Immune Regulatory Factors Research Articles

Mesenchymal Stem Cells Derived from Human Urine-Derived iPSCs Exhibit Low Immunogenicity and Reduced Immunomodulatory Profile.

Human-induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (iMSCs) represent a promising and renewable cell source for therapeutic applications. A systematic evaluation of the immunological properties and engraftment potential of iMSCs generated from urine-derived iPSCs is lacking, which has impeded their broader application. In this study, we differentiated urine-derived iPSCs into iMSCs and assessed their fundamental MSC characteristics, immunogenicity, immunomodulatory capacity and in vivo engraftment. Compared to umbilical cord-derived MSCs (UCMSCs), iMSCs demonstrated an enhanced proliferative capacity, a higher level of regenerative gene expression, and lower immunogenicity, strengthening resistance to apoptosis induced by allogeneic peripheral blood mononuclear cells (PBMCs) and the NK-92 cell line. In addition, iMSCs exhibited a diminished ability to inhibit T cell proliferation and activation compared with UCMSCs. Transcriptomic analyses further revealed the decreased expression of immune regulatory factors in iMSCs. After transfusion into mouse models, iMSCs engrafted in the lungs, liver, and spleen and exhibited the ability to migrate to tumor tissues. Our results indicated that iMSCs generated from urine-derived iPSCs have a significant replicative capacity, low immunogenicity and unique immunomodulatory properties, and hence offer obvious advantages in immune privilege and allogenic therapeutic application prospects.

Tumor-produced immune regulatory factors as a therapeutic target in cancer treatment.

Tumor-produced immune regulatory factors as a therapeutic target in cancer treatment.

Integration of QTL and comprehensive analysis in the circulating inflammatory cytokines for pan-cancer

BackgroundChemokines and cytokines are components of the tumor microenvironment and also influence tumorigenesis and its composition. However, whether they genetically proxy tumorigenesis is unclear. For causal inferences, eQTL and pQTL were used to determine the role of chemokines and cytokines in pan-cancer. The impact on the tumor immune microenvironment was also explored.MethodsThis study leveraged summary statistics from respective genome-wide association studies (GWAS) of 109 cytokines and chemokines in 18 types of solid tumors. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines and chemokines, located in or close to their coding gene (cis), were used as instrumental variables. A two-sample MR design was employed, followed by comprehensive sensitivity analyses to validate the robustness of results. The impact on immune infiltration was investigated using the TIMER and TISIDB websites. Survival analysis was conducted using the K-M plotter and TIMER 2.0 websites. The TISCH and GEO databases were used to carry out scRNA cell analysis.Analyzing relevant proteins using the STRING database and conducting enrichment pathways for GO analysis of the identified proteins.ResultsThe results of the inverse-variance weighted (IVW) method using cis-protein QTL (cis-pQTL) instruments showed the causal effects of TNF in reducing the risk of squamous cell lung cancer (LUSC) and HGF in reducing the risk of head and neck cancer (HNSC).The results were consistent with the eQTL. HGF was associated with better overall survival (OS) in HNSC, regardless of the types of cells enriched. However, high expression of the ligand MET for HGF leads to a decrease in overall survival in LUSC. TNF was related to poor OS in LUSC with no significant impact. However, in CD8 + T cell-enriched, eosinophil-enriched, macrophage-enriched, and NK cell-deficient types of LUSC, high expression of TNF leads to a poor prognosis, and there is statistical significance. The results showed a significant positive correlation between TNF and most immune cell infiltration, immunomodulator and chemokine in LUSC. HGF is positively correlated with the majority of immune cells except CD56 + cells, as well as some immune regulatory factors and chemotactic factors. According to single-cell sequencing results, HGF is mainly secreted by fibroblasts and myofibroblasts in HNSC, while in LUSC, it is primarily secreted by macrophages and CD8 + T cells secrete TNF. The GO/KEGG analysis suggests that proteins related to HGF are mainly involved in regulating peptidyl-tyrosine phosphorylation and positive regulation of the MAPK cascade. Proteins related to TNF are primarily associated with the regulation of I-kappaB kinase/NF-kappaB signaling and cytokine-mediated signaling pathway.ConclusionsHGF is primarily secreted by fibroblasts in HNSC and may have a protective effect on the occurrence and prognosis of HNSC. These effects are independent of immune cell influence, and this role may not necessarily be mediated through the HGF/MET pathway. On the other hand, TNF in LUSC is mainly secreted by immune cells like CD8 + T cell, and it may have a protective effect on the occurrence of LUSC. However, it’s impact on the prognosis of LUSC through the immune microenvironment may have a different effect.

Bioproduction and immunogenic evaluation of SARS-CoV-2 prototype vaccine in silkworm BmN cells

COVID-19, caused by the novel coronavirus SARS-CoV-2, has presented a significant challenge to global health, security, and the economy. Vaccination is considered a crucial measure in preventing virus transmission. The silkworm bioreactor has gained widespread usage in antigen presentation, monoclonal antibody preparation, and subunit vaccine development due to its safety, efficiency, convenience, and cost-effectiveness. In this study, we employed silkworm BmN cells and the silkworm MultiBac multigene co-expression system to successfully produce two prototype vaccines: a recombinant baculovirus vector vaccine (NPV) co-displaying the SARS-CoV-2 virus capsid protein and a capsid protein virus-like particle (VLP) vaccine. Following the purification of these vaccines, we immunized BALB/c mice to evaluate their immunogenicity. Our results demonstrated that both VLP and NPV prototype vaccines effectively elicited robust immune responses in mice. However, when equal inoculation doses between groups were compared, the recombinant NPV vaccine exhibited significantly higher serum antibody titers and increased expression of spleen cytokines and lymphocyte immune regulatory factors compared to the VLP group. These results suggested an increased immune efficacy of the recombinant NPV vaccine. Conversely, the VLP prototype vaccine displayed more pronounced effects on lymphocyte cell differentiation induction. This study successfully constructed two distinct morphological recombinant vaccine models and systematically elucidated their differences in humoral immune response and lymphocyte differentiation rate. Furthermore, it has fully harnessed the immense potential of silkworm bioreactors for vaccine research and development, providing valuable technical insights for studying mutated viruses like coronaviruses.

Clinical significance and biological function of interferon regulatory factor 1 in non-small cell lung cancer.

The clinical application and biological function of interferon regulatory factor 1 (IRF1) in non-small cell lung cancer (NSCLC) patients undergoing chemoimmunotherapy remain elusive. The aim of this study was to investigate the predictive and prognostic significance of IRF1 in NSCLC patients. We employed the cBioPortal database to predict frequency changes in IRF1 and explore its target genes. Bioinformatic methods were utilized to analyze the relationship between IRF1 and immune regulatory factors. Retrospective analysis of clinical samples was conducted to assess the predictive and prognostic value of IRF1 in chemoimmunotherapy. Additionally, A549 cells with varying IRF1 expression levels were constructed to investigate its effects on NSCLC cells, while animal experiments were performed to study the role of IRF1 in vivo. Our findings revealed that the primary mutation of IRF1 is deep deletion and it exhibits a close association with immune regulatory factors. KRAS and TP53 are among the target genes of IRF1, with interferon and IL-2 being the predominantly affected pathways. Clinically, IRF1 levels significantly correlate with the efficacy of chemoimmunotherapy. Patients with high IRF1 levels exhibited a median progression-free survival (mPFS) of 9.5 months, whereas those with low IRF1 levels had a shorter mPFS of 5.8 months. IRF1 levels positively correlate with PD-L1 distribution and circulating IL-2 levels. IL-2 enhances the biological function of IRF1 and recapitulates its role in vivo in the knockdown group. Therefore, IRF1 may possess predictive and prognostic value for chemoimmunotherapy in NSCLC patients through the regulation of the IL-2 inflammatory pathway.

SLAMF8 can predict prognosis of pan-cancer and the immunotherapy response effectivity of gastric cancer.

SLAMF8, the eighth member of the Signaling Lymphocytic Activation Molecule Family (SLAMF), functions in the regulation of the development and activity of diverse immune cells as a costimulatory receptor within the SLAMF family. Studies had revealed that SLAMF8 is expressed higher in several autoimmune inflammation diseases and tumors. Nevertheless, the connection between SLAMF8 and pan-cancer remains undisclosed. The research investigated the correlation between SLAMF8 and various factors including the immune microenvironment, microsatellite instability, immune novel antigen, gene mutation, immune regulatory factors, immune blockade TMB, and immune or molecular subtypes of SLAMF8 in verse cancer types. Immunohistochemistry was ultimately employed to validate the presence of the SLAMF8 gene in various tumor types including hepatocellular carcinoma, prostate adenocarcinoma, and kidney renal clear cell carcinoma. Furthermore, the relationship between SLAMF8 expression and the therapeutic efficacy of the PD1 blockade agent, Sintilimab, treatment in gastric cancer was validated. The result of differential analysis suggested that SLAMF8 was over-expressed in pan-cancer compared with paracancerous tissues. The analysis of survival indicated a connection between SLAMF8 and the overall prognosis in different types of cancers, where higher levels of SLAMF8 were found to be significantly linked to unfavorable outcomes in patients but favorable outcome of immunotherapy in gastric cancer. Significant correlations were observed between SLAMF8 levels and pan-cancer tumorigenesis, tumor metabolism, and immunity. As a result, SLAMF8 may become an important prognostic biomarker in the majority of tumors and a hopeful gene target for immunotherapy against gastric cancer.

Comprehensive prognostic and immunological analysis of Cullin2 in pan-cancer and its identification in hepatocellular carcinoma.

As a member of the Cullin family, Cullin2 (CUL2) is involved in the development and spread of different types of cancers. However, the precise role of CUL2 in human cancer remains largely elusive. In this study, various databases were applied to observe the CUL2 expression. Kaplan-Meier and Spearman correlation analyses were employed to investigate the potential links between CUL2 level, patient prognosis, and the infiltration of immune cells. In addition, the association between CUL2 and the efficacy of immunotherapy in an immunotherapy cohort was investigated. Moreover, the expression and distribution of CUL2 in cells were observed using the Human Protein Atlas (THPA) database. Finally, clinical tissue specimens and in vitro function assays were conducted to validate the expressions and effects of CUL2 on the biological functions in hepatocellular carcinoma (HCC) cells. While there are variations in CUL2 expression across different organs and cell types, it is notably upregulated in a majority of tumor tissues. In addition, CUL2 gene mutations are common in multiple cancers with low mutation rates and CUL2 is closely related to the prognosis of some cancer's patients, some immune regulatory factors, TMB, MSI, MMR genes, and DNA methylation. Further, our results found that downregulating CUL2 inhibits the proliferation, and migration abilities. The expression of CUL2 has an impact on the prognosis of various tumors, and this correlation is particularly noteworthy due to its significant association with the infiltration of immune cells within tumors. CUL2 was an oncogene contributing to the progression of HCC.

Early application of IFNγ mediated the persistence of HBV in an HBV mouse model

The antiviral activity of interferon gamma (IFNγ) against hepatitis B virus (HBV) was demonstrated both in vivo and in vitro in a previous study. IFNγ can suppress HBV replication by accelerating the decay of replication-competent nucleocapsids of HBV. However, in this study, we found that the direct application of the mouse IFNγ (mIFNγ) expression plasmid to the liver of an HBV hydrodynamic injection (HI) mouse model led to the persistence of HBV, as indicated by sustained HBsAg and HBeAg levels in the serum as well as an increased percentage of the HBsAg positive mice, whereas the level of HBV DNA in the serum and the expression of HBcAg in the liver were inhibited at the early stage after HI. Meanwhile, we found that the productions of both HBcAb and HBsAb were suppressed after the application of mIFNγ. In addition, we found that HBV could be effectively inhibited in mice immunized with HBsAg expression plasmid before the application of mIFNγ. Furthermore, mIFNγ showed antiviral effect and promoted the production of HBsAb when the mice subjected to the core-null HBV plasmid. These results indicate that the application of mIFNγ in the HBV HI mouse model, the mice showed defective HBcAg-specific immunity that impeded the production of HBcAb and HBsAb, finally allowing the persistence of the virus. Moreover, IFNγ-induced negative immune regulatory factors also play an important role in virus persistence.

Mesenchymal stem cells derived from CHIR99021 and TGF‑β induction remained on the colicomentum and improved cardiac function of a rat model of acute myocardium infarction.

Human induced pluripotent stem cells (hiPSCs) have been regarded as a potential stem cell source for cell therapy. However, the production of cells with mesenchymal potential from hiPSCs through spontaneous differentiation is time consuming and laborious. In the present study, the combined use of the GSK-3 inhibitor CHIR99021 and TGF-β was used to obtain mesenchymal stem cell (MSC)-like cells from hiPSCs. During the induction process, the transcription of epithelial-mesenchymal transition (EMT)-related genes N-cadherin and Vimentin in the transformed cells was upregulated, whereas the transcription of E-cadherin and pluripotency-related transcription factors SOX2, OCT4 and NANOG did not change significantly. This indicated that whilst cells were pluripotent, EMT was initiated by the upregulation of transcription of EMT promoting genes. Both SMAD-dependent and independent signalling pathways were significantly activated by the combined induction treatment compared with the single factor induction. The hiPSC-derived MSC-like cells (hiPSC-MSCs) expressed MSC-related markers and acquired osteogenic, chondrogenic and adipogenic differentiation potentials. After being injected into the peritoneal cavity of rats, the hiPSC-MSCs secreted angiogenic and immune-regulatory factors and remained on the colicomentum for 3 weeks. Within an 11-week period, four intraperitoneal hiPSC-MSC injections (1x107 cells/injection) into acute myocardial infarction (AMI) model rats significantly increased the left ventricular ejection fraction, left ventricular fractional shortening and angiogenesis and significantly reduced scar size and the extent of apoptosis in the infarcted area compared with that of the control PBS injection. Symptoms of hiPSC-MSC-induced immune reaction or tumour formation were not observed over the course of the experiment in the hiSPC-MSC treated rats. In conclusion, the CHIR99021 and TGF-β combined induction was a rapid and effective method to obtain MSC-like cells from hiPSCs and multiple high dose intraperitoneal injections of hiPSC-derived MSCs were safe and effective at restoring cardiac function in an AMI rat model.

High-throughput screening identification of novel immunomodulatory combinations for the generation of tolerogenic dendritic cells.

Tolerogenic Dendritic Cells (tolDCs) have an exceptional promise as a potential therapy for autoimmune disease and transplantation rejection. TolDCs are a unique phenotype of antigen presenting cells (APCs) that can influence naïve T cells into antigen specific T regulatory cells (Tregs), which can re-establish tolerance against auto/allo-antigens in the long term. Despite their promise, tolDCs have not found clinical success. Most strategies seek to generate tolDCs ex vivo by differentiating naïve dendritic cells (DCs) with immunosuppressive agents. Recently, we developed a tolDC generation strategy, which we call Push/Pull Immunomodulation (PPI). In PPI, DCs are treated with combinations of toll-like-receptor (TLR) agonists and immunomodulatory agents, which generate more robust, Treg-inducing tolDCs than previous strategies. Here, we seek to identify more potent and clinically viable PPI formulations using data from a high-throughput screening project. Over 40,000 combinations of pathogen-associated molecular patterns (PAMPs) and immunomodulatory small molecules were screened using a modified murine macrophage line, RAW dual cells, to observe the effect of these combinations on two major immune regulatory transcription factors, NF-κB and IRF. Combinations were further screened for inflammatory cytokine activity using a human monocyte cell line, THP-1, then on murine DCs. Leading candidates were co-cultured with T cells to assess antigen specific T cell responses. From this data, we identified 355 combinations that showed low or moderate IRF activity, low NF-κB activity, low inflammatory cytokine generation and good viability: all hallmarks of tolerogenic potential. We further screened these 355 combinations using bone marrow derived DCs (BMDCs) and identified 10 combinations that demonstrated high IL-10 (tolerogenic) and low TNF-α (inflammatory) secretion. After further optimizing these combinations, we identified two combinations that generate robust tolDCs from BMDCs ex vivo. We further show that these PPI-tolDCs can also generate antigen specific Tregs but do not increase overall Treg populations. These second-generation PPI formulations have significant potential to generate robust tolDCs and strong antigen specific Tregs.

AGTR1: a potential biomarker associated with the occurrence and prognosis of lung adenocarcinoma.

Lung adenocarcinoma, a disease with complex pathogenesis, high mortality and poor prognosis, is one of the subtypes of lung cancer. Hence, it is very crucial to find novel biomarkers as diagnostic and therapeutic targets for LUAD. GSE10072 was used for DEGs and WGCNA, and the intersection genes were subjected to enrichment analysis through Metascape and GSEA. Key genes were screened by three machine learning methods. Further, the reliability of key genes was identified by ROC, COX regression analysis and qRT-PCR. CIBERSORT and Spearman analysis were used for understanding the relationships of LUAD, immunity and key genes. In addition, ceRNA networks and potential drugs of key genes were constructed and predicted. After overlapping 631 DEGs and key module genes, 623 intersection genes were obtained. Subsequently, DUOX1, CD36, AGTR1, FHL5 and SSR4 were further selected using three machine learning methods. Reliability analysis demonstrated that AGTR1 possesses important predictive value for the occurrence and prognosis of LUAD. The enrichment analysis showed that AGTR1 was significantly enriched in the GPCR-related pathways. Immune infiltration analysis showed that the development of LUAD was related to the changes of immune cells such as M2 macrophages and neutrophils, which were regulated by AGTR1. Further, AGTR1 is also involved in regulating immune chemokines, checkpoints and immune regulatory factors such as PECAM1, ADARB1, SPP1 and ENO1, all of them playing important roles in immune cell regulation, tumor cell proliferation and migration. Further, the drug-gene interaction network screened out 13 potential drugs such as Benazepril, Valsartan, Eprosartan, and so on. AGTR1 is a potential biomarker for the occurrence and progression of LUAD, closely related to tumor immunity, proliferation and migration. It can serve as a new target for the diagnosis and treatment of LUAD.

Expression of immune regulatory factors, chemokines and growth factorsin differentiated gastric cancer cells treated with an anticancer bioactive peptide combined with oxaliplatin.

Gastric cancer is one of the most common malignant tumors of the digestive system. An anticancer bioactive peptide (ACBP) was previously shown to have an important role in inhibiting the differentiation of the MKN-45, N87 and GES-1 cell lines. However, to date, research on the effects of inflammatory factors in MKN-45, N87 and GES-1 cell lines after treatment with ACBP combined with oxaliplatin (OXA) has not been performed. To investigate the expression of immune regulatory factors, tumor growth factors and chemotactic factors in differentiated gastric cancer cells treated with ACBP combined with OXA, the expression of cytokines, including interleukin (IL)-1β, IL-1 receptor antagonist, IL-2, IL-4, IL-6-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, basic fibroblast growth factor (bFGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ, monocyte chemoattractant protein (MCP)-1, IFN-γ-induced protein-10, macrophage inflammatory protein (MIP)-1α, platelet-derived growth factor (PDGF)-BB, MIP-1β, regulated upon activation, normal T cell expressed and presumably secreted, TNF-α and VEGF, was assessed with cell experiments using the Bio-Plex ProT Human Cytokine 27-plex Assay. The results indicated that immune regulatory factor, tumor growth factor and chemotactic factor expression levels were different after treatment with ACBP alone or ACBP combined with OXA. IFN-γ, IL-1β, IL-17, IL-9, IL-10, IL-15, bFGF, GM-CSF and PDGF-BB expression was decreased in MKN-45 and N87 cells after ACBP treatment (P<0.01) and ACBP+OXA treatment (P<0.01) compared with the control cells, which indicated that ACBP inhibited tumor growth by regulating these cytokines, and the combination treatment inhibited tumor growth by regulating these cytokines. MIP-1β, MCP-1 and IL-13 expression was decreased in MKN-45 and N87 cells after the combination treatment compared with ACBP treatment alone, which indicated that ACBP combined with OXA was able to inhibit tumor growth by regulating these cytokines, while the mechanism of action of the ACBP and OXA is actually different, e.g. for OXA, this would be to cause DNA damage response. Therefore, the ACBP and OXA combination treatment may be closely associated with tumor progression and metastasis with immunological competence by MCP-1, MIP-1β and IL-13 expression.

Dysregulation of Immune Regulators in AML Bone Marrow Promotes Dysfunction of CD8 + T Cells

Background: Acute myeloid leukemia (AML) originates in the bone marrow, evading immune recognition and destruction. The bone marrow microenvironment (BME), comprising diverse immune cells and regulators, profoundly influences AML development. However, the impact of immune regulators in the BME, particularly on T-cell anti-AML immunity, remains inadequately understood. Therefore, evaluating the impact of immune regulators in the AML bone marrow microenvironment on T cell dysfunction is of paramount importance and necessity. M ethod : Bone marrow blood samples were obtained from pediatric AML patients at diagnosis and age-matched healthy individuals considered as hematopoietic stem cell transplantation (HSCT) donors after written informed consent. By centrifuging at 2000-3000rpm for 10min, we obtained the supernatant as plasma and stored it in a -80°C refrigerator. After using proteomics to identify the expression of 180 immune regulatory factors in plasma samples, we performed GO and KEGG functional enrichment analysis. After density gradient centrifugation, we isolated bone marrow mononuclear cells (BMMNCs) and immediately identified frequencies of T cell populations and expression levels of functional markers by flow cytometry when they were fresh. Moreover, the co-culture model of CD8 +T cells and THP-1 cell line was used to evaluate the anti-AML effector function of T cells. CD8 +T cells in BMMNCs were sorted by FACS and then subjected to whole transcriptome sequencing and in vitro experiments. After using the TRRUST and KnockTF databases for transcription factor prediction analysis, we selected phospho-flow cytometry to detect and verify the association between the level of phosphorylation of transcription factors and the function of CD8 +T cells. The data were analyzed using R software. Results: Using proteomics techniques, we uncovered a substantial presence of immune-suppressive regulatory factors in AML bone marrow plasma. Interestingly, the canonical NF-κB pathway, mediated by immune regulators and vital for immune regulation in BME, displayed significant downregulation, implying T-cell dysfunction. In our investigation, we identified dysfunctional CD8 +T cells in the primary AML bone marrow, characterized by heightened expression of co-inhibitory receptors and pro-dysfunctional transcription factors, as well as significantly decreased anti-AML effector function. Transcriptome sequencing further linked AML CD8 +T cell dysfunction to reduced transcriptional activity of NF-κB p65 in the canonical NF-κB signaling pathway. Intriguingly, in vitro inhibition of NF-κB p65 and its phosphorylation led to elevated expression of exhaustion markers, such as PD-1, LAG-3, and TIM-3 on primary CD8 +T cells. Most notably, the stimulation of the canonical NF-κB signaling pathway effectively restored activation and effector function-related pathways in dysfunctional AML CD8 +T cells. Conclusion: Immune regulators in the bone marrow microenvironment play a vital role in maintaining dysfunctional AML CD8 +T cells. These findings provide a novel strategy to investigate the potential mechanisms and interventions for T-cell dysfunction.

Interleukin-13 Mediates Non-Steroidal Anti-Inflammatory-Drug-Induced Small Intestinal Mucosal Injury with Ulceration.

Non-steroidal anti-inflammatory drugs (NSAIDs), which are antipyretics and analgesics, cause gastrointestinal disorders, such as inflammation and ulcers. To prescribe NSAIDs more safely, it is important to clarify the mechanism of NSAID-induced gastrointestinal mucosal injury. However, there is a paucity of studies on small intestinal mucosal damage by NSAIDs, and it is currently unknown whether inflammation and ulceration also occur in the small intestine, and whether mediators are involved in the mechanism of injury. Therefore, in this study, we created an animal model in which small intestinal mucosal injury was induced using NSAIDs (indomethacin; IDM). Focusing on the dynamics of immune regulatory factors related to the injury, we aimed to elucidate the pathophysiological mechanism involved. We analyzed the pathological changes in the small intestine, the expression of immunoregulatory factors (cytokines), and identified cytokine secretion and expression cells from isolated lamina propria mononuclear cells (LPMCs). Ulcers were formed in the small intestine by administering IDM. Although the mRNA expression levels of IL-1β, IL-6, and TNFα were decreased on day 7 after IDM administration, IL-13 mRNA levels increased from day 3 after IDM administration and remained high even on day 7. The IL-13 mRNA expression and the secretion of IL-13 were increased in small intestinal LPMCs isolated from the IDM-treated group. In addition, we confirmed that IL-13 was expressed in CD4-positive T cells. These results provided new evidence that IL-13 production from CD4-positive T cells in the lamina propria of the small intestine contributes to NSAID-induced mucosal injury.

The Transcription Factor RXRα in CD11c+ APCs Regulates Intestinal Immune Homeostasis and Inflammation.

APCs such as dendritic cells and macrophages play a pivotal role in mediating immune tolerance and restoring intestinal immune homeostasis by limiting inflammatory responses against commensal bacteria. However, cell-intrinsic molecular regulators critical for programming intestinal APCs to a regulatory state rather than an inflammatory state are unknown. In this study, we report that the transcription factor retinoid X receptor α (RXRα) signaling in CD11c+ APCs is essential for suppressing intestinal inflammation by imparting an anti-inflammatory phenotype. Using a mouse model of ulcerative colitis, we demonstrated that targeted deletion of RXRα in CD11c+ APCs in mice resulted in the loss of T cell homeostasis with enhanced intestinal inflammation and increased histopathological severity of colonic tissue. This was due to the increased production of proinflammatory cytokines that drive Th1/Th17 responses and decreased expression of immune-regulatory factors that promote regulatory T cell differentiation in the colon. Consistent with these findings, pharmacological activation of the RXRα pathway alleviated colitis severity in mice by suppressing the expression of inflammatory cytokines and limiting Th1/Th17 cell differentiation. These findings identify an essential role for RXRα in APCs in regulating intestinal immune homeostasis and inflammation. Thus, manipulating the RXRα pathway could provide novel opportunities for enhancing regulatory responses and dampening colonic inflammation.

Transcriptome sequencing and single-cell sequencing analysis identify GARS1 as a potential prognostic and immunotherapeutic biomarker for multiple cancers, including bladder cancer.

Glycyl-tRNA synthetase 1 (GARS1) belongs to the aminoacyl-tRNA synthetase family, playing a crucial role in protein synthesis. Previous studies have reported a close association between GARS1 and various tumors. However, the role of GARS1 in human cancer prognosis and its impact on immunology remain largely unexplored. In this study, we comprehensively analyzed GARS1 expression at the mRNA and protein levels, examined genetic alterations, and assessed its prognostic implications in pan-cancer, with a specific emphasis on the immune landscape. Furthermore, we investigated the functional enrichment of genes related to GARS1 and explored its biological functions using single-cell data. Finally, we conducted cellular experiments to validate the biological significance of GARS1 in bladder cancer cells. In general, GARS1 expression was significantly upregulated across multiple cancer types, and it demonstrated prognostic value in various cancers. Gene Set Enrichment Analysis (GSEA) revealed the association of GARS1 expression with multiple immune regulatory pathways. Moreover, GARS1 exhibited significant correlations with immune infiltrating cells (such as DC, CD8+T cells, Neutrophils, and Macrophages), immune checkpoint genes (CD274, CD276), and immune regulatory factors in tumors. Additionally, we observed that GARS1 could effectively predict the response to anti-PD-L1 therapy. Notably, Ifosfamide, auranofin, DMAPT, and A-1331852 emerged as potential therapeutic agents for GARS1-upregulated tumors. Our experimental findings strongly suggest that GARS1 promotes the proliferation and migration of bladder cancer cells. GARS1 holds promise as a potential prognostic marker and therapeutic target for pan-cancer immunotherapy, offering valuable insights for the development of more precise and personalized approaches to tumor treatment in the future.

A Microphysiological Device to Model the Choriodecidual Interface Immune Status during Pregnancy.

During human pregnancy the chorion (fetal) lines decidua (maternal) creating the feto-maternal interface. Despite their proximity, resident decidual immune cells remain quiescent during gestation and do not invade the chorion. Infection and infiltration of activated immune cells toward the chorion are often associated with preterm birth. However, the mechanisms that maintain choriodecidual immune homeostasis or compromise immune barrier functions remain unclear. To understand these processes, a two-chamber microphysiological system (MPS) was created to model the human choriodecidual immune interface under normal and infectious conditions invitro. This MPS has outer (fetal chorion trophoblast cells) and inner chambers (maternal decidual + CD45+ cells [70:30 ratio]) connected by microchannels. Decidual cells were treated with LPS to mimic maternal infection, followed by immunostaining for HLA-DR and HLA-G, immune panel screening by imaging cytometry by time of flight, and immune regulatory factors IL-8 and IL-10, soluble HLA-G, and progesterone (ELISA). LPS induced a proinflammatory phenotype in the decidua characterized by a decrease in HLA-DR and an increase in IL-8 compared with controls. LPS treatment increased the influx of immune cells into the chorion, indicative of chorionitis. Cytometry by time offlight characterized immune cells in both chambers as active NK cells and neutrophils, with a decrease in the abundance of nonproinflammatory cytokine-producing NK cells and T cells. Conversely, chorion cells increased progesterone and soluble HLA-G production while maintaining HLA-G expression. These results highlight the utility of MPS to model choriodecidual immune cell infiltration and determine the complex maternal-fetal crosstalk to regulate immune balance during infection.

Biomaterials delivery strategies to repair degenerated intervertebral discs by regulating the inflammatory microenvironment.

Intervertebral disc degeneration (IVDD) is one of the leading causes of lower back pain. Although IVDD cannot directly cause death, it can cause pain, psychological burdens, and economic burdens to patients. Current conservative treatments for IVDD can relieve pain but cannot reverse the disease. Patients who cannot tolerate pain usually resort to a strategy of surgical resection of the degenerated disc. However, the surgical removal of IVDD can affect the stability of adjacent discs. Furthermore, the probability of the reherniation of the intervertebral disc (IVD) after surgery is as high as 21.2%. Strategies based on tissue engineering to deliver stem cells for the regeneration of nucleus purposes (NP) and annulus fibrosus (AF) have been extensively studied. The developed biomaterials not only locally withstand the pressure of the IVD but also lay the foundation for the survival of stem cells. However, the structure of IVDs does not provide sufficient nutrients for delivered stem cells. The role of immune mechanisms in IVDD has recently become clear. In IVDD, the IVD that was originally in immune privilege prevents the attack of immune cells (mainly effector T cells and macrophages) and aggravates the disease. Immune regulatory and inflammatory factors released by effector T cells, macrophages, and the IVD further aggravate IVDD. Reversing IVDD by regulating the inflammatory microenvironment is a potential approach for the treatment of the disease. However, the biological factors modulating the inflammatory microenvironment easily degrade in vivo. It makes it possible for different biomaterials to modulate the inflammatory microenvironment to repair IVDD. In this review, we have discussed the structures of IVDs and the immune mechanisms underlying IVDD. We have described the immune mechanisms elicited by different biological factors, including tumor necrosis factors, interleukins, transforming growth factors, hypoxia-inducible factors, and reactive oxygen species in IVDs. Finally, we have discussed the biomaterials used to modulate the inflammatory microenvironment to repair IVDD and their development.

A sustained decrease in serum CD83 in pregnant women

Maternal immunity regulates tolerance to the semi-allogeneic fetus during pregnancy via modulation of immune regulatory factors. The serum factor CD83 is known to undergo changes during gestation in mice. Here we characterize serum levels of CD83 in women for the first time, revealing a consistent decline as pregnancy progresses and recovery to non-pregnant levels in miscarriage. Serum CD83 levels correlated negatively with rising progesterone (Pearson coefficient r = −0.489, ****p < 0.0001) and estradiol (r = −0.419, ***p = 0.0003). This result suggests that the regulation of soluble CD83 levels possibly depend on pregnancy hormones and on other yet unknown factors.

Immunomodulatory Factor TIM3 of Cytolytic Active Genes Affected the Survival and Prognosis of Lung Adenocarcinoma Patients by Multi-Omics Analysis.

[Objective] Using multi-omics research methods to explore cytolytic activity-related genes through the immunoregulatory factors HAVCR2 (TIM3) affecting the survival and prognosis of lung adenocarcinoma. [Methods] We combined Cox single factor regression and lasso regression feature selection algorithm to screen out the key genes of cytolytic activity in lung adenocarcinoma, and applied multi-omics research to explore the clinical predictive value of the model, including onset risk, independent prognosis, clinical relevance, signal transduction pathways, drug sensitivity, and the correlation of immune regulatory factors, etc. TCGA data are used as the experimental group, and GEO data is used as the external data control group to verify the stability of the model. The survival curve was generated by the Kaplan–Meier method and compared by log-rank, and the Cox proportional hazard model was used for multivariate analysis. In this study, 10 fresh tissue samples of lung adenocarcinoma were collected for cellular immunohistochemical experiments to analyze the expression of immunoregulatory factors in cancer tissues, and the key immunoregulatory factors were verified and screened out. [Results] A total of 450 genes related to cytolytic activity were differentially expressed, of which 273 genes were up-regulated and 177 genes were down-regulated. A total of 91 key genes related to cytolytic activity related to the prognosis of lung adenocarcinoma were screened through Cox single factor regression. The ROC curve results showed that the AUC values of 1, 3, and 5 years in the training set and test set were all greater than 0.7, indicating that the model has a valid verification. The level of risk score is significantly related to the sensitivity of patients to AKT inhibitor VIII, Lenalidomide, and Tipifarnib. In addition, our study also found that receptor and MHC genes related to immunomodulatory, and chemokines, including HAVCR2, are more highly expressed in the low-risk group. [Conclusions] HAVCR2 (TIM3) immunoregulatory factors affect the expression of key genes that affect cytolytic activity in lung adenocarcinoma cells, and to some extent indirectly affect the survival and prognosis of patients with lung adenocarcinoma.