Immunobiology最新文献

Background

Mesenchymal stromal cells (MSCs) have shown promising therapeutic options for acute lung injury (ALI) caused by multiple factors. Here, we evaluated the therapeutic potential of adipose tissue-derived mesenchymal stromal cells (ADSCs) in trauma and hemorrhagic shock (THS)-induced ALI.

Methods

ALI model induced by THS was constructed by fractures plus abdominal trauma plus acute hemorrhage plus fluid resuscitation. The ADSCs group rats were generated by injecting 2 × 10⁶ ADSCs at 0 and 1 h after THS. The sham, ALI, and ADSCs group rats were sacrificed at 24 h after resuscitation. The changes in lung histopathology, total protein in bronchoalveolar lavage fluid (BALF), mRNA expression of pro-inflammatory/anti-inflammatory cytokines, antioxidant, and anti-apoptotic indicator, and the activity of Toll-like receptor 4 (TLR4) signaling in lung tissues were evaluated.

Results

Administration of the ADSCs reversed ALI induced by THS, including lung histopathological changes/scores, and BALF total protein concentration. Additionally, ADSCs therapy also significantly down-regulated mRNA expression of pro-inflammatory TNF-α, IL-1β, and IL-6, up-regulated mRNA expression of anti-inflammatory IL-10, anti-apoptotic molecule Bcl-2, and anti-oxidative molecule HO-1 in THS rats. Furthermore, ADSCs suppressed the expression of TLR4 in lung tissue.

Conclusion

Our data show that ADSCs administration can exert therapeutic effects on THS-induced ALI in rats and may provide beneficial in preventative strategies for ALI.

Antigen-presenting cells (APCs) constantly express major histocompatibility complex II (MHC II), including macrophages and dendritic cells (DCs) which deliver antigens to CD4⁺ T cells and play an important role in adaptive immunity. The expression of MHC II is controlled by the transcriptional coactivator CIITA. Interleukin-27 (IL-27), a newly discovered IL-12 family cytokine, is composed of p28 and EBI3 subunits. In this study, we used IL-27p28 conditional knock-out mice to investigate the regulatory effects of IL-27p28 on macrophage polarization and the expression of MHC II in macrophages. We found that MHC II expression was upregulated in the bone marrow-derived and peritoneal exudate macrophages (BMDMs; PEMs) from IL-27p28-deficient mice, with their inflammation regulating function unaffected. We also demonstrated that in the APCs, IL-27p28 selectively regulated MHC II expression in macrophages but not in dendritic cells. During Pseudomonas aeruginosa (P. aeruginosa) reinfection, higher survival rate, bacterial clearance, and ratio of CD4⁺/CD8⁺ T cells in the spleen during the specific immune phase were observed in IL-27p28 defect mice, as well as an increased MHC II expression in alveolar macrophages (AMs). But these did not occur in the first infection. For the first time we discovered that IL-27p28 specifically regulates the expression of MHC II in macrophages by regulating CIITA, while its absence enhances antigen presentation and adaptive immunity against P. aeruginosa.

Calmodulin (CaM)-lysine N-methyltransferase (CAMKMT) is a novel methyltransferase that catalyzes lysine trimethylation in CaM. However, its specific roles in inflammatory responses and diseases remain unclear. In this study, we investigated the effects of CAMKMT on caspase-11 non-canonical inflammasomes. CAMKMT expression levels were significantly decreased during inflammatory responses activated by caspase-11 non-canonical inflammasome in macrophages. Moreover, CaM lysine trimethylation was markedly inhibited, but no change was observed in CaM expression during these inflammatory responses in macrophages. Activation of the CaM downstream effectors, CaM-dependent protein kinase kinase 2 and CaM-dependent protein kinase type IV, was also inhibited during inflammatory responses activated by caspase-11 non-canonical inflammasome in macrophages. Notably, forced expression of CAMKMT restrained caspase-11 non-canonical inflammasome activation via inhibiting proteolytic activation of caspase-11 and gasdermin D (GSDMD), which in turn suppressed pyroptosis and the release of interleukin (IL)-1β and IL-18 in macrophages. Finally, an in vivo study revealed that CAMKMT ameliorated lipopolysaccharide (LPS)-stimulated acute lethal sepsis in mice by increasing the survival rate and reducing the serum levels of IL-1 β. These findings suggest CAMKMT as a novel methyltransferase that plays an anti-inflammatory role through restraining caspase-11 non-canonical inflammasome in macrophages.

It is well established that some differences exist between the male and female immune systems. Despites this, a sex-based analysis is not frequently performed in most scientific published reports. Knowing that inflammation is a common undesired effect observed resulting from nanoparticle (NP) exposure, we investigate here how in vitro treatment of gold NPs with a primary size of 20 and 70 nm (AuNP₂₀ and AuNP₇₀, respectively) will alter the biology of human eosinophils isolated from men and women blood. We found that treatment of AuNP₇₀, but not AuNP₂₀, significantly delay apoptosis only in eosinophils isolated from women. AuNPs were found to decrease eosinophil phagocytosis, however, significance was only observed in AuNP₂₀-induced eosinophils isolated from women. The production of IL-8 was significantly increased in response to both AuNPs but only in eosinophils isolated from men and the production of IL-1β was increased in AuNPs-induced eosinophils, although significance was observed only in AuNP₇₀-induced eosinophils isolated from women. We conclude that future studies investigating the toxicity of AuNPs (or other NPs) should include a sex-based analysis, especially if the tested NPs have potential medical applications knowing the increased interest in the development of personalized precision medicine.

Phosphatidylinositol 3-kinase delta (PI3Kδ) and gamma (PI3Kγ) are predominantly located in immune and hematopoietic cells. It is well-established that PI3Kδ/γ plays important roles in the immune system and participates in inflammation; hence, it could be a potential target for anti-inflammatory therapy. Currently, several PI3K inhibitors are used clinically to treat cancers with aberrant PI3K signaling; however, their role in treating acute respiratory inflammatory diseases has rarely been explored. Herein, we investigated the potential anti-inflammatory activities of several pharmacological PI3K inhibitors, including marketed drugs idelalisib (PI3Kδ), duvelisib (PI3Kδ/γ), and copanlisib (pan-PI3K with preferential α/δ) and the clinical drug eganelisib (PI3Kγ), for treating acute lung injury (ALI). In the lipopolysaccharide-induced RAW264.7 macrophage inflammatory model, the four inhibitors significantly suppressed proinflammatory cytokine expression by inhibiting the PI3K signaling pathway. Oral administration of PI3K inhibitors markedly improved lung injury in a murine model of ALI. PI3K pathway inhibition decreased inflammatory cell infiltration and total protein levels, as well as reduced the expression of associated lung inflammatory factors. Collectively, all four representative PI3K inhibitors exerted prominent anti-inflammatory properties, indicating that PI3K δ and/or γ inhibition could be ideal targets to treat respiratory inflammatory diseases by reducing the inflammatory response. The findings of the current study provide a new basis for utilizing PI3K inhibitors to treat acute respiratory inflammatory diseases.

Psoriasis and inflammatory bowel disease (IBD) have a similar etiology, including abnormal activation of T cells. Differentially expressed genes (DEGs) analysis was used to search for shared genes. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis were then performed. Secondly, single-cell RNA analysis (scRNA-seq) and immune infiltration were employed to explore the immune imbalance of the diseases. By weighted gene co expression network analysis (WGCNA), we obtained hub shared genes. Furthermore, we analyzed the diagnostic performance and immune association with the hub genes. Finally, functional enrichment of miRNAs related to hub shared genes was carried out. Single-cell analysis showed a high proportion of T cells among infiltrated immune cells and immune infiltration showed CD4⁺ T and γδ T cells were significantly elevated in diseases. Hub shared genes, LCN2, CXCL1 and PI3 had excellent diagnostic properties and were positively correlated with neutrophils, CD4⁺ T and γδ T cells. IL17 and TNF signaling pathway were the common pathway. In conclusion, CD4⁺ and γδ T cells and hub shared genes may play a crucial part in common mechanism between psoriasis and IBD. Moreover, hub shared genes may be potential diagnostic markers.

Tissue transglutaminase (TG2) expressed in monocytes and macrophage is known to participate in processes during either early and resolution stages of inflammation. The alternative splicing of tissue transglutaminase gene is a mechanism that increases its functional diversity. Four spliced variants are known with truncated C-terminal domains (TGM2_v2, TGM2_v3, TGM2_v4a, TGM2_v4b) but scarce information is available about its expression in human monocyte and macrophages.

We studied the expression of canonical TG2 (TGM2_v1) and its short spliced variants by RT-PCR during differentiation of TPH-1 derived macrophages (dTHP-1) using two protocols (condition I and II) that differ in Phorbol-12-myristate-13-acetate dose and time schedule. The production of TNF-α and IL-1β in supernatant of dTHP-1, measured by ELISA in supernatants showed higher proinflammatory milieu in condition I.

We found that the expression of all mRNA TG2 spliced variants were up-regulated during macrophage differentiation and after IFN-γ treatment of dTHP-1 cells in both conditions. Nevertheless, the relative fold increase or TGM2_v3 in relation with TGM2_v1 was higher only with the condition I.

M1/M2-like THP-1 macrophages obtained with IFN-γ/IL-4 treatments showed that the up-regulation of TGM2_v1 induced by IL-4 was higher in relation with any short spliced variants. The qualitative profile of relative contribution of spliced variants in M1/M2-like THP-1 cells showed a trend to higher expression of TGM2_v3 in the inflammatory functional phenotype.

Our results contribute to the knowledge about TG2 spliced variants in the biology of monocyte/macrophage cells and show how the differentiation conditions can alter their expression and cell function.

Background

Kawasaki disease (KD) is a systemic vasculitis that commonly affects children and its etiology remains unknown. Growing evidence suggests that immune-mediated inflammation and immune cells in the peripheral blood play crucial roles in the pathophysiology of KD. The objective of this research was to find important biomarkers and immune-related mechanisms implicated in KD, along with their correlation with immune cells in the peripheral blood.

Material/Methods

Gene microarray data from the Gene Expression Omnibus (GEO) was utilized in this study. Three datasets, namely GSE63881 (341 samples), GSE73463 (233 samples), and GSE73461 (279 samples), were obtained. To find intersecting genes, we employed differentially expressed genes (DEGs) analysis and weighted gene co-expression network analysis (WGCNA). Subsequently, functional annotation, construction of protein–protein interaction (PPI) networks, and Least Absolute Shrinkage and Selection Operator (LASSO) regression were performed to identify hub genes. The accuracy of these hub genes in identifying KD was evaluated using the receiver operating characteristic curve (ROC). Furthermore, Gene Set Variation Analysis (GSVA) was employed to explore the composition of circulating immune cells within the assessed datasets and their relationship with the hub gene markers.

Results

WGCNA yielded eight co-expression modules, with one hub module (MEblue module) exhibiting the strongest association with acute KD. 425 distinct genes were identified. Integrating WGCNA and DEGs yielded a total of 277 intersecting genes. By conducting LASSO analysis, five hub genes (S100A12, MMP9, TLR2, NLRC4 and ARG1) were identified as potential biomarkers for KD. The diagnostic value of these five hub genes was demonstrated through ROC curve analysis, indicating their high accuracy in diagnosing KD. Analysis of the circulating immune cell composition within the assessed datasets revealed a significant association between KD and various immune cell types, including activated dendritic cells, neutrophils, immature dendritic cells, macrophages, and activated CD8 T cells. Importantly, all five hub genes exhibited strong correlations with immune cells.

Conclusion

Activated dendritic cells, neutrophils, and macrophages were closely associated with the pathogenesis of KD. Furthermore, the hub genes (S100A12, MMP9, TLR2, NLRC4, and ARG1) are likely to participate in the pathogenic mechanisms of KD through immune-related signaling pathways.

Background

The prevalence and fatality rates of lung cancer are experiencing a rapid escalation. Natural Killer (NK) cells have been established to have a crucial role in both tumor initiation and progression. Nevertheless, uncertainties persist regarding their precise implications in the prognosis of LUAD.

Methods

The data were obtained from reputable sources, such as the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) database, and our internally generated sequencing data. Utilizing the TCGA data as a background, we selected intersecting genes, validated by cluster analysis, to establish a Cox model and validated it using the GEO datasets. Furthermore, we conducted extensive analyses to investigate the significance of potential biomarkers in relation to immune cell infiltration, single-cell data, differential gene expression, and drug sensitivity.

Results

67 immune-related genes associated with NK cells (NK-IRGs) were identified in the TCGA datasets, whose research potential was demonstrated by cluster analysis. A prognostic signature was identified utilizing the univariate and multivariate Cox model, resulting in the identification of five genes, which was validated using GEO datasets. Additionally, the nomogram's calibration curve demonstrated exceptional concordance between the projected and actual survival rates. Subsequent investigations uncovered that this prognostic signature demonstrated its independence as a risk factor. Notably, in the low-risk group, NK cells exhibited elevated levels of immune checkpoint molecules, indicating heightened sensitivity to immune therapy. These findings highlight the potential of utilizing this signature as a valuable tool in the selection of patients who could benefit from targeted immune interventions.

Objective

This study aimed to investigate the changes and significance of circulating Helios-associated T cell subsets in patients with early-stage lung adenocarcinoma (LUAD).

Methods

Blood samples were collected from 35 healthy controls and 34 patients with early-stage LUAD. Flow cytometry was used to analyze various CD4+ T cell subsets, including regulatory T(Treg) cells, follicular regulatory T(Tfr) cells, follicular helper T (Tfh) cells, and conventional T (con-T) cells. Correlation analysis was conducted to investigate the association of Helios-related subsets with clinical indicators. The ROC curve was used to explore the potential clinical value of Helios+ T cell subsets in the screening of patients with early LUAD. Fifteen of these patients were tracked after lung cancer resection and changes in Helios+ T cell subsets before and after treatment were analyzed.

Results

The percentage and absolute number of Tregs were up-regulated in LUAD patients while Tfh and con-T cells expressing Helios were down-regulated. Absolute counts of Tfr and con-T cells and Helios expression in Tfr and Treg decreased significantly after resection. Helios+ Tfh and con-T were negatively correlated with certain tumor markers. Areas under the curve (AUCs) of percentages and absolute counts of Helios+ Tfh, Treg, Tfr and con-T cells to distinguish early LUAD from healthy individuals were 0.7277, 0.5697, 0.5718, 0.7210 (percentages), 0.7336, 0.7378, 0.5908 and 0.7445(absolute numbers), respectively.

Conclusion

Helios+ T cell subsets in peripheral blood of early-stage LUAD patients has changed significantly, which may be related to the pathogenesis of LUAD and could help for early diagnosis of LUAD.