ATP as a Pathophysiologic Mediator of Bacteria-Host Crosstalk in the Gastrointestinal Tract

Extracellular nucleotides, such as adenosine triphosphate (ATP), are released from host cells including nerve termini, immune cells, injured or dead cells, and the commensal bacteria that reside in the gut lumen. Extracellular ATP interacts with the host through purinergic receptors, and promotes intercellular and bacteria-host communication to maintain the tissue homeostasis. However, the release of massive concentrations of ATP into extracellular compartments initiates acute and chronic inflammatory responses through the activation of immunocompetent cells (e.g., T cells, macrophages, and mast cells). In this review, we focus on the functions of ATP as a pathophysiologic mediator that is required for the induction and resolution of inflammation and inter-species communication.

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Sensing of HIV-1 by TLR8 activates human T cells and reverses latency

Nature Communications ◽

10.1038/s41467-019-13837-4 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 8

Author(s):

Hany Zekaria Meås ◽

Markus Haug ◽

Marianne Sandvold Beckwith ◽

Claire Louet ◽

Liv Ryan ◽

...

Keyword(s):

T Cells ◽

Immune Cells ◽

Cd4 T Cells ◽

Vaccine Development ◽

Inflammatory Responses ◽

Cell Receptor ◽

Low Grade ◽

Activation Markers ◽

Adaptive Immune Cells ◽

Hiv 1

AbstractDuring HIV infection, cell-to-cell transmission results in endosomal uptake of the virus by target CD4+ T cells and potential exposure of the viral ssRNA genome to endosomal Toll-like receptors (TLRs). TLRs are instrumental in activating inflammatory responses in innate immune cells, but their function in adaptive immune cells is less well understood. Here we show that synthetic ligands of TLR8 boosted T cell receptor signaling, resulting in increased cytokine production and upregulation of surface activation markers. Adjuvant TLR8 stimulation, but not TLR7 or TLR9, further promoted T helper cell differentiation towards Th1 and Th17. In addition, we found that endosomal HIV induced cytokine secretion from CD4+ T cells in a TLR8-specific manner. TLR8 engagement also enhanced HIV-1 replication and potentiated the reversal of latency in patient-derived T cells. The adjuvant TLR8 activity in T cells can contribute to viral dissemination in the lymph node and low-grade inflammation in HIV patients. In addition, it can potentially be exploited for therapeutic targeting and vaccine development.

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Early Induction of Interleukin-10 Limits Antigen-Specific CD4+T Cell Expansion, Function, and Secondary Recall Responses during Persistent Phagosomal Infection

Infection and Immunity ◽

10.1128/iai.02101-14 ◽

2014 ◽

Vol 82 (10) ◽

pp. 4092-4103 ◽

Cited By ~ 5

Author(s):

Abinav Kumar Singh ◽

Nagaraja R. Thirumalapura

Keyword(s):

T Cells ◽

T Cell ◽

Functional Status ◽

Persistent Infection ◽

Inflammatory Responses ◽

Critical Role ◽

Interleukin 10 ◽

Host Cells ◽

Content Type ◽

Ifn Γ

ABSTRACTDiverse pathogens have evolved to survive and replicate in the endosomes or phagosomes of the host cells and establish persistent infection. Ehrlichiae are Gram-negative, intracellular bacteria that are transmitted by ticks. Ehrlichiae reside in the endosomes of the host phagocytic or endothelial cells and establish persistent infection in their vertebrate reservoir hosts. CD4+T cells play a critical role in protection against phagosomal infections. In the present study, we investigated the expansion, maintenance, and functional status of antigen-specific CD4+T cells during persistentEhrlichia murisinfection in wild-type and interleukin-10 (IL-10)-deficient mice. Our study indicated that early induction of IL-10 led to reduced inflammatory responses and impaired bacterial clearance during persistentEhrlichiainfection. Notably, we demonstrated that the functional production of gamma interferon (IFN-γ) by antigen-specific CD4+T cells maintained during a persistent phagosomal infection progressively deteriorates. The functional loss of IFN-γ production by antigen-specific CD4+T cells was reversed in the absence of IL-10. Furthermore, we demonstrated that transient blockade of IL-10 receptor during the T cell priming phase early in infection was sufficient to enhance the magnitude and the functional capacity of antigen-specific effector and memory CD4+T cells, which translated into an enhanced recall response. Our findings provide new insights into the functional status of antigen-specific CD4+T cells maintained during persistent phagosomal infection. The study supports the concept that a better understanding of the factors that influence the priming and differentiation of CD4+T cells may provide a basis to induce a protective immune response against persistent infections.

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The Construction and Exploration of the CeRNA Network and Patterns of Tumor-infiltrating Immune Cells in Kidney Renal Clear Cell Carcinoma

10.21203/rs.3.rs-113464/v2 ◽

2021 ◽

Author(s):

Weiwei Jia ◽

Pengjia Li ◽

Mingxia Ma ◽

Xiaochen Niu ◽

Lina Bai ◽

...

Keyword(s):

T Cells ◽

Regression Analysis ◽

Mast Cells ◽

Immune Cells ◽

Prognostic Model ◽

Cox Regression ◽

Cox Regression Analysis ◽

Cerna Network ◽

Follicular Helper ◽

Lncrna Malat1

Abstract KIRC is the malignant tumor with the highest incidence and poor prognosis in renal cell carcinoma. We want to explore the possible mechanisms of KIRC and effective prognostic-related biomarkers. The sequencing information of 3 types of RNA (mRNA, lncRNA and miRNA) in 539 cases of KIRC tissues and 72 cases of normal tissues is obtained from the TCGA database. Methods such as univariate Cox regression analysis, lasso regression screening, and multivariate Cox regression analysis were used to construct a prognostic model based on the CeRNA network. There are 3074 mRNAs, 359 lncRNAs and 132 miRNAs differentially expressed that have been identified through differential analysis. A complete mRNA-miRNA-lncRNA (SIX1-hsa-miR-200b-3p-MALAT1) network was obtained based on the CeRNA network. The CIBERSORT algorithm was used to analyze the degree of infiltration of 22 kinds of immune cells from each sample of KIRC. Construction of a prognostic model based on tumor-infiltrating immune cells, 2 immune cells (Mast cells resting, T cells follicular helper) were identified by constructing a prognostic model. There was a negative correlation between lncRNA MALAT1 and Mast cells resting (R= -0.27, P < 0.001); while there was a positive correlation between lncRNA MALAT1 and T cells follicular helper (R = 0.23, P < 0.001).

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Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation

Blood ◽

10.1182/blood-2009-05-220004 ◽

2009 ◽

Vol 114 (13) ◽

pp. 2639-2648 ◽

Cited By ~ 125

Author(s):

Silvia Piconese ◽

Giorgia Gri ◽

Claudio Tripodo ◽

Silvia Musio ◽

Andrea Gorzanelli ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mast Cells ◽

Interleukin 6 ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Effector T Cells ◽

Treg Suppression

Abstract The development of inflammatory diseases implies inactivation of regulatory T (Treg) cells through mechanisms that still are largely unknown. Here we showed that mast cells (MCs), an early source of inflammatory mediators, are able to counteract Treg inhibition over effector T cells. To gain insight into the molecules involved in their interplay, we set up an in vitro system in which all 3 cellular components were put in contact. Reversal of Treg suppression required T cell–derived interleukin-6 (IL-6) and the OX40/OX40L axis. In the presence of activated MCs, concomitant abundance of IL-6 and paucity of Th1/Th2 cytokines skewed Tregs and effector T cells into IL-17–producing T cells (Th17). In vivo analysis of lymph nodes hosting T-cell priming in experimental autoimmune encephalomyelitis revealed activated MCs, Tregs, and Th17 cells displaying tight spatial interactions, further supporting the occurrence of an MC-mediated inhibition of Treg suppression in the establishment of Th17-mediated inflammatory responses.

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Combining Bioinformatics Techniques to Study the Key Immune-Related Genes in Abdominal Aortic Aneurysm

Frontiers in Genetics ◽

10.3389/fgene.2020.579215 ◽

2020 ◽

Vol 11 ◽

Author(s):

Han Nie ◽

Jiacong Qiu ◽

Si Wen ◽

Weimin Zhou

Keyword(s):

Immune Response ◽

T Cells ◽

Abdominal Aortic Aneurysm ◽

Mast Cells ◽

Aortic Aneurysm ◽

Immune Cells ◽

Functional Enrichment ◽

Differentially Expressed ◽

Abdominal Aortic ◽

Significant Difference

Approximately 13,000 people die of an abdominal aortic aneurysm (AAA) every year. This study aimed to identify the immune response-related genes that play important roles in AAA using bioinformatics approaches. We downloaded the GSE57691 and GSE98278 datasets related to AAA from the Gene Expression Omnibus database, which included 80 AAA and 10 normal vascular samples. CIBERSORT was used to analyze the samples and detect the infiltration of 22 types of immune cells and their differences and correlations. The principal component analysis showed significant differences in the infiltration of immune cells between normal vascular and AAA samples. High proportions of CD4+ T cells, activated mast cells, resting natural killer cells, and 12 other types of immune cells were found in normal vascular tissues, whereas high proportions of macrophages, CD8+ T cells, resting mast cells, and six other types of immune cells were found in AAA tissues. In the selected samples, we identified 39 upregulated (involved in growth factor activity, hormone receptor binding, and cytokine receptor activity) and 133 downregulated genes (involved in T cell activation, cell chemotaxis, and regulation of immune response mediators). The key differentially expressed immune response-related genes were screened using the STRING database and Cytoscape software. Two downregulated genes, PI3 and MAP2K1, and three upregulated genes, SSTR1, GPER1, and CCR10, were identified by constructing a protein–protein interaction network. Functional enrichment of the differentially expressed genes was analyzed, and the expression of the five key genes in AAA samples was verified using quantitative polymerase chain reaction, which revealed that MAP2K1 was downregulated in AAA, whereas SSTR1, GEPR1, and CCR10 were upregulated; there was no significant difference in PI3 expression. Our study shows that normal vascular and AAA samples can be distinguished via the infiltration of immune cells. Five genes, PI3, MAP2K1, SSTR1, GPER1, and CCR10, may play important roles in the development, diagnosis, and treatment of AAA.

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High Mast Cell Density Predicts a Favorable Prognosis in Patients with Pancreatic Neuroendocrine Neoplasms

Neuroendocrinology ◽

10.1159/000521651 ◽

2021 ◽

Author(s):

Shengwei Mo ◽

Liju Zong ◽

Xianlong Chen ◽

Xiaoyan Chang ◽

Zhaohui Lu ◽

...

Keyword(s):

T Cells ◽

Mast Cell ◽

Mast Cells ◽

Cell Density ◽

Immune Cells ◽

Clinicopathological Parameters ◽

Neuroendocrine Neoplasms ◽

Pancreatic Neuroendocrine Neoplasms ◽

Entire Cohort ◽

Mast Cell Density

Introduction: Mast cells are involved in allergic diseases, immune regulation, and tumor microenvironment modulation, with both pro- and anti-tumorigenic functions, and could serve as a prognostic factor in various cancers. However, their potential role in pancreatic neuroendocrine neoplasms (PanNENs) is largely unknown. Here, our aim was to investigate the presence of mast cells in PanNENs and evaluate their association with clinicopathological parameters and other common tumor-infiltrating immune cells. Methods: Tissue microarrays containing PanNEN samples from 187 patients were constructed and stained immunohistochemically for CD117, CD15, CD68, CD3, CD4, and CD8. Immune cells were counted from four high-power fields (HPFs; 400×) at maximal concentrations, and the mean counts were calculated per HPF. The cut-off values were set by X-tile. Results: The median (interquartile range) counts of CD117+ mast cells, CD15+ neutrophils, CD68+ macrophages, CD3+ T cells, and CD4+ T cells were 3.5 (2.0–6.0), 3.0 (1.3–6), 3.8 (2.5–5.8), 13 (8.0–24.0), 2.0 (1.0–4.0)/HPF, respectively. CD8+ T cells were not detected. The cut-off values for these immune cells were 1.5/HPF, 6/HPF, 4.8/HPF, 32.5/HPF, and 2/HPF, respectively. Low mast cell density was correlated with higher grades, non-insulinoma, and advanced stages. Moreover, high mast cell infiltration was associated with elevated CD4+ T cell and CD15+ neutrophil counts. Multivariate analysis revealed that high mast cell density was an independent predictor of prolonged progression-free survival in the entire cohort, in pancreatic neuroendocrine tumors, and in intermediate-grade, non-insulinoma, and advanced stage subgroups. Conclusions: These findings suggest a protective role of mast cells in PanNENs.

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Identification of Potential Risk Genes and the Immune Landscape of Idiopathic Pulmonary Arterial Hypertension via Microarray Gene Expression Dataset Reanalysis

Genes ◽

10.3390/genes12010125 ◽

2021 ◽

Vol 12 (1) ◽

pp. 125

Author(s):

Jing Xu ◽

Yicheng Yang ◽

Yuejin Yang ◽

Changming Xiong

Keyword(s):

T Cells ◽

Pulmonary Arterial Hypertension ◽

Mast Cells ◽

Arterial Hypertension ◽

Signaling Pathway ◽

Immune Cells ◽

Molecular Targets ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Cox Regression Analysis ◽

Pulmonary Arterial

Gene dysfunction and immune cell infiltration play an essential role in the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). We aimed to investigate the immune landscape and novel differentially expressed genes (DEGs) of IPAH. In addition, potential druggable molecular targets for IPAH were also explored. In this study, the GSE117261 dataset was reanalyzed to explore the immune landscape and hub DEGs of IPAH. Lasso Cox regression analysis and receiver operating characteristic curve analysis were performed to detect the predictive value of IPAH. Additionally, the underlying drug targets for IPAH treatment were determined by drug–gene analysis. IPAH was significantly associated with the transforming growth factor-β (TGF-β) signaling pathway and Wnt signaling pathway as well as energetic metabolism dysfunction. We identified 31 upregulated and 39 downregulated DEGs in IPAH patients. Six hub genes, namely, SAA1, CCL5, CXCR1, CXCR2, CCR1, and ADORA3, were related to IPAH pathogenesis regardless of sex differences. Prediction model analysis showed that the area under the curve values of the hub DEGs except CXCR2 were all above 0.9 for distinguishing IPAH patients. In addition, the relative proportions of 5 subtypes of immune cells, namely, CD8+ T cells, CD4+ memory resting T cells, γ delta T cells, M1 macrophages, and resting mast cells, were significantly upregulated in the IPAH samples, while 6 subtypes of immune cells, namely, CD4+ naive T cells, resting NK cells, monocytes, M0 macrophages, activated mast cells, and neutrophils, were downregulated. Additionally, a total of 17 intersecting drugs targeting 5 genes, CCL5, CXCR1, CXCR2, CCR1, and ADORA3, were generated as potential druggable molecular targets for IPAH. Our study revealed the underlying correlations between genes and immune cells in IPAH and demonstrated for the first time that SAA1, CCL5, CXCR1, CCR1, and ADORA3 may be novel genetic targets for IPAH.

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The Dynamic Interactions between Salmonella and the Microbiota, within the Challenging Niche of the Gastrointestinal Tract

International Scholarly Research Notices ◽

10.1155/2014/846049 ◽

2014 ◽

Vol 2014 ◽

pp. 1-23 ◽

Cited By ~ 7

Author(s):

C. M. Anjam Khan

Keyword(s):

Gastrointestinal Tract ◽

Inflammatory Responses ◽

Anaerobic Respiration ◽

Electron Acceptors ◽

Effector Proteins ◽

Host Cells ◽

Gastrointestinal Microbiota ◽

Dynamic Interactions ◽

Fierce Competition ◽

Type 3

Understanding how Salmonella species establish successful infections remains a foremost research priority. This gastrointestinal pathogen not only faces the hostile defenses of the host’s immune system, but also faces fierce competition from the large and diverse community of microbiota for space and nutrients. Salmonella have solved these challenges ingeniously. To jump-start growth, Salmonella steal hydrogen produced by the gastrointestinal microbiota. Type 3 effector proteins are subsequently secreted by Salmonella to trigger potent inflammatory responses, which generate the alternative terminal electron acceptors tetrathionate and nitrate. Salmonella exclusively utilize these electron acceptors for anaerobic respiration, permitting metabolic access to abundant substrates such as ethanolamine to power growth blooms. Chemotaxis and flagella-mediated motility enable the identification of nutritionally beneficial niches. The resulting growth blooms also promote horizontal gene transfer amongst the resident microbes. Within the gastrointestinal tract there are opportunities for chemical signaling between host cells, the microbiota, and Salmonella. Host produced catecholamines and bacterial autoinducers form components of this chemical dialogue leading to dynamic interactions. Thus, Salmonella have developed remarkable strategies to initially shield against host defenses and to transiently compete against the intestinal microbiota leading to successful infections. However, the immunocompetent host is subsequently able to reestablish control and clear the infection.

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Innate Immune Cells in Pressure Overload-Induced Cardiac Hypertrophy and Remodeling

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.659666 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xin Liu ◽

Guo-Ping Shi ◽

Junli Guo

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Mast Cells ◽

Immune Cells ◽

Immune Cell ◽

Pressure Overload ◽

Natural Killer T Cells ◽

Innate Immune ◽

Innate Immune Cells ◽

Killer T Cells

Pressure overload and heart failure are among the leading causes of cardiovascular morbidity and mortality. Accumulating evidence suggests that inflammatory cell activation and release of inflammatory mediators are of vital importance during the pathogenesis of these cardiac diseases. Yet, the roles of innate immune cells and subsequent inflammatory events in these processes remain poorly understood. Here, we outline the possible underlying mechanisms of innate immune cell participation, including mast cells, macrophages, monocytes, neutrophils, dendritic cells, eosinophils, and natural killer T cells in these pathological processes. Although these cells accumulate in the atrium or ventricles at different time points after pressure overload, their cardioprotective or cardiodestructive activities differ from each other. Among them, mast cells, neutrophils, and dendritic cells exert detrimental function in experimental models, whereas eosinophils and natural killer T cells display cardioprotective activities. Depending on their subsets, macrophages and monocytes may exacerbate cardiodysfunction or negatively regulate cardiac hypertrophy and remodeling. Pressure overload stimulates the secretion of cytokines, chemokines, and growth factors from innate immune cells and even resident cardiomyocytes that together assist innate immune cell infiltration into injured heart. These infiltrates are involved in pro-hypertrophic events and cardiac fibroblast activation. Immune regulation of cardiac innate immune cells becomes a promising therapeutic approach in experimental cardiac disease treatment, highlighting the significance of their clinical evaluation in humans.

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LYMPH NODE REGULATORY T-CELL IN Muc2-/- MICE WITH HELICOBACTER SPP.

Medical Immunology (Russia) ◽

10.15789/1563-0625-lnr-2268 ◽

2021 ◽

Vol 23 (4) ◽

pp. 629-634

Author(s):

K. M. Achasova ◽

O. V. Gvozdeva ◽

E. N. Kozhevnikova ◽

E. A. Litvinova

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Lymph Nodes ◽

Immune Cells ◽

Inflammatory Responses ◽

Regulatory Function ◽

Wild Type ◽

Mesenteric Lymph Nodes ◽

Mesenteric Lymph ◽

Vital Functions

The immune processes associated with the formation of resistance to pathogens in the intestine depend on the microbiome. The maintenance of homeostasis in the intestine is provided by regulatory T-cells. In inflammatory bowel disease (IBD), both a disturbance of the T-regulatory function and changes in microflora are observed. Aggravation of the disease is accompanied by various infections. However, pathobionts such as Helicobacter spp., can affect regulatory T-cells. One of the genetic models for studying IBD is Muc2 knockout mice. In these mice, as in humans with IBD, intestinal epithelial and immune cells closely interact with the microflora. It is believed that the immune cells of the lymph nodes Muc2-/- mice are sensitive to changes in the microflora formed in them. In this study, the effect of Helicobacter spp. on the number and percentage of different types of leukocytes and T regulatory cells in the mesenteric lymph nodes of Muc2-/- mice was studied. The number of CD45+CD19+, CD45+CD3+, CD45+CD3+CD4+, CD45+CD3+CD8+-cells in the mesenteric lymph nodes of Muc2-/- mice was significantly higher to compare with wild-type Muc2+/+ mice. However, the presence of infection in Muc2-/- mice canceled the increase in the number of CD45+CD19+, CD45+CD3+, CD45+CD3+CD4+, CD45+CD3+CD8+-cells. In wild-type Muc2+/+ mice, infection had no significant effect on cells in mesenteric lymph nodes. This change in the decrease in immune cells in the mesenteric lymph nodes under the Helicobacter spp. may be associated with the activation of regulatory T-cells. Indeed, it has been shown that the presence of a congenital Helicobacter spp. infection increased of the number of regulatory T-cells (CD45+CD4+CD25+FoxP3+) in the mesenteric lymph nodes. Well known that regulatory T-cells mediate anti-inflammatory responses in the gut. Thus, an increase in regulatory T-cells promotes a decrease in all types of immune cells in the mesenteric lymph nodes of Muc2-/- mice infected with Helicobacter spp. It could provide an improvement in the vital functions of these mice and possibly reduces inflammatory responses in the intestine. This may indicate that some congenital pathobionts activate of the regulatory mechanisms of immunity and, thereby, have a beneficial effect on the host.

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