AXL as immune regulator and therapeutic target in Acute Myeloid Leukemia: from current progress to novel strategies.

Until recently, treatment options for patients diagnosed with Acute Myeloid Leukemia (AML) were limited and predominantly relied on various combinations, dosages, or schedules of traditional chemotherapeutic agents. Patients with advanced age, relapsed/refractory disease or comorbidities were often left without effective treatment options. Novel advances in the understanding of leukemogenesis at the molecular and genetic levels, alongside recent progress in drug development, have resulted in the emergence of novel therapeutic agents and strategies for AML patients. Among these innovations, the receptor tyrosine kinase AXL has been established as a promising therapeutic target for AML. AXL is a key regulator of several cellular functions, including epithelial-to-mesenchymal transition in tumor cells, immune regulation, apoptosis, angiogenesis and the development of chemoresistance. Clinical studies of AXL inhibitors, as single agents and in combination therapy, have demonstrated promising efficacy in treating AML. Additionally, novel AXL-targeted therapies, such as AXL-specific antibodies or antibody fragments, present potential solutions to overcome the limitations associated with traditional small-molecule AXL inhibitors or multikinase inhibitors. This review provides a comprehensive overview of the structure and biological functions of AXL under normal physiological conditions, including its role in immune regulation. We also summarize AXL's involvement in cancer, with a specific emphasis on its role in the pathogenesis of AML, its contribution to immune evasion and drug resistance. Moreover, we discuss the AXL inhibitors currently undergoing (pre)clinical evaluation for the treatment of AML.

Trends and research foci in immunoregulatory mechanisms of allergic rhinitis: a bibliometric analysis (2014-2024).

Background: This study aims to provide a comprehensive bibliometric analysis of research trends, hotspots, and future directions in the immunoregulatory mechanisms of allergic rhinitis (AR) from 2014 to 2024. Methods: Data were sourced from the Web of Science Core Collection (WoSCC), covering articles and reviews published between April 1, 2014, and March 31, 2024. The search terms included "Allergic Rhinitis," "AR," and related terms along with specific keywords related to immune cells and inflammatory mediators. Bibliometric tools such as CiteSpace, VOSviewer, and SCImago Graphica were used to analyze institutional cooperation networks, keyword co-occurrence, citation bursts, and research topic evolution. Microsoft Excel 2019 was employed to display annual publication trends. Results: A total of 2200 papers met the inclusion and exclusion criteria. The number of publications showed an upward trend over the past decade, with a significant peak in 2021. China (583 papers) and the United States (454 papers) were the major contributing countries. Imperial College London emerged as the leading institution. Key research frontiers identified include the roles of NF kappa B and air pollution in AR. Keyword burst analysis revealed emerging topics such as respiratory allergy and personalized treatment strategies. Notable limitations include the exclusive use of the WoSCC database and the restriction to English-language publications. Conclusion: The field of immunoregulatory mechanisms in allergic rhinitis has seen significant growth, with China and the United States leading the research. Future research should focus on developing personalized treatment plans and understanding the comprehensive impact of environmental factors. Continued interdisciplinary collaboration and international cooperation will be essential for advancing therapeutic strategies in AR.

Topical Application of 0.05% Cyclosporine for the Treatment of Neurotrophic Keratopathy Secondary to Herpes Simplex Keratitis.

PURPOSE: The purpose of this study was to assess the effectiveness and tolerability of 0.05% cyclosporine A (CsA) eye drops for neurotrophic keratopathy (NK) secondary to herpes simplex keratitis (HSK). METHODS: Fifteen patients (15 eyes) with prior HSK and secondary NK, classified as stage 2 or 3 on the basis of the Mackie classification, were enrolled. All patients received a combined treatment regimen of 0.05% CsA eye drops (1 drop 4 times daily), a silicone hydrogel bandage contact lens, and 0.15% ganciclovir ophthalmic gel (1 drop 3 times daily). For patients achieving corneal healing, CsA was continued at a reduced dosage of twice daily for an additional 2 months and other treatments were discontinued. Follow-ups were scheduled at weeks 1, 2, 3, and 4 and at months 2 and 3 after treatment initiation, followed by a 3-month follow-up period. Key outcomes, including best-corrected visual acuity, Schirmer I test, and corneal sensitivity, were assessed at each visit before and after treatment. FINDINGS: Significant reductions were observed in the area of corneal defects, expressed as proportion of total corneal area, throughout follow-up period. Complete corneal healing was achieved by 13.3% of patients by week 2, 60.0% by week 3, 86.7% by week 4, and 100.0% by week 8, with the mean (SD) time to healing being 3.8 (1.8) weeks (range, 2-8 weeks). Additionally, significant improvements were noted in diseased eyes for best-corrected visual acuity, tear secretion (Schirmer I test values), and corneal sensitivity after treatment. IMPLICATIONS: CsA eye drops, with bandage lenses and ganciclovir, effectively resolve NK from HSK, without adverse effects. This combination therapy shows promise for future clinical use and research. CLINICAL TRIAL REGISTRATION: Our study is a retrospective observational study because it involves the analysis of previously collected data, so the study was not registered prior to its commencement. However, if it is necessary for publication, we are willing to proceed with retrospective registration.

Immunostimulatory Effects of Gamisoyosan on Macrophages via TLR4-Mediated Signaling Pathways.

BACKGROUND: This study aimed to analyze the immunostimulatory activity of gamisoyosan (GSS) on the activation of macrophages in RAW 264.7 cells and its underlying mechanisms. METHODS: The effects of GSS on the secretion of nitric oxide (NO), immunomodulatory mediators, cytokines and mRNAs, and related proteins were assessed using the Griess assay, Western blotting, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and H2DCFDA, respectively. The level of phagocytosis was determined by the neutral red method while the immune function of GSS was determined using adhesion and wound-healing assays. RESULTS: GSS-treated macrophages significantly increased the production of NO, immunomodulatory enzymes, cytokines, and intracellular reactive oxygen species without causing cytotoxicity. GSS effectively improved macrophage immune function by increasing their phagocytic level, adhesion function, and migration activity. Mechanistic studies via Western blotting revealed that GSS notably induced the activation of the Toll-like receptor (TLR) 4-mediated mitogen-activated protein kinase, nuclear factor-κB, and protein kinase B signaling pathways. CONCLUSIONS: Overall, our results indicated that GSS could activate macrophages through the secretion of immune-mediated transporters via TLR4-dependent signaling pathways. Thus, GSS has potential value as an immunity-enhancing agent.

Study on the synthesis of iron-based nanomedicine assisted by angelica sinensis polysaccharide with enhanced retention performance and its application in anemia treatment.

Inappropriate treatment of chronic inflammation and infection can lead to serious consequences, with anemia being the most common secondary disease that often requires systematic treatment. However, the complex pathology and gastrointestinal irritation associated with oral iron supplements limit their effectiveness. To address this, a bioactive ingredient derived from natural herbs, Angelica sinensis polysaccharide (ASP), was utilized as an ideal adjuvant for regulating the size and stability of iron oxide nanoparticles (IONPs). Highly hydrophilic ASP-modified IONPs (IONPs@ASP) with a mesoporous structure were developed under the induction of microemulsion.The as-prepared IONPs@ASP exhibited enhanced stability, retention performance and controlled degradation in blood and lysosomal environments, respectively, which is beneficial for long-term intravenous iron maintenance in anemia treatment. After confirming the biosafety of IONPs@ASP, pharmacodynamic results showed that hemoglobin levels increased significantly and rapidly returned to normal levels in anemia model rats treated with IONPs@ASP, even surpassing the effects of IONPs or ASP monotherapy. Additionally, analysis of inflammatory factors in rat serum suggested that ASP effectively upregulated the expression of anti-inflammatory factors, indicating synergistic effects of iron-based nanomedicine and immune regulation in anemia treatment. These findings represent a significant advancement in anemia treatment and open new possibilities for developing versatile nanoparticles based on ASP.

Autoimmunity-Associated SNP rs3024505 Disrupts STAT3 Binding in B Cells, Leading to IL10 Dysregulation.

Interleukin 10 (IL10) is a major anti-inflammatory cytokine that acts as a master regulator of the immune response. A single nucleotide polymorphism rs3024505(C/T), located downstream of the IL10 gene, is associated with several aggressive inflammatory diseases, including systemic lupus erythematosus, Sjögren's syndrome, Crohn's disease, and ulcerative colitis. In such autoimmune pathologies, IL10-producing B cells play a protective role by decreasing the level of inflammation and restoring immune homeostasis. This study demonstrates that rs3024505 is located within an enhancer that augments the activity of the IL10 promoter in a reporter system based on a human B cell line. The common rs3024505(C) variant creates a functional binding site for the transcription factor STAT3, whereas the risk allele rs3024505(T) disrupts STAT3 binding, thereby reducing the IL10 promoter activity. Our findings indicate that B cells from individuals carrying the minor rs3024505(T) allele may produce less IL10 due to the disrupted STAT3 binding site, contributing to the progression of inflammatory pathologies.

Dipeptidyl peptidase-4 marks distinct subtypes of human adipose stromal/stem cells with different hepatocyte differentiation and immunoregulatory properties.

BACKGROUND: Human adipose-derived stromal/stem cells (hASCs) play important roles in regenerative medicine and numerous inflammatory diseases. However, their cellular heterogeneity limits the effectiveness of treatment. Understanding the distinct subtypes of hASCs and their phenotypic implications will enable the selection of appropriate subpopulations for targeted approaches in regenerative medicine or inflammatory diseases. METHODS: hASC subtypes expressing dipeptidyl peptidase-4 (DPP4) were identified via fluorescence-activated cell sorting (FACS) analysis. DPP4 expression was knocked down in DPP4+ hASCs via DPP4 siRNA. The capacity for proliferation, hepatocyte differentiation, inflammatory factor secretion and T-cell functionality regulation of hASCs from DPP4-, DPP4+, and control siRNA-treated DPP4+ hASCs and DPP4 siRNA-treated DPP4+ hASCs were assessed. RESULTS: DPP4+ hASCs and control siRNA-treated DPP4+ hASCs presented a lower proliferative capacity but greater hepatocyte differentiation capacity than DPP4- hASCs and DPP4 siRNA-treated DPP4+ hASCs. Both DPP4+ hASCs and DPP4- hASCs secreted high levels of vascular endothelial growth factor-A (VEGF-A), monocyte chemoattractant protein-1 (MCP-1), and interleukin 6 (IL-6), whereas the levels of other factors, including matrix metalloproteinase (MMP)-1, eotaxin-3, fractalkine (FKN, CX3CL1), growth-related oncogene-alpha (GRO-alpha, CXCL1), monokine induced by interferon-gamma (MIG), macrophage inflammatory protein (MIP)-1beta, and macrophage colony-stimulating factor (M-CSF), were significantly greater in the supernatants of DPP4+ hASCs than in those of DPP4- hASCs. Exposure to hASC subtypes and their conditioned media triggered changes in the secreted cytokine profiles of T cells from healthy donors. The percentage of functional T cells that secreted factors such as MIP-1beta and IL-8 increased when these cells were cocultured with DPP4+ hASCs. The percentage of polyfunctional CD8+ T cells that secreted multiple factors, such as IL-17A, tumour necrosis factor alpha (TNF-α) and TNF-ß, decreased when these cells were cocultured with supernatants derived from DPP4+ hASCs. CONCLUSIONS: DPP4 may regulate proliferation, hepatocyte differentiation, inflammatory cytokine secretion and T-cell functionality of hASCs. These data provide a key foundation for understanding the important role of hASC subpopulations in the regulation of T cells, which may be helpful for future immune activation studies and allow them to be customized for clinical application.

Passive protection of chicken egg yolk immunoglobulin (IgY) against Streptococcus agalactiae infection in Nile tilapia (Oreochromis niloticus).

IgY is an immunoglobulin primarily found in the serum and egg yolk of birds, amphibians, and reptiles. Recent years, IgY is considered to have a good application prospect in the immunodiagnostics and passive immunotherapy of aquatic diseases. In this study, we prepared a specific IgY against Streptococcus agalactiae in tilapia after immunizing the hens for 4 times. The result of ELISA detection showed that the IgY titers in water-soluble fraction (WSF) after 6 weeks of immunization reached 1:51200 and last for 4 weeks. Western blot (WB) analysis data showed that the specific IgY could recognize the target band, the specific IgY showed a concentration-dependent inhibitory effect on the growth of S. agalactiae, altered cell wall structure and aggluted of S. agalactiae. The quantitative reverse transcription PCR (qRT-PCR) analysis data suggested that the specific IgY downregulated the expression of pro-inflammatory factors (IL-8, TNF-α), upregulated the anti-inflammatory factors (IL-10, TGF-ß). In addition, the histopathological results showed that the specific IgY significantly decreased the pathological manifestations, dramatically improved the survival rates of tilapia in injection, feeding, and immersion experiments. Collectively, our findings demonstrated that the broad potential of specific IgY for the prevention and treatment of S. agalactiae infection in tilapia.

Computational recognition of regulator genes and signature for ferroptosis with implications on immunological properties and clinical management of atopic dermatitis.

Background: Atopic dermatitis (AD) is a common chronic dermatitis of autoimmune origin that considerably affects the quality of life of patients. Ferroptosis, a newly regulated form of cell death, is essential for inflammation-related damage-associated molecular patterns (DAMPs). In this study, we aimed to identify ferroptosis regulators relevant to AD pathogenesis and reveal the mechanisms by which ferroptosis regulates the pathogenesis of AD. Methods: We analyzed the GEO AD cohorts (GSE16161, GSE32924, GSE107361, and GSE120721), identifying AD-related differentially expressed genes (DEGs) using edgeR. Co-expression and STRING database analyses were used to elucidate the interactions between DEGs and ferroptosis markers. Through functional enrichment analysis, we defined potential biological functions within the protein-protein interaction (PPI) network and developed FerrSig using LASSO regression. The utility of FerrSig in guiding the clinical management of AD was evaluated using the GSE32473 cohort. Subsequently, our in silico findings were confirmed, and mechanistic insights were expanded through both in vitro and in vivo studies, validating the relevance of FerrSig. Results: In the GEO AD cohort, 278 DEGs were identified, including seven ferroptosis signature genes. Co-expression analysis and STRING database review revealed a 63-node PPI network linked to cell cycle and pro-inflammatory pathways. Four ferroptosis genes (ALOXE3, FABP4, MAP3K14, and EGR1) were selected to create FerrSig, which was significantly downregulated in samples collected from patients with AD. In addition, immune-related signaling pathways were significantly differentially enriched between the stratifications of samples collected from patients with AD with high and low ferritin levels, whereas in the GSE32473 cohort, FerrSig was significantly increased in cohorts effectively treated with pimecrolimus or betamethasone. Finally, in vitro and in vivo models showed a notable FerrSig decrease in patients with AD versus healthy control. Treatment with betamethasone and tacrolimus restored FerrSig, and the magnitude of the increase in FerrSig was higher in samples collected from patients with AD with better efficacy assessments. In addition, FerrSig was significantly positively correlated with the ferroptosis inhibitors GPX4 and SLC7A11 and negatively correlated with reactive oxygen species (ROS) levels and p-STAT3/STAT3. This implies that the FerrSig signature genes may regulate ferroptosis through the JAK/STAT3 signaling pathway. Conclusion: Our study further explored the pathogenesis of AD, and FerrSig could serve as a potential biomarker for identifying AD morbidity risks and determining treatment efficacy.

Mesenchymal stem cell therapy for liver transplantation: clinical progress and immunomodulatory properties.

Although liver transplantation (LT) is an effective strategy for end-stage liver diseases, the shortage of donor organs and the immune rejection hinder its widespread implementation in clinical practice. Mesenchymal stem cells (MSCs) transplantation offers a promising approach for patients undergoing liver transplantation due to their immune regulatory capabilities, hepatic protection properties, and multidirectional differentiation potential. In this review, we summarize the potential applications of MSCs transplantation in various LT scenarios. MSCs transplantation has demonstrated effectiveness in alleviating hepatic ischemia-reperfusion injury, enhancing the viability of liver grafts, preventing acute graft-versus-host disease, and promoting liver regeneration in split LT therapy. We also discuss the clinical progress, and explore the immunomodulatory functions of MSCs in response to both adaptive and innate immune responses. Furthermore, we emphasize the interactions between MSCs and different immune cells, including T cells, B cells, plasma cells, natural killer cells, dendritic cells, Kupffer cells, and neutrophils, to provide new insights into the immunomodulatory properties of MSCs in adoptive cell therapy.

Phenotypic, Metabolic, and Functional Characterization of Experimental Models of Foamy Macrophages: Toward Therapeutic Research in Atherosclerosis.

Different types of macrophages (Mφ) are involved in atherogenesis, including inflammatory Mφ and foamy Mφ (FM). Our previous study demonstrated that two-photon excited fluorescence (TPEF) imaging of NADH and FAD autofluorescence (AF) could distinguish experimental models that mimic the different atherosclerotic Mφ types. The present study assessed whether optical differences correlated with phenotypic and functional differences, potentially guiding diagnostic and therapeutic strategies. Phenotypic differences were investigated using three-dimensional principal component analysis and multi-color flow cytometry. Functional analyses focused on cytokine production, metabolic profiles, and cellular oxidative stress, in LDL dose-dependent assays, to understand the origin of AF in the FAD spectrum and assess FM ability to transition toward an immunoregulatory phenotype and function. Phenotypic studies revealed that FM models generated with acetylated LDL (Mac) were closer to immunoregulatory Mφ, while those generated with oxidized LDL (Mox) more closely resembled inflammatory Mφ. The metabolic analysis confirmed that inflammatory Mφ primarily used glycolysis, while immunoregulatory Mφ mainly depended on mitochondrial respiration. FM models employed both pathways; however, FM models generated with high doses of modified LDL showed reduced mitochondrial respiration, particularly Mox FM. Thus, the high AF in the FAD spectrum in Mox was not linked to increased mitochondrial respiration, but correlated with the dose of oxidized LDL, leading to increased production of reactive oxygen species (ROS) and lysosomal ceroid accumulation. High FAD-like AF, ROS, and ceroid accumulation were reduced by incubation with α-tocopherol. The cytokine profiles supported the phenotypic analysis, indicating that Mox FM exhibited greater inflammatory activity than Mac FM, although both could be redirected toward immunoregulatory functions, albeit to different degrees. In conclusion, in the context of immunoregulatory therapies for atherosclerosis, it is crucial to consider FM, given their prevalence in plaques and our results, as potential targets, regardless of their inflammatory status, alongside non-foamy inflammatory Mφ.

Immune-Enhancing Effects of Gwakhyangjeonggi-san in RAW 264.7 Macrophage Cells through the MAPK/NF-κB Signaling Pathways.

Gwakhyangjeonggi-san (GJS) is a traditional herbal medicine used in East Asia for the treatment of symptoms involving lower intestinal abnormalities; however, the effects of GJS on innate immunity and its cellular mechanisms of action have not been elucidated. In this study, we assessed the immune-enhancing activity and underlying mechanisms of GJS using RAW 264.7 murine macrophages. The results showed that GJS treatment significantly increased the secretion of nitric oxide and cytokines and their mRNA expression in macrophage RAW 264.7 cells without causing cytotoxicity. GJS treatment also significantly increased the production of reactive oxygen species, as well as inducing phagocytic activity, adhesion function, and migration ability, all of which improved the immune response. In addition, GJS activated nuclear factor-κB by promoting the phosphorylation and degradation of inhibitor of nuclear factor-κB alpha. Furthermore, GJS markedly increased the phosphorylation of mitogen-activated protein kinase in RAW 264.7 cells. These findings indicate that GJS has potential value as a dietary supplement for strengthening immunity.

Cell volume regulation modulates macrophage-related inflammatory responses via JAK/STAT signaling pathways.

Cell volume as a characteristic of changes in response to external environmental cues has been shown to control the fate of stem cells. However, its influence on macrophage behavior and macrophage-mediated inflammatory responses have rarely been explored. Herein, through mediating the volume of macrophages by adding polyethylene glycol (PEG), we demonstrated the feasibility of fine-tuning cell volume to regulate macrophage polarization towards anti-inflammatory phenotypes, thereby enabling to reverse macrophage-mediated inflammation response. Specifically, lower the volume of primary macrophages can induce both resting macrophages (M0) and stimulated pro-inflammatory macrophages (M1) to up-regulate the expression of anti-inflammatory factors and down-regulate pro-inflammatory factors. Further mechanistic investigation revealed that macrophage polarization resulting from changing cell volume might be mediated by JAK/STAT signaling pathway evidenced by the transcription sequencing analysis. We further propose to apply this strategy for the treatment of arthritis via direct introduction of PEG into the joint cavity to modulate synovial macrophage-related inflammation. Our preliminary results verified the credibility and effectiveness of this treatment evidenced by the significant inhibition of cartilage destruction and synovitis at early stage. In general, our results suggest that cell volume can be a biophysical regulatory factor to control macrophage polarization and potentially medicate inflammatory response, thereby providing a potential facile and effective therapy for modulating macrophage mediated inflammatory responses. STATEMENT OF SIGNIFICANCE: Cell volume has recently been recognized as a significantly important biophysical signal in regulating cellular functionalities and even steering cell fate. Herein, through mediating the volume of macrophages by adding polyethylene glycol (PEG), we demonstrated the feasibility of fine-tuning cell volume to induce M1 pro-inflammatory macrophages to polarize towards anti-inflammatory M2 phenotype, and this immunomodulatory effect may be mediated by the JAK/STAT signaling pathway. We also proposed the feasible applications of this PEG-induced volume regulation approach towards the treatment of osteoarthritis (OA), wherein our preliminary results implied an effective alleviation of early synovitis. Our study on macrophage polarization mediated by cell volume may open up new pathways for immune regulation through microenvironmental biophysical clues.

An integrated transcription factor framework for Treg identity and diversity.

Vertebrate cell identity depends on the combined activity of scores of transcription factors (TF). While TFs have often been studied in isolation, a systematic perspective on their integration has been missing. Focusing on FoxP3+ regulatory T cells (Tregs), key guardians of immune tolerance, we combined single-cell chromatin accessibility, machine learning, and high-density genetic variation, to resolve a validated framework of diverse Treg chromatin programs, each shaped by multi-TF inputs. This framework identified previously unrecognized Treg controllers (Smarcc1) and illuminated the mechanism of action of FoxP3, which amplified a pre-existing Treg identity, diversely activating or repressing distinct programs, dependent on different regulatory partners. Treg subpopulations in the colon relied variably on FoxP3, Helios+ Tregs being completely dependent, but RORγ+ Tregs largely independent. These differences were rooted in intrinsic biases decoded by the integrated framework. Moving beyond master regulators, this work unravels how overlapping TF activities coalesce into Treg identity and diversity.

Structural characterization and immune activity evaluation of a polysaccharide from Lyophyllum Decastes.

An innovative acidic hydrolysate fingerprinting workflow was proposed for the characterization of Lyophyllum Decastes polysaccharide (LDP) by ultra performance liquid chromatography-mass spectrometry (UPLC-MS). The crude polysaccharides were firstly separated and purified by using DE-52 column and the BRT GPC purification system, respectively. The molecular weight and monosaccharide content of homogeneous polysaccharides were ascertained by utilizing HPGPC and ion chromatography separately. Secondly, the linkage of LDP was identified by methylation analysis and 1D/2D NMR spectra. The UPLC-MS/MS was used to scan and identify the acidic hydrolysate products of LDP using the PGC column. The oligosaccharides were collected by chromatography and identified by mass spectrometry. Thirdly, the expression of IL-1ß, IL-6, iNOS, TNF-α and IFNAR-I was measured in order to assess the immunological activity of LDP. Besides, the targeted receptors identification of polysaccharides was performed by screening the expression of TLRs family protein. The results showed that oligosaccharide fragments with different molecular weights can be obtained by partial hydrolysis, which further verified that the structures of LDP polysaccharides was a 1-6-linked ß-glucan. Moreover, the LDP polysaccharide can up-regulate the content of IL-1ß, IL-6, iNOS, TNF-α and IFNAR-I and plays an important immunoregulation role through TLRs family.

The YTH domain-containing protein family: Emerging players in immunomodulation and tumour immunotherapy targets.

BACKGROUND: The modification of N6-methyladenosine (m6A) plays a pivotal role in tumor by altering both innate and adaptive immune systems through various pathways, including the regulation of messenger RNA. The YTH domain protein family, acting as "readers" of m6A modifications, affects RNA splicing, stability, and immunogenicity, thereby playing essential roles in immune regulation and antitumor immunity. Despite their significance, the impact of the YTH domain protein family on tumor initiation and progression, as well as their involvement in tumor immune regulation and therapy, remains underexplored and lacks comprehensive review. CONCLUSION: This review introduces the molecular characteristics of the YTH domain protein family and their physiological and pathological roles in biological behavior, emphasizing their mechanisms in regulating immune responses and antitumor immunity. Additionally, the review discusses the roles of the YTH domain protein family in immune-related diseases and tumor resistance, highlighting that abnormal expression or dysfunction of YTH proteins is closely linked to tumor resistance. KEY POINTS: This review provides an in-depth understanding of the YTH domain protein family in immune regulation and antitumor immunity, suggesting new strategies and directions for immunotherapy of related diseases. These insights not only deepen our comprehension of m6A modifications and YTH protein functions but also pave the way for future research and clinical applications.

Enkephalin-mediated modulation of basal somatic sensitivity by regulatory T cells in mice.

CD4+CD25+Foxp3+ regulatory T cells (Treg) have been implicated in pain modulation in various inflammatory conditions. However, whether Treg cells hamper pain at steady state and by which mechanism is still unclear. From a meta-analysis of the transcriptomes of murine Treg and conventional T cells (Tconv), we observe that the proenkephalin gene (Penk), encoding the precursor of analgesic opioid peptides, ranks among the top 25 genes most enriched in Treg cells. We then present various evidence suggesting that Penk is regulated in part by members of the Tumor Necrosis Factor Receptor (TNFR) family and the transcription factor Basic leucine zipper transcription faatf-like (BATF). Using mice in which the promoter activity of Penk can be tracked with a fluorescent reporter, we also show that Penk expression is mostly detected in Treg and activated Tconv in non-inflammatory conditions in the colon and skin. Functionally, Treg cells proficient or deficient for Penk suppress equally well the proliferation of effector T cells in vitro and autoimmune colitis in vivo. In contrast, inducible ablation of Penk in Treg leads to heat hyperalgesia in both male and female mice. Overall, our results indicate that Treg might play a key role at modulating basal somatic sensitivity in mice through the production of analgesic opioid peptides.

Endocannabinoids and their receptors modulate endometriosis pathogenesis and immune response.

Endometriosis (EM), characterized by the presence of endometrial-like tissue outside the uterus, is the leading cause of chronic pelvic pain and infertility in females of reproductive age. Despite its high prevalence, the molecular mechanisms underlying EM pathogenesis remain poorly understood. The endocannabinoid system (ECS) is known to influence several cardinal features of this complex disease including pain, vascularization, and overall lesion survival, but the exact mechanisms are not known. Utilizing CNR1 knockout (k/o), CNR2 k/o, and wild-type (WT) mouse models of EM, we reveal contributions of ECS and these receptors in disease initiation, progression, and immune modulation. Particularly, we identified EM-specific T cell dysfunction in the CNR2 k/o mouse model of EM. We also demonstrate the impact of decidualization-induced changes on ECS components, and the unique disease-associated transcriptional landscape of ECS components in EM. Imaging mass cytometry (IMC) analysis revealed distinct features of the microenvironment between CNR1, CNR2, and WT genotypes in the presence or absence of decidualization. This study, for the first time, provides an in-depth analysis of the involvement of the ECS in EM pathogenesis and lays the foundation for the development of novel therapeutic interventions to alleviate the burden of this debilitating condition.

Modified Titanium Implants Satisfy the Demands of Diabetic Osseointegration via Sequential Regulation of Macrophages and Mesenchymal Stem Cells.

The application of titanium (Ti) implants for patients with diabetes mellitus (DM) is still facing a significant challenge due to obstacles such as hyperglycemia, reactive oxygen species (ROS), and chronic inflammation, which hinders osseointegration. To address this issue, a Ti implant with dual functions of regulating polarization of macrophages and facilitating osseointergration is developed via hydrothermal reaction and hydrogel coating. The reactive oxygen species (ROS) and glucose (Glu) responsive hydrogel coating can locally deliver adenosine (ADO) in the early stage of implantation. The controlled release of ADO regulated the phenotype of macrophages, restored oxidative balance, and enhanced mitochondrial function during the early stages of implantation. Subsequently, strontium (Sr) ions will be released to promote osteogenic differentiation and proliferation of mesenchymal stem cells (MSCs), as the hydrogel coating degraded. It eventually leads to bone reconstruction during the late stages, aligning with the biological cascade of bone healing. The modified Ti implants showed effective osteogenesis for bone defects in DM patients, shedding light on the design and biological mechanisms of surface modification. This research offers promising potential for improving the treatment of bone-related complications in diabetic patients.

The implications of the TNFα-TNFR2 immune checkpoint signaling pathway in cancer treatment: From immunoregulation to angiogenesis.

Despite the tremendous advances that have been made in biomedical research, cancer remains one of the leading causes of death worldwide. Several therapeutic approaches have been suggested and applied to treat cancer with impressive results. Immunotherapy based on targeting immune checkpoint signaling pathways proved to be one of the most efficient. In this review article, we will focus on the recently discovered TNFα-TNFR2 signaling pathway, which controls the immunological and pro-angiogenic properties of many immunoregulatory and pro-angiogenic cells such as endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs), and regulatory T cells (Tregs). Due to their biological properties, these cells can play a major role in cancer progression and metastasis. Therefore, we will discuss the advantages and disadvantages of an anti-TNFR2 treatment that could carry two faces under one hood. It interrupts the immunosuppressive and pro-angiogenic behaviors of the above-mentioned cells and interferes with tumor growth and survival.