Regulation Of Immune Responses Research Articles

Association Between Cervical Inflammatory Mediators and Prevalent Cervical Human Papillomavirus Infection.

Inflammatory mediators are important regulators of immune response and can modulate the inflammation caused by viral infections, including human papillomavirus (HPV). In this study, we evaluated the association between cervical immune mediators, including chemokines, cytokines, and growth factors with HPV infections. We used a nonmagnetic bead-based multiplex assay to determine 27 immune mediators in cervical secretions collected from 275 women in a prospective longitudinal cohort design. All the study participants were age 18 years or older, had a history of vaginal sexual intercourse, were not currently pregnant, and had no history of cervical disease or hysterectomy. The mean (±standard deviation) age of the participants was 41 (±8) years, and about half (51% [141/275]) were HPV-positive, of whom 7% (10/141) had low-risk HPV (lrHPV), 61% (86/141) had high-risk HPV (hrHPV), and 32% (45/141) had both lrHPV and hrHPV infections. Higher concentrations of some immune mediators were associated with HPV infections, including eotaxin, interferon-gamma, interleukin (IL)-1β, IL-2, IL-4, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-15, macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated upon activation normal T-cell expressed and secreted (RANTES), and tumor necrosis factor (TNF)-α and any HPV; IL-2, IL-4, IL-5, IL-7, IL-10, IL-12p70, and IL-13 and lrHPV; and eotaxin, interferon, IL-1B, IL-4, IL-7, IL-8, IL-9, IL-10, IL-13, IL-15, MIP-1α, MIP-1β, RANTES, TNF-α concentrations, and hrHPV infections. Higher concentrations of granulocyte macrophage colony-stimulating factor, IL-1 receptor antagonist (IL-1Ra), and monocyte chemotactic protein-1 (MCP-1) were associated with reduced odds of any HPV, while IL-1Ra and MCP-1 were associated with reduced odds of hrHPV infections. Several chemokines, cytokines, and growth factors are associated with group-specific HPV infections in this population of women. These important findings contribute to the understanding of the immune response to HPV, cytokine profiles and their potential implications for cervical pathogenesis, and can guide future research in this field.

Metformin blocks BIK1-mediated CPK28 phosphorylation and enhances plant immunity

IntroductionMetformin (MET), derived from Galega officinalis, stands as the primary first-line medication for the treatment of type 2 diabetes (T2D). Despite its well-documented benefits in mammalian cellular processes, its functions and underlying mechanisms in plants remain unclear. ObjectivesThis study aimed to elucidate MET’s role in inducing plant immunity and investigate the associated mechanisms. MethodsTo investigate the impact of MET on enhancing plant immune responses, we conducted assays measuring defense gene expression, reactive oxygen species (ROS) accumulation, mitogen-activated protein kinase (MAPK) phosphorylation, and pathogen infection. Additionally, surface plasmon resonance (SPR) and microscale thermophoresis (MST) techniques were employed to identify MET targets. Protein-protein interactions were analyzed using a luciferase complementation assay and a co-immunoprecipitation assay. ResultsOur findings revealed that MET boosts plant disease resistance by activating MAPKs, upregulating the expression of downstream defense genes, and fortifying the ROS burst. CALCIUM-DEPENDENT PROTEIN KINASE 28 (CPK28) was identified as a target of MET. It inhibited the interaction between BOTRYTIS-INDUCED KINASE 1 (BIK1) and CPK28, blocking CPK28 threonine 76 (T76) transphosphorylation by BIK1, and alleviating the negative regulation of immune responses by CPK28. Moreover, MET enhanced disease resistance in tomato, pepper, and soybean plants. ConclusionCollectively, our data suggest that MET enhances plant immunity by blocking BIK1-mediated CPK28 phosphorylation.

Exosomes as Emerging Regulators of Immune Responses in Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by high blood glucose levels resulting from insulin resistance and impaired insulin secretion. Immune dysregulation-mediated chronic low-grade inflammation is a critical factor that poses a significant risk to the metabolic disorders of T2DM and its related complications. Exosomes, as small extracellular vesicles secreted by various cells, have emerged as essential regulators of intercellular communication and immune regulation. In this review, we summarize the current understanding of the role of exosomes derived from immune and nonimmune cells in modulating immune responses in T2DM by regulating immune cell functions and cytokine production. More importantly, we suggest potential strategies for the clinical applications of exosomes in T2DM management, including biomarkers for disease diagnosis and monitoring, exosome-based therapies for drug delivery vehicles, and targeted therapy for exosomes.

Control of immune cell signaling by the immuno-metabolite itaconate.

Immune cell activation triggers signaling cascades leading to transcriptional reprogramming, but also strongly impacts on the cell's metabolic activity to provide energy and biomolecules for inflammatory and proliferative responses. Macrophages activated by microbial pathogen-associated molecular patterns and cytokines upregulate expression of the enzyme ACOD1 that generates the immune-metabolite itaconate by decarboxylation of the TCA cycle metabolite cis-aconitate. Itaconate has anti-microbial as well as immunomodulatory activities, which makes it attractive as endogenous effector metabolite fighting infection and restraining inflammation. Here, we first summarize the pathways and stimuli inducing ACOD1 expression in macrophages. The focus of the review then lies on the mechanisms by which itaconate, and its synthetic derivatives and endogenous isomers, modulate immune cell signaling and metabolic pathways. Multiple targets have been revealed, from inhibition of enzymes to the post-translational modification of many proteins at cysteine or lysine residues. The modulation of signaling proteins like STING, SYK, JAK1, RIPK3 and KEAP1, transcription regulators (e.g. Tet2, TFEB) and inflammasome components (NLRP3, GSDMD) provides a biochemical basis for the immune-regulatory effects of the ACOD1-itaconate pathway. While the field has intensely studied control of macrophages by itaconate in infection and inflammation models, neutrophils have now entered the scene as producers and cellular targets of itaconate. Furthermore, regulation of adaptive immune responses by endogenous itaconate, as well as by exogenously added itaconate and derivatives, can be mediated by direct and indirect effects on T cells and antigen-presenting cells, respectively. Taken together, research in ACOD1-itaconate to date has revealed its relevance in diverse immune cell signaling pathways, which now provides opportunities for potential therapeutic or preventive manipulation of host defense and inflammation.

Cystatin from the helminth Ascaris lumbricoides upregulates mevalonate and cholesterol biosynthesis pathways and immunomodulatory genes in human monocyte-derived dendritic cells.

Ascaris lumbricoides cystatin (Al-CPI) prevents the development of allergic airway inflammation and dextran-induced colitis in mice models. It has been suggested that helminth-derived cystatins inhibit cathepsins in dendritic cells (DC), but their immunomodulatory mechanisms are unclear. We aimed to analyze the transcriptional profile of human monocyte-derived DC (moDC) upon stimulation with Al-CPI to elucidate target genes and pathways of parasite immunomodulation. moDC were generated from peripheral blood monocytes from six healthy human donors of Denmark, stimulated with 1 µM of Al-CPI, and cultured for 5 hours at 37°C. RNA was sequenced using TrueSeq RNA libraries and the NextSeq 550 v2.5 (75 cycles) sequencing kit (Illumina, Inc). After QC, reads were aligned to the human GRCh38 genome using Spliced Transcripts Alignment to a Reference (STAR) software. Differential expression was calculated by DESEq2 and expressed in fold changes (FC). Cell surface markers and cytokine production by moDC were evaluated by flow cytometry. Compared to unstimulated cells, Al-CPI stimulated moDC showed differential expression of 444 transcripts (|FC| ≥1.3). The top significant differences were in Kruppel-like factor 10 (KLF10, FC 3.3, PBH = 3 x 10-136), palladin (FC 2, PBH = 3 x 10-41), and the low-density lipoprotein receptor (LDLR, FC 2.6, PBH = 5 x 10-41). Upregulated genes were enriched in regulation of cholesterol biosynthesis by sterol regulatory element-binding proteins (SREBP) signaling pathways and immune pathways. Several genes in the cholesterol biosynthetic pathway showed significantly increased expression upon Al-CPI stimulation, even in the presence of lipopolysaccharide (LPS). Regarding the pathway of negative regulation of immune response, we found a significant decrease in the cell surface expression of CD86, HLA-DR, and PD-L1 upon stimulation with 1 µM Al-CPI. Al-CPI modifies the transcriptome of moDC, increasing several transcripts encoding enzymes involved in cholesterol biosynthesis and SREBP signaling. Moreover, Al-CPI target several transcripts in the TNF-alpha signaling pathway influencing cytokine release by moDC. In addition, mRNA levels of genes encoding KLF10 and other members of the TGF beta and the IL-10 families were also modified by Al-CPI stimulation. The regulation of the mevalonate pathway and cholesterol biosynthesis suggests new mechanisms involved in DC responses to helminth immunomodulatory molecules.

Potential role of POFUT1 as a prognostic predictor in low-grade gliomas: Immune microenvironment insights from a pan-cancer analysis

The POFUT1 gene, known to be up-regulated in various tumor tissues and associated with tumor biology, has yet to be explored for its potential role in immune response regulation and tumor immune microenvironment. The normalized pan-cancer dataset (TCGA Pan-Cancer) was downloaded from the UCSC database, followed by analysis of POFUT1 expression in various tumors and functional enrichment analysis. The correlation between POFUT1 expression levels and patient prognosis was assessed. GSEA of POFUT1 based on low-grade glioma (LGG) samples and immune infiltration analyses of LGG and glioblastoma (GBM) were conducted. The correlation between POFUT1 expression levels and infiltration levels of 22 immune cells in LGG and GBM was examined, as well as the correlation between immune cell infiltration levels and LGG patient prognosis. Additionally, the relationship between POFUT1 expression levels and characteristic gene expression of identified immune cells was evaluated. Lastly, external dataset validation was performed using the integrated CGGA dataset. Significant differences were observed in POFUT1 expression levels across 20 tumor types. High POFUT1 expression correlated with poor prognosis in GBMLGG, and LGG patients. Enrichment analysis and GSEA of POFUT1 in LGG demonstrated involvement in tumor-related and immune-related pathways. A positive correlation was identified between POFUT1 expression levels and infiltration levels of resting memory CD4+ T cells, as well as M2 macrophages or M2-like TAMs in the LGG immune microenvironment, potentially contributing to poor prognosis. External dataset validation revealed a positive correlation between M2 macrophages or M2-like TAMs and POFUT1 expression levels in LGG, and a negative correlation with LGG patient prognosis. POFUT1's negative impact on LGG prognosis may result from its influence on M2 macrophage and M2-like TAM infiltration levels within the immune microenvironment. This suggests its potential as a prognostic predictor and therapeutic target for LGG.

Mapping the functional form of the trade-off between infection resistance and reproductive fitness under dysregulated immune signaling.

Immune responses benefit organismal fitness by clearing parasites but also exact costs associated with immunopathology and energetic investment. Hosts manage these costs by tightly regulating the induction of immune signaling to curtail excessive responses and restore homeostasis. Despite the theoretical importance of turning off the immune response to mitigate these costs, experimentally connecting variation in the negative regulation of immune responses to organismal fitness remains a frontier in evolutionary immunology. In this study, we used a dose-response approach to manipulate the RNAi-mediated knockdown efficiency of cactus (IκBα), a central regulator of Toll pathway signal transduction in flour beetles (Tribolium castaneum). By titrating cactus activity across four distinct levels, we derived the shape of the relationship between immune response investment and traits associated with host fitness, including infection susceptibility, lifespan, fecundity, body mass, and gut homeostasis. Cactus knock-down increased the overall magnitude of inducible immune responses and delayed their resolution in a dsRNA dose-dependent manner, promoting survival and resistance following bacterial infection. However, these benefits were counterbalanced by dsRNA dose-dependent costs to lifespan, fecundity, body mass, and gut integrity. Our results allowed us to move beyond the qualitative identification of a trade-off between immune investment and fitness to actually derive its functional form. This approach paves the way to quantitatively compare the evolution and impact of distinct regulatory elements on life-history trade-offs and fitness, filling a crucial gap in our conceptual and theoretical models of immune signaling network evolution and the maintenance of natural variation in immune systems.

Indoleamine 2,3-dioxygenase 1-mediated iron metabolism in macrophages contributes to lipid deposition in nonalcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is a rapidly progressing chronic liver disease of global significance. However, the underlying mechanisms responsible for NASH remain unknown. Indoleamine 2,3-dioxygenase 1 (IDO1) has been recognized as essential factor in immune response and metabolic regulation. Here we aimed to investigate the functions and mechanisms of the IDO1 in macrophages on hepatic lipid deposition and iron metabolism in NASH. The effect of IDO1 in NASH was evaluated by WT and IDO1-/- mice model fed with methionine/choline-deficient (MCD) diet in vivo. Macrophages scavenger clodronate liposomes (CL) and overexpressing of IDO1 in macrophages by virus were employed as well. Lipid deposition was assessed through pathological examination and lipid droplet staining, while iron levels were measured using an iron assay kit and western blotting. Primary hepatocytes and bone marrow-derived macrophages were treated with oleic acid/palmitic acid (OA/PA) to assess IDO1 expression via Oil Red O staining and immunofluorescence staining in vitro. Pathological images demonstrated that the increase of IDO1 exacerbated lipid accumulation in the livers of mice with MCD diet, while reduction of iron accumulation was observed in the liver and the serum of MCD-fed mice. Scavenging of macrophages effectively mitigated both lipid and iron accumulation. In addition, the deficiency of IDO1 in macrophages significantly mitigated lipid accumulation and iron overload in hepatic parenchymal cells. Finally, lentivirus-mediated overexpression of IDO1 in liver macrophages exacerbated hepatic steatosis and iron deposition in NASH. Our results demonstrated that effective inhibition of IDO1 expression in macrophages in NASH alleviated hepatic parenchymal cell lipid accumulation and iron deposition, which provided new insights for the future treatment of NASH.

Viroporins Manipulate Cellular Powerhouses and Modulate Innate Immunity.

Viruses have a wide repertoire of molecular strategies that focus on their replication or the facilitation of different stages of the viral cycle. One of these strategies is mediated by the activity of viroporins, which are multifunctional viral proteins that, upon oligomerization, exhibit ion channel properties with mild ion selectivity. Viroporins facilitate multiple processes, such as the regulation of immune response and inflammasome activation through the induction of pore formation in various cell organelle membranes to facilitate the escape of ions and the alteration of intracellular homeostasis. Viroporins target diverse membranes (such as the cellular membrane), endoplasmic reticulum, and mitochondria. Cumulative data regarding the importance of mitochondria function in multiple processes, such as cellular metabolism, energy production, calcium homeostasis, apoptosis, and mitophagy, have been reported. The direct or indirect interaction of viroporins with mitochondria and how this interaction affects the functioning of mitochondrial cells in the innate immunity of host cells against viruses remains unclear. A better understanding of the viroporin-mitochondria interactions will provide insights into their role in affecting host immune signaling through the mitochondria. Thus, in this review, we mainly focus on descriptions of viroporins and studies that have provided insights into the role of viroporins in hijacked mitochondria.

The Role of Opioid Receptor Antagonists in Regulation of Blood Pressure and T-Cell Activation in Mice Selected for High Analgesia Induced by Swim Stress.

Opioid peptides and their G protein-coupled receptors are important regulators within the cardiovascular system, implicated in the modulation of both heart and vascular functions. It is known that naloxone-an opioid antagonist-may exert a hypertensive effect. Recent experimental and clinical evidence supports the important role of inflammatory mechanisms in hypertension. Since opioids may play a role in the regulation of both blood pressure and immune response, we studied these two processes in our model. We aimed to evaluate the effect of selective and non-selective opioid receptor antagonists on blood pressure and T-cell activation in a mouse model of high swim stress-induced analgesia. Blood pressure was measured before and during the infusion of opioid receptor antagonists using a non-invasive tail-cuff measurement system. To assess the activation of T-cells, flow cytometry was used. We discovered that the non-selective antagonism of the opioid system by naloxone caused a significant elevation of blood pressure. The selective antagonism of μ and κ but not δ opioid receptors significantly increased systolic blood pressure. Subsequently, a brief characterization of T-cell subsets was performed. We found that the blockade of μ and δ receptors is associated with the increased expression of CD69 on CD4 T-cells. Moreover, we observed an increase in the central memory CD4 and central memory CD8 T-cell populations after the δ opioid receptor blockade. The antagonism of the μ opioid receptor increased the CD8 effector and central memory T-cell populations.

TF-FVIIa PAR2-β-Arrestin Signaling Sustains Organ Dysfunction in Coxsackievirus B3 Infection of Mice.

Accumulating evidence implicates the activation of G-protein-coupled PARs (protease-activated receptors) by coagulation proteases in the regulation of innate immune responses. Using mouse models with genetic alterations of the PAR2 signaling platform, we have explored contributions of PAR2 signaling to infection with coxsackievirus B3, a single-stranded RNA virus provoking multiorgan tissue damage, including the heart. We show that PAR2 activation sustains correlates of severe morbidity-hemodynamic compromise, aggravated hypothermia, and hypoglycemia-despite intact control of the virus. Following acute viral liver injury, canonical PAR2 signaling impairs the restoration process associated with exaggerated type I IFN (interferon) signatures in response to viral RNA recognition. Metabolic profiling in combination with proteomics of liver tissue shows PAR2-dependent reprogramming of liver metabolism, increased lipid droplet storage, and gluconeogenesis. PAR2-sustained hypodynamic compromise, reprograming of liver metabolism, as well as imbalanced IFN responses are prevented in β-arrestin coupling-deficient PAR2 C-terminal phosphorylation mutant mice. Thus, wiring between upstream proteases and immune-metabolic responses results from biased PAR2 signaling mediated by intracellular recruitment of β-arrestin. Importantly, blockade of the TF (tissue factor)-FVIIa (coagulation factor VIIa) complex capable of PAR2 proteolysis with the NAPc2 (nematode anticoagulant protein c2) mitigated virus-triggered pathology, recapitulating effects seen in protease cleavage-resistant PAR2 mice. These data provide insights into a TF-FVIIa signaling axis through PAR2-β-arrestin coupling that is a regulator of inflammation-triggered tissue repair and hemodynamic compromise in coxsackievirus B3 infection and can potentially be targeted with selective coagulation inhibitors.

Immunomodulation effects of isochlorogenic acid a from apple on RAW264.7 cells via modulation of TLR2 and TLR4 target proteins

The incorporation of nutrients with immunomodulatory properties into the daily diet has emerged as a pressing health requirement. The aim of this study was to screen apple polyphenols with immunomodulatory activitiy using molecular docking and to investigate the modulatory effects of apple polyphenol-isochlorogenic acid A on the activation of macrophage immune responses and the inhibition of inflammation through the immunoreceptors TLR2 and TLR4. The results showed that isochlorogenic acid A of apple polyphenols had high docking scores with TLR2 and TLR4. The isochlorogenic acid A exhibited favorable ADMET properties and water solubility. Cellular assays results showed that isochlorogenic acid A enhanced the viability of RAW264.7 cells and promoted the expression of NO, TNF-α, IL-1β, TLR2, and TLR4 in cells, and inhibited the expression of NO, TNF-α, IL-6, TLR2, and TLR4 in inflammatory cells. The isochlorogenic acid A bound to residues Phe325, Phe349, Leu350 and Pro352 of TLR2 by hydrogen bonding and hydrophobic interactions, and to residues Val82, Arg90, Ser127, Cys133 and Ser441 of TLR4-MD-2 via π-alkyl and hydrogen bonds. In summary, the immunoreceptors TLR2 and TLR4 play a crucial role as recognition receptors for isochlorogenic acid A of apple polyphenols in the regulation of cellular immune response and inflammation.

Exploiting Tertiary Lymphoid Structures to Stimulate Antitumor Immunity and Improve Immunotherapy Efficacy.

Tumor-associated tertiary lymphoid structures (TLS) have been associated with favorable clinical outcomes and response to immune checkpoint inhibitors in many cancer types, including non-small cell lung cancer. Although the detailed cellular and molecular mechanisms underlying these clinical associations have not been fully elucidated, growing preclinical and clinical studies are helping to elucidate the mechanisms at the basis of TLS formation, composition, and regulation of immune responses. However, a major challenge remains how to exploit TLS to enhance naïve and treatment-mediated antitumor immune responses. Here, we discuss the current understanding of tumor-associated TLS, preclinical models that can be used to study them, and potential therapeutic interventions to boost TLS formation, with a particular focus on lung cancer research.

Cancer cell immunity-related protein co-expression networks are associated with early-stage solid-predominant lung adenocarcinoma.

Solid-predominant lung adenocarcinoma (SPA), which is one of the high-risk subtypes with poor prognosis and unsatisfactory response to chemotherapy and targeted therapy in lung adenocarcinoma, remains molecular profile unclarified. Weighted correlation network analysis (WGCNA) was used for data mining, especially for studying biological networks based on pairwise correlations between variables. This study aimed to identify disease-related protein co-expression networks associated with early-stage SPA. We assessed cancerous cells laser-microdissected from formalin-fixed paraffin-embedded (FFPE) tissues of a SPA group (n = 5), referencing a low-risk subtype, a lepidic predominant subtype group (LPA) (n = 4), and another high-risk subtype, micropapillary predominant subtype (MPA) group (n = 3) and performed mass spectrometry-based proteomic analysis. Disease-related co-expression networks associated with the SPA subtype were identified by WGCNA and their upstream regulators and causal networks were predicted by Ingenuity Pathway Analysis. Among the forty WGCNA network modules identified, two network modules were found to be associated significantly with the SPA subtype. Canonical enriched pathways were highly associated with cellular growth, proliferation, and immune response. Upregulated HLA class I molecules HLA-G and HLA-B implicated high mutation burden and T cell activation in the SPA subtype. Upstream analysis implicated the involvement of highly activated oncogenic regulators, MYC, MLXIPL, MYCN, the redox master regulator NFE2L2, and the highly inhibited LARP1, leading to oncogenic IRES-dependent translation, and also regulators of the adaptive immune response, including highly activated IFNG, TCRD, CD3-TCR, CD8A, CD8B, CD3, CD80/CD86, and highly inhibited LILRB2. Interestingly, the immune checkpoint molecule HLA-G, which is the counterpart of LILRB2, was highly expressed characteristically in the SPA subtype and might be associated with antitumor immunity. Our findings provide a disease molecular profile based on protein co-expression networks identified for the high-risk solid predominant adenocarcinoma, which will help develop future therapeutic strategies.

Chlamydia trachomatis enhances HPV persistence through immune modulation

Chlamydia trachomatis (CT) is the most common sexually transmitted infections globally, and CT infection can enhance HPV persistence. Epidemiological analysis has shown that patients with CT/HPV coinfection have a higher risk of developing cervical cancer and exhibit more rapid progression to cervical cancer than patients with HPV infection alone. However, the mechanism has not been fully elucidated. Here, we report that CT infection supports HPV persistence by further suppressing the functions of Langerhans cells (LCs); in particular, CT further activates the PI3K pathway and inhibits the MAPK pathways in LCs, and these pathways are frequently involved in the regulation of immune responses. CT/HPV coinfection also impairs LC functions by reducing the antigen-presenting ability and density of LCs. Moreover, CT/HPV coinfection can alter T-cell subsets, resulting in fewer CD4 + and CD8 + T cells and more infiltrating Tregs. Moreover, CT/HPV coinfection decreases the CD4 + /CD8 + T cell ratio to below 1, coinfection also induces greater T lymphocytes’ apoptosis than HPV infection, thus impairing cell-mediated immunity and accelerating the progress to cervical cancer.

Epigenomic analyses identify FOXM1 as a key regulator of anti-tumor immune response in esophageal adenocarcinoma

Unlike most cancer types, the incidence of esophageal adenocarcinoma (EAC) has rapidly escalated in the western world over recent decades. Using whole genome bisulfite sequencing (WGBS), we identify the transcription factor (TF) FOXM1 as an important epigenetic regulator of EAC. FOXM1 plays a critical role in cellular proliferation and tumor growth in EAC patient-derived organoids and cell line models. We identify ERBB2 as an upstream regulator of the expression and transcriptional activity of FOXM1. Unexpectedly, gene set enrichment analysis (GSEA) unbiased screen reveals a prominent anti-correlation between FOXM1 and immune response pathways. Indeed, syngeneic mouse models show that FOXM1 inhibits the infiltration of CD8+ T cells into the tumor microenvironment. Consistently, FOXM1 suppresses CD8+ T cell chemotaxis in vitro and antigen-dependent CD8+ T cell killing. This study characterizes FOXM1 as a significant EAC-promoting TF and elucidates its novel function in regulating anti-tumor immune response.

Accumulation of circulating myeloid-derived suppressor cell subsets: predicting poor clinical efficacy and prognosis through T cell suppression in non-Hodgkin's lymphoma.

Myeloid-derived suppressor cells (MDSCs) are implicated in the regulation of immune responses closely associated with poor clinical outcomes in cancer. However, the MDSC subtypes in non-Hodgkin's lymphoma (NHL) have not been systematically investigated. So, we investigated the percentage of MDSC subsets in 78 newly diagnosed NHL patients by flow cytometry. The results showed that all MDSC subsets increased in NHL patients compared with healthy donors. Notably, MDSCs, monocytic MDSCs, and CD14 + CD66b + MDSCs significantly increased in NHL patients compared with those with lymphadenitis donors. polymorphonuclear MDSCs (PMN-MDSCs), early-stage MDSCs (e-MDSCs), and the International Prognostic Index were independent risk factors for poor clinical efficacy and were involved in constructing the nomogram for predicting clinical efficacy. Progression-free survival (PFS) was significantly shorter in patients with high level of MDSC subsets, and PMN-MDSCs emerged as an independent prognostic factor for PFS. PMN-MDSCs, e-MDSCs, and the International Prognostic Index were involved in constructing the nomogram for predicting PFS. Patients with a higher percentage of MDSCs, PMN-MDSCs, e-MDSCs, and CD14 + CD66b + MDSCs experienced a shorter overall survival compared with those with lower percentages. In addition, research on mechanisms found that T cell function was suppressed and mediated by the expansion of MDSCs via involving arginase-1 and interleukin-10 in vitro and in vivo. In conclusion, our study demonstrates that the increased circulating MDSC subsets predict poor clinical efficacy and prognosis in NHL, potentially involving T cell suppression through MDSC subset expansion. These findings indicate the potential of MDSC subsets as comprehensive diagnostic, prognostic biomarkers, and therapeutic targets for NHL.

Primary Human M2 Macrophage Subtypes Are Distinguishable by Aqueous Metabolite Profiles.

The complexity of macrophage (MΦ) plasticity and polarization states, which include classically activated pro-inflammatory (M1) and alternatively activated anti-inflammatory (M2) MΦ phenotypes, is becoming increasingly appreciated. Within the M2 MΦ polarization state, M2a, M2b, M2c, and M2d MΦ subcategories have been defined based on their expression of specific cell surface receptors, secreted cytokines, and specialized immune effector functions. The importance of immunometabolic networks in mediating the function and regulation of MΦ immune responses is also being increasingly recognized, although the exact mechanisms and extent of metabolic modulation of MΦ subtype phenotypes and functions remain incompletely understood. In this study, proton (1H) nuclear magnetic resonance (NMR) metabolomics was employed to determine the polar metabolomes of M2 MΦ subtypes and to investigate the relationship between aqueous metabolite profiles and M2 MΦ functional phenotypes. Results from this study demonstrate that M2a MΦs are most distinct from M2b, M2c, and M2d MΦ subtypes, and that M2b MΦs display several metabolic traits associated with an M1-like MΦ phenotype. The significance of metabolome differences for metabolites implicated in glycolysis, the tricarboxylic acid (TCA) cycle, phospholipid metabolism, and creatine-phosphocreatine cycling is discussed. Altogether, this study provides biochemical insights into the role of metabolism in mediating the specialized effector functions of distinct M2 MΦ subtypes and supports the concept of a continuum of macrophage activation states rather than two well-separated and functionally distinct M1/M2 MΦ classes, as originally proposed within a classical M1/M2 MΦ framework.

A new perspective on gut-lung axis affected through resident microbiome and their implications on immune response in respiratory diseases.

The highly diverse microbial ecosystem of the human body colonizes the gastrointestinal tract has a profound impact on the host's immune, metabolic, endocrine, and other physiological processes, which are all interconnected. Specifically, gut microbiota has been found to play a crucial role in facilitating the adaptation and initiation of immune regulatory response through the gastrointestinal tract affecting the other distal mucosal sites such as lungs. A tightly regulated lung-gut axis during respiratory ailments may influence the various molecular patterns that instructs priming the disease severity to dysregulate the normal function. This review provides a comprehensive summary of current research on gut microbiota dysbiosis in respiratory diseases including asthma, pneumonia, bronchopneumonia, COPD during infections and cancer. A complex-interaction among gut microbiome, associated metabolites, cytokines, and chemokines regulates the protective immune response activating the mucosal humoral and cellular response. This potential mechanism bridges the regulation patterns through the gut-lung axis. This paper aims to advance the understanding of the crosstalk of gut-lung microbiome during infection, could lead to strategize to modulate the gut microbiome as a treatment plan to improve bad prognosis in various respiratory diseases.

Systems genetics of influenza A virus-infected mice identifies TRIM21 as a critical regulator of pulmonary innate immune response

Tripartite motif 21 (TRIM21) is a cytosolic Fc receptor that targets antibody-bound, internalized pathogens for destruction. Apart from this intrinsic defense role, TRIM21 is implicated in autoimmune diseases, inflammation, and autophagy. Whether TRIM21 participates in host interactions with influenza A virus (IAV), however, is unknown. By computational modeling of body weight and lung transcriptome data from the BXD parents (C57BL/6 J (B6) and DBA/2 J (D2)) and 41 BXD mouse strains challenged by IAV, we reveal that a Trim21-associated gene network modulates the early host responses to IAV infection. Trim21 transcripts were significantly upregulated in infected mice of both B6 and D2 backgrounds. Its expression was significantly higher in infected D2 than in infected B6 early after infection and significantly correlated with body weight loss. We identified significant trans-eQTL on chromosome 14 that regulates Trim21 expression. Nr1d2 and Il3ra were among the strongest candidate genes. Pathway analysis found Trim21 to be involved in inflammation and immunity related pathways, such as inflammation signaling pathways (TNF, IL-17, and NF-κB), viral detection signaling pathways (NOD-like and RIG-I-like), influenza, and other respiratory viral infections. Knockdown of TRIM21 in human lung epithelial A549 cells significantly augmented IAV-induced expression of IFNB1, IFNL1, CCL5, CXCL10, and IFN-stimulated genes including DDX58 and IFIH1, among others. Our data suggest that a TRIM21-associated gene network is involved in several aspects of inflammation and viral detection mechanisms during IAV infection. We identify and validate TRIM21 as a critical regulator of innate immune responses to IAV in human lung epithelial cells.