammation.

Inflammatory bowel disease (IBD) is a debilitating and symptomatic disorder of the gastrointestinal tract, featuring dysregulated inflammation, intestinal injury, and barrier dysfunction. IBD is also a risk factor for colorectal cancer (CRC), which remains a leading cause of cancer-related mortalities worldwide. Matrix metalloproteinases (MMPs) are a diverse family of proteases that play critical roles in both intestinal homeostasis and disease pathogenesis. Produced by epithelial, stromal, and immune cells, MMPs can regulate stem cell function, immune cell recruitment, microbial composition, barrier integrity, angiogenesis, and cell proliferation through extracellular matrix remodeling, cytokine activation, or direct interactions with target cells, thereby impacting the progression of both IBD and CRC. In this review we discuss the roles of MMPs in the maintenance of intestinal homeostasis and their contributions to imbalanced immune responses, epithelial integrity, and wound healing in IBD. Additionally, we highlight their contribution to epithelial-to-mesenchymal transition, angiogenesis, and metastasis in CRC. Finally, we review the potential utilization of MMPs as biomarkers for IBD/CRC diagnosis, prognosis, and treatment response. MMPs remain central to both IBD and CRC biology and present both challenges and opportunities for therapeutic intervention and disease monitoring.

As its discovery nears a half century, the widespread use of F4/80 antigen as a differentiation marker of tissue macrophages of the mouse, continues to raise questions in and beyond experimental cellular immunology. Its structure as a 7 transmembrane G Protein-Coupled Receptor initiated the discovery of a diverse family of plasma membrane receptors. This review will trace milestones of research into the expression of F4/80, also known as Emr1, its value as a marker in formulation of the Mononuclear Phagocyte System and its function in a model of peripheral immune tolerance in the anterior chamber of the eye. Human EMR1 is closely related to a primate-restricted myeloid mechanoreceptor, EMR2, with a novel autocatalytic activation mechanism. We describe their relation to structurally related members of the group E adhesion GPCR subfamily and their contributions to homeostatic systems of the body through local plasma membrane cellular interactions.

Psoriasis is a systemic inflammatory skin disorder with a prevalence of 2% in adults. Up to 30% of affected individuals further develop psoriatic arthritis (PsA), which is characterized by additional joint inflammation. Myeloperoxidase (MPO) is strongly expressed by neutrophils and, to a lesser extent, also by other myeloid cells. MPO converts hydrogen peroxide to secondary reactive oxygen species (ROS) and is thus primarily considered to induce tissue damage. However, recent studies suggest a protective role of MPO in psoriatic diseases. We aimed to investigate the role of MPO in PsA using the mouse model of mannan-induced PsA. MPO-deficient (Mpo-/-) mice showed exacerbated skin inflammation, joint swelling, and bone degradation associated with increased infiltration of neutrophils, classically activated macrophages, and T cells as well as increased inflammatory cytokine expression in the affected tissues. In the absence or blockade of MPO, in vitro neutrophil stimulation resulted in reduced NET formation and enhanced degranulation characterized by increased neutrophil elastase (NE) activity. In addition, in vitro differentiated macrophages from Mpo-/- mice showed increased interleukin (Il)-6 mRNA expression. Altogether, our findings suggest that MPO controls inflammatory responses in PsA, at least in part, by reducing neutrophil degranulation and serine protease release and, putatively, by reducing inflammatory cytokine production by macrophages.