Comparative analysis of decidual and peripheral immune cells and immune-checkpoint molecules during pregnancy in wild-type and PACAP-deficient mice

2018 ◽  
Vol 80 (4) ◽  
pp. e13035 ◽  
Author(s):  
Adrienn Lajko ◽  
Matyas Meggyes ◽  
Balazs Daniel Fulop ◽  
Noemi Gede ◽  
Dora Reglodi ◽  
...  
Keyword(s):  
Comparative Analysis ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Wild Type ◽  
Immune Checkpoint Molecules ◽  
Peripheral Immune Cells ◽  
Deficient Mice

scholarly journals Dietary AhR Ligands Regulate AhRR Expression in Intestinal Immune Cells and Intestinal Microbiota Composition

2020 ◽  
Vol 21 (9) ◽  
pp. 3189 ◽  
Author(s):  
Oliver Schanz ◽  
Rieka Chijiiwa ◽  
Sevgi Can Cengiz ◽  
Yasmin Majlesain ◽  
Heike Weighardt ◽  
...  
Keyword(s):  
Intestinal Microbiota ◽  
Immune Cells ◽  
High Fat Diet ◽  
Target Gene ◽  
Microbiota Composition ◽  
Wild Type ◽  
Aryl Hydrocarbon ◽  
Reporter Mice ◽  
Induced Changes ◽  
Deficient Mice

A diet rich in vegetables and fruit is generally considered healthy because of a high content of phytochemicals, vitamins, and fiber. The phytochemical indole-3-carbinol (I3C), a derivative of glucobrassicin, is sold as a dietary supplement promising diverse health benefits. I3C metabolites act as ligands of the aryl hydrocarbon receptor (AhR), an important sensor for environmental polyaromatic chemicals. Here, we investigated how dietary AhR ligand supplementation influences AhR target gene expression and intestinal microbiota composition. For this, we used AhR repressor (AhRR)-reporter mice as a tool to study AhR activation in the intestine following dietary I3C-supplementation in comparison with AhR ligand-deprived diets, including a high fat diet. AhRR expression in intestinal immune cells was mainly driven by dietary AhR ligands and was independent of microbial metabolites. A lack of dietary AhR ligands caused enhanced susceptibility to dextran sodium sulfate (DSS)-induced colitis and correlated with the expansion of Enterobacteriaceae, whereas Clostridiales, Muribaculaceae, and Rikenellaceae were strongly reduced. I3C supplementation largely reverted this effect. Comparison of I3C-induced changes in microbiota composition using wild-type (WT), AhRR-deficient, and AhR-deficient mice revealed both AhR-dependent and -independent alterations in the microbiome. Overall, our study demonstrates that dietary AhR ligand supplementation has a profound influence on Ahrr expression in intestinal immune cells as well as microbiota composition.

scholarly journals Identification of an immune-related signature indicating the dedifferentiation of thyroid cells

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xuemin Wang ◽  
Wen Peng ◽  
Chunyan Li ◽  
Rujia Qin ◽  
Zhaoming Zhong ◽  
...  
Keyword(s):  
Risk Score ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Tumour Microenvironment ◽  
The Cancer Genome Atlas ◽  
Risk Scores ◽  
Thyroid Cells ◽  
Normal Thyroid ◽  
Thyroid Carcinomas ◽  
Immune Checkpoint Molecules

Abstract Background Immune cells account for a large proportion of the tumour microenvironment in anaplastic thyroid carcinomas (ATCs). However, the expression pattern of immune-related genes (IRGs) in ATCs is unclear. Our study aimed to identify an immune-related signature indicating the dedifferentiation of thyroid cells. Methods We compared the differences in thyroid differentiation score (TDS), infiltration of immune cells and enriched pathways between ATCs and papillary thyroid carcinomas (PTCs) or normal thyroid tissues in the Gene Expression Omnibus database. Univariate and multivariable Cox analyses were used to screen prognosis-associated IRGs in The Cancer Genome Atlas database. After constructing a risk score, we investigated its predictive value for differentiation and survival by applying receiver operating characteristic and Kaplan–Meier curves. We further explored its associations with important immune checkpoint molecules, infiltrating immune cells and response to immunotherapy. Results Compared with PTCs or normal thyroid tissues, ATCs exhibited lower TDS values and higher enrichment of immune cells and activation of the inflammatory response. The quantitative analyses and immunohistochemical staining validated that most ATC cell lines and ATC tissues had higher expression of MMP9 and lower expression of SDC2 than normal thyroid samples and PTC. Higher risk scores indicates dedifferentiation and a worse prognosis. Additionally, the risk score was positively correlated with the immune checkpoint molecules PDL1, CTLA4, IDO1, and HAVCR2 and infiltration of multiple immune cells. Importantly, we found that the samples with higher risk scores tended to have a better response to immunotherapy than those with lower scores. Conclusion Our findings indicate that the risk score may not only contribute to the determination of differentiation and prognosis of thyroid carcinomas but also help the prediction of immune cells infiltration and immunotherapy response.

scholarly journals Protective role of neuronal and lymphoid cannabinoid CB2 receptors in neuropathic pain

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
David Cabañero ◽  
Angela Ramírez-López ◽  
Eva Drews ◽  
Anne Schmöle ◽  
David M Otte ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Immune Cells ◽  
Protective Role ◽  
Spontaneous Pain ◽  
Wild Type ◽  
Self Administration ◽  
Psychotropic Effects ◽  
Peripheral Immune Cells ◽  
Simultaneous Activity

Cannabinoid CB2 receptor (CB2) agonists are potential analgesics void of psychotropic effects. Peripheral immune cells, neurons and glia express CB2; however, the involvement of CB2 from these cells in neuropathic pain remains unresolved. We explored spontaneous neuropathic pain through on-demand self-administration of the selective CB2 agonist JWH133 in wild-type and knockout mice lacking CB2 in neurons, monocytes or constitutively. Operant self-administration reflected drug-taking to alleviate spontaneous pain, nociceptive and affective manifestations. While constitutive deletion of CB2 disrupted JWH133-taking behavior, this behavior was not modified in monocyte-specific CB2 knockouts and was increased in mice defective in neuronal CB2 knockouts suggestive of increased spontaneous pain. Interestingly, CB2-positive lymphocytes infiltrated the injured nerve and possible CB2transfer from immune cells to neurons was found. Lymphocyte CB2depletion also exacerbated JWH133 self-administration and inhibited antinociception. This work identifies a simultaneous activity of neuronal and lymphoid CB2that protects against spontaneous and evoked neuropathic pain.

scholarly journals Identification of an immune-related signature indicating the dedifferentiation of thyroid cells

2021 ◽  
Author(s):  
Xuemin Wang ◽  
Wen Peng ◽  
Chunyan Li ◽  
Rujia Qin ◽  
Zhaoming Zhong ◽  
...  
Keyword(s):  
Risk Score ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Tumour Microenvironment ◽  
The Cancer Genome Atlas ◽  
Risk Scores ◽  
Thyroid Cells ◽  
Normal Thyroid ◽  
Thyroid Carcinomas ◽  
Immune Checkpoint Molecules

Abstract Background: Immune cells account for a large proportion of the tumour microenvironment in anaplastic thyroid carcinomas (ATCs). However, the expression pattern of immune-related genes (IRGs) in ATCs is unclear. Our study aimed to identify an immune-related signature indicating the dedifferentiation of thyroid cells.Methods: We compared the differences in thyroid differentiation score (TDS), infiltration of immune cells and enriched pathways between ATCs and papillary thyroid carcinomas (PTCs) or normal thyroid tissues in the Gene Expression Omnibus database. Univariate and multivariable Cox analyses were used to screen prognosis-associated IRGs in The Cancer Genome Atlas database. After constructing a risk score, we investigated its predictive value for differentiation and survival by applying receiver operating characteristic and Kaplan-Meier curves. We further explored its associations with important immune checkpoint molecules, infiltrating immune cells and response to immunotherapy. Results: Compared with PTCs or normal thyroid tissues, ATCs exhibited lower TDS values and higher enrichment of immune cells and activation of the inflammatory response. The quantitative analyses and immunohistochemical staining validated that most ATC cell lines and ATC tissues had higher expression of MMP9 and lower expression of SDC2 than normal thyroid samples and PTC. Higher risk scores indicates dedifferentiation and a worse prognosis. Additionally, the risk score was positively correlated with the immune checkpoint molecules PDL1, CTLA4, IDO1, and HAVCR2 and infiltration of multiple immune cells. Importantly, we found that the samples with higher risk scores tended to have a better response to immunotherapy than those with lower scores. Conclusion: Our findings indicate that the risk score may not only contribute to the determination of differentiation and prognosis of thyroid carcinomas but also help the prediction of immune cells infiltration and immunotherapy response.

scholarly journals Identification of an Immune-related Signature That Indicates the Dedifferentiation of Thyroid Cells

2020 ◽  
Author(s):  
Xuemin Wang ◽  
Chunyan Li ◽  
Rujia Qin ◽  
Zhaoming Zhong ◽  
Chuan-Zheng Sun
Keyword(s):  
Thyroid Carcinoma ◽  
Risk Score ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Predictive Value ◽  
The Cancer Genome Atlas ◽  
Term Survival ◽  
Thyroid Cells ◽  
Normal Thyroid ◽  
Immune Checkpoint Molecules

Abstract Background: Patients with well-differentiated thyroid carcinoma can achieve long-term survival after reasonable treatments, but there is no standard treatment mode for poorly or undifferentiated thyroid carcinoma and its prognosis is very poor. Immune cells, especially tumor-associated macrophages, account for a large proportion of the tumor microenvironment of anaplastic thyroid carcinomas (ATCs). However, whether immune-related genes can mediate the dedifferentiation of thyroid cells is unclear.Methods: We initially compared the differences of thyroid differentiation score, infitration of immune cells and enriched pathways between ATCs and papillary thyroid carcionma (PTCs) or normal thyroid tissues in Gene Expression Omnibus database. Then, The Cancer Genome Atlas database was used to screen out the prognosis associated IRGs. A risk score was constructed and we next investigated its predictive value for differentiation by applying receiver operating characteristic (ROC) curves and correlation analyses. Kaplan-Meier curves were used to evaluated its prognostic value. We further explored the associations of the risk score with important immune checkpoint molecules, infiltrating immune cells and response to immunotherapy.Results: Compared with PTCs or normal thyroid tissues, ATCs exhibited lower thyroid differentiation scores, higher infiltration of most immune cells and higher activation of inflammatory response. The risk score composed of MMP9 and SDC2 was significantly increased in ATCs and low differentiated PTCs. Moreover, it showed favorable predictive value for differentiation and survival. Higher risk score displayed dedifferentiation status and a worse prognosis. Additionly, the risk score was positively correlated with immune checkpoint molecules PDL1, CTLA4, IDO1, HAVCR2 and infiltration of multiple immune cells. Importantly, we found that samples with higher risk score tend to have a better response to immune checkpoint agents than lower ones.Conclusion: Our findings indicate that the risk score may not only contribute to the judgement of differentiation and prognosis of thyroid cancer, but also help to the prediction of immune cell infiltration and immune checkpoint inhibitor response.

scholarly journals Deoxyribonuclease 1-Mediated Clearance of Circulating Chromatin Prevents From Immune Cell Activation and Pro-inflammatory Cytokine Production, a Phenomenon Amplified by Low Trap1 Activity: Consequences for Systemic Lupus Erythematosus

2021 ◽  
Vol 12 ◽  
Author(s):  
Jasmin Felux ◽  
Annika Erbacher ◽  
Magali Breckler ◽  
Roxane Hervé ◽  
Delphine Lemeiter ◽  
...  
Keyword(s):  
Immune Cells ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Immune Cell ◽  
Wild Type ◽  
Systemic Lupus ◽  
Immune Cell Activation ◽  
Deficient Mice

Increased concentrations of circulating chromatin, especially oligo-nucleosomes, are observed in sepsis, cancer and some inflammatory autoimmune diseases like systemic lupus erythematosus (SLE). In SLE, circulating nucleosomes mainly result from increased apoptosis and decreased clearance of apoptotic cells. Once released, nucleosomes behave both as an autoantigen and as a damage-associated molecular pattern (DAMP) by activating several immune cells, especially pro-inflammatory cells. Deoxyribonuclease 1 (DNase1) is a major serum nuclease whose activity is decreased in mouse and human lupus. Likewise, the mitochondrial chaperone tumor necrosis factor (TNF) receptor-associated protein-1 (Trap1) protects against oxidative stress, which is increased in SLE. Here, using wild type, DNase1-deficient and DNase1/Trap1-deficient mice, we demonstrate that DNase1 is a major serum nuclease involved in chromatin degradation, especially when the plasminogen system is activated. In vitro degradation assays show that chromatin digestion is strongly impaired in serum from DNase1/Trap1-deficient mice as compared to wild type mice. In vivo, after injection of purified chromatin, clearance of circulating chromatin is delayed in DNase1/Trap1-deficient mice in comparison to wild type mice. Since defective chromatin clearance may lead to chromatin deposition in tissues and subsequent immune cell activation, spleen cells were stimulated in vitro with chromatin. Splenocytes were activated by chromatin, as shown by interleukin (IL)-12 secretion and CD69 up-regulation. Moreover, cell activation was exacerbated when Trap1 is deficient. Importantly, we also show that cytokines involved in lupus pathogenesis down-regulate Trap1 expression in splenocytes. Therefore, combined low activities of both DNase1 and Trap1 lead to an impaired degradation of chromatin in vitro, delayed chromatin clearance in vivo and enhanced activation of immune cells. This situation may be encountered especially, but not exclusively, in SLE by the negative action of cytokines on Trap1 expression.

Removal of Normal Competition Increases Proliferation of Pre-Leukemic Cells in a Mouse Model of Pre-B Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1430-1430
Author(s):  
Gregor SD Reid ◽  
David Barrett ◽  
Alix Eden Seif ◽  
Valerie I. Brown ◽  
Stephan A. Grupp
Keyword(s):  
Bone Marrow ◽  
Immune Cells ◽  
Bone Marrow Cells ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Cell Populations ◽  
Wild Type ◽  
Abnormal Cells ◽  
Deficient Mice

Abstract Abstract 1430 Poster Board I-453 B cell precursor (BCP) acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. While the peak age of onset for this disease is 4 years, abnormal cells that will eventually give rise to disease can be detected in blood taken from patients at birth. Interestingly, similar abnormal cell populations can also be detected in blood taken at birth from many children who do not go onto develop ALL. Understanding the factors that influence the survival and expansion or elimination of these abnormal pre-leukemic cells will shed light on the process of leukemogenesis and may suggest strategies for the prevention of BCP-ALL progression. We have used a mouse model of BCP-ALL to investigate the influence of normal immune cells on the pre-leukemic population. An abnormal BCP population arises in Eμ-RET (RFP) transgenic mice during fetal development, with overt leukemia developing between 3 and 9 months of age. We show that purified BCP from bone marrow of 4-week old pre-leukemic RFP mice undergo rapid expansion when adoptively transferred into immune-deficient mice, in many cases reaching white blood cell counts of >105 (with >90% showing the abnormal BCP phenotype). Secondary and tertiary transfer of expanded BCP into immune-deficient mice again produced a severe BCP lymphoproliferative disease. Such an expansion was not observed when purified BCP were transferred into wild-type mice or when unsorted pre-leukemic RFP bone marrow was transferred into immune-deficient mice. In addition, outgrowth of the abnormal cells was significantly curtailed if the purified RFP cells were mixed with a tenfold excess of wild-type bone marrow cells prior to adoptive transfer. This inhibition of BCP outgrowth was not achieved with Rag1-deficient bone marrow cells, suggesting that competition with normal adaptive immune cells for limited growth factors may impair the expansion of RFP pre-leukemic cells. Consistent with this hypothesis, blockade of the IL-7 receptor on pre-leukemic cells abrogated their expansion following adoptive transfer. As production of IL-7 is elevated in lymphopenic settings, we evaluated the impact of T cell-depletion on pre-leukemic cells in RFP mice. Pre-leukemic cell populations were significantly elevated in the spleen (31.3% +/- 15.4 vs 9% +/- 9, p<0.01) and blood (17% +/-19.2 vs 3% +/- 4.8, p<0.05) of T cell-depleted mice compared to controls. Taken together, these results suggest that competition for growth factors such as IL-7 may be a limiting step in the early expansion of pre-leukemic cell populations and may provide a mechanistic link between immune responses and pediatric ALL through the cytokine-mediated expansion of the pre-leukemic cell pool. Disclosures No relevant conflicts of interest to declare.

scholarly journals Endogenous IL-33 Deficiency Exacerbates Liver Injury and Increases Hepatic Influx of Neutrophils in Acute Murine Viral Hepatitis

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Virginie Carrière ◽  
Muhammad Imran Arshad ◽  
Jacques Le Seyec ◽  
Benjamin Lefevre ◽  
Muhammad Farooq ◽  
...  
Keyword(s):  
Viral Hepatitis ◽  
Immune Cells ◽  
Hepatitis Virus ◽  
Mouse Hepatitis Virus ◽  
Wild Type ◽  
Significant Weight Loss ◽  
Survival Effect ◽  
Deficient Mice ◽  
B And T Lymphocytes

The alarmin IL-33 has been described to be upregulated in human and murine viral hepatitis. However, the role of endogenous IL-33 in viral hepatitis remains obscure. We aimed to decipher its function by infecting IL-33-deficient mice (IL-33 KO) and their wild-type (WT) littermates with pathogenic mouse hepatitis virus (L2-MHV3). The IL-33 KO mice were more sensitive to L2-MHV3 infection exhibiting higher levels of AST/ALT, higher tissue damage, significant weight loss, and earlier death. An increased depletion of B and T lymphocytes, NKT cells, dendritic cells, and macrophages was observed 48 h postinfection (PI) in IL-33 KO mice than that in WT mice. In contrast, a massive influx of neutrophils was observed in IL-33 KO mice at 48 h PI. A transcriptomic study of inflammatory and cell-signaling genes revealed the overexpression of IL-6, TNFα, and several chemokines involved in recruitment/activation of neutrophils (CXCL2, CXCL5, CCL2, and CCL6) at 72 h PI in IL-33 KO mice. However, the IFNγ was strongly induced in WT mice with less profound expression in IL-33 KO mice demonstrating that endogenous IL-33 regulated IFNγ expression during L2-MHV3 hepatitis. In conclusion, we demonstrated that endogenous IL-33 had multifaceted immunoregulatory effect during viral hepatitis via induction of IFNγ, survival effect on immune cells, and infiltration of neutrophils in the liver.

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