Card9 controls Dectin-1-induced T-cell cytotoxicity and tumor growth in mice.
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ABSTRACT:
SUBMITTER: Haas T
PROVIDER: S-EPMC5434796 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Inflammatory reactions activated by pattern recognition receptors (PRRs) on the membrane of innate immune cells play an important role in atherosclerosis. Whether the PRRs of the C-type lectin receptor (CLR) family including Dectin-2 may be involved in the pathogenesis of atherosclerosis remains largely unknown. Recently, the CLR-adaptor molecule caspase recruitment domain family member 9 (CARD9) has been suggested to play a role in cardiovascular pathologies as it provides the link between CLR activation and transcription of inflammatory cytokines as well as immune cell recruitment. We therefore evaluated whether hematopoietic deletion of Dectin-2 or CARD9 reduces inflammation and atherosclerosis development. Low-density lipoprotein receptor (Ldlr)-knockout mice were transplanted with bone marrow from wild-type, Dectin-2- or Card9-knockout mice and fed a Western-type diet containing 0.1% (w/w) cholesterol. After 10 weeks, lipid and inflammatory parameters were measured and atherosclerosis development was determined. Deletion of hematopoietic Dectin-2 or CARD9 did not influence plasma triglyceride and cholesterol levels. Deletion of hematopoietic Dectin-2 did not affect atherosclerotic lesion area, immune cell composition, ex vivo cytokine secretion by peritoneal cells or bone marrow derived macrophages. Unexpectedly, deletion of hematopoietic CARD9 increased atherosclerotic lesion formation and lesion severity. Deletion of hematopoietic CARD9 did also not influence circulating immune cell composition and peripheral cytokine secretion. Besides a tendency to a reduced macrophage content within these lesions, plasma MCP-1 levels decreased upon WTD feeding. Deletion of hematopoietic Dectin-2 did not influence atherosclerosis development in hyperlipidemic mice. The absence of CARD9 unexpectedly increased atherosclerotic lesion size and severity, suggesting that the presence of CARD9 may protect against initiation of atherosclerosis development.
| S-EPMC6416398 | biostudies-literature
Project description:Coccidioides species are fungal pathogens that can cause a widely varied clinical manifestation from mild pulmonary symptom to disseminated, life-threatening disease. We have previously created a subunit vaccine by encapsulating a recombinant coccidioidal Ag (rCpa1) in glucan-chitin particles (GCPs) as an adjuvant-delivery system. The GCP-rCpa1 vaccine has shown to elicit a mixed Th1 and Th17 response and confers protection against pulmonary coccidioidomycosis in mice. In this study, we further delineated the vaccine-induced protective mechanisms. Depletion of IL-17A in vaccinated C57BL/6 mice prior to challenge abrogated the protective efficacy of GCP-rCpa1 vaccine. Global transcriptome and Ingenuity Pathway Analysis of murine bone marrow-derived macrophages after exposure to this vaccine revealed the upregulation of proinflammatory cytokines (TNF-α, IL-6, and IL-1β) that are associated with activation of C-type lectin receptors (CLR) Dectin-1- and Dectin-2-mediated CARD9 signaling pathway. The GCP formulation of rCpa1 bound soluble Dectin-1 and Dectin-2 and triggered ITAM signaling of corresponding CLR reporter cells. Furthermore, macrophages that were isolated from Dectin-1 -/-, Dectin-2 -/-, and CARD9 -/- mice significantly reduced production of inflammatory cytokines in response to the GCP-rCpa1 vaccine compared with those of wild-type mice. The GCP-rCpa1 vaccine had significantly reduced protective efficacy in Dectin-1 -/-, Dectin-2 -/-, and CARD9 -/- mice that showed decreased acquisition of Th cells in Coccidioides-infected lungs compared with vaccinated wild-type mice, especially Th17 cells. Collectively, we conclude that the GCP-rCpa1 vaccine stimulates a robust Th17 immunity against Coccidioides infection through activation of the CARD9-associated Dectin-1 and Dectin-2 signal pathways.
| S-EPMC7323849 | biostudies-literature
Project description:Macrophages are critical immune effector cells of the tumor microenvironment that promote seeding, extravasation and persistent growth of tumor cells in primary tumors and metastatic sites. Tumor progression and metastasis are affected by dynamic changes in the specific phenotypes of macrophage subpopulations; however, the mechanisms by which tumor cells modulate macrophage polarization remain incompletely understood. Caspase recruitment domain-containing protein 9 (CARD9) is a central adaptor protein of innate immune responses to extracellular pathogens. We report that increased CARD9 expression is primarily localized in infiltrated macrophages and significantly associated with advanced histopathologic stage and the presence of metastasis. Using CARD9-deficient (CARD9(-/-)) mice, we show that bone marrow-derived CARD9 promotes liver metastasis of colon carcinoma cells. Mechanistic studies reveal that CARD9 contributes to tumor metastasis by promoting metastasis-associated macrophage polarization through activation of the nuclear factor-kappa B signaling pathway. We further demonstrate that tumor cell-secreted vascular endothelial growth factor facilitates spleen tyrosine kinase activation in macrophages, which is necessary for formation of the CARD9-B-cell lymphoma/leukemia 10-mucosa-associated lymphoid tissue lymphoma translocation protein 1 complex. Taken together, our results indicating that CARD9 is a regulator of metastasis-associated macrophages will lead to new insights into evolution of the microenvironments supporting tumor metastasis, thereby providing targets for anticancer therapies.
| S-EPMC4085533 | biostudies-literature
Project description:BackgroundC-type lectin receptors, including Dectin-2, are pattern recognition receptors on monocytes and macrophages that mainly recognize sugars and sugar-like structures present on fungi. Activation of C-type lectin receptors induces downstream CARD9 signalling, leading to the production of cytokines. We hypothesized that under hyperglycaemic conditions, as is the case in diabetes mellitus, glycosylated protein (sugar-like) structures activate C-type lectin receptors, leading to immune cell activation and increased atherosclerosis development.MethodsLow-density lipoprotein receptor-deficient mice were lethally irradiated and transplanted with bone marrow from control wild-type, Dectin-2-/- or Card9-/- mice. After 6 weeks of recovery, mice received streptozotocin injections (50 mg/g BW; 5 days) to induce hyperglycaemia. After an additional 2 weeks, mice were fed a Western-type diet (0.1% cholesterol) for 10 weeks.Results and conclusionDeletion of haematopoietic Dectin-2 reduced the number of circulating Ly6Chi monocytes, increased pro-inflammatory cytokine production, but did not affect atherosclerosis development. Deletion of haematopoietic CARD9 tended to reduce macrophage and collagen content in atherosclerotic lesions, again without influencing the lesion size. Deletion of haematopoietic Dectin-2 did not influence atherosclerosis development under hyperglycaemic conditions, despite some minor effects on inflammation. Deletion of haematopoietic CARD9 induced minor alterations in plaque composition under hyperglycaemic conditions, without affecting lesion size.
| S-EPMC7510497 | biostudies-literature
Project description:Fibronectin is ubiquitously expressed in the extracellular matrix, and experimental evidence has shown that it modulates blood vessel formation. The relative contribution of local and circulating fibronectin to blood vessel formation in vivo remains unknown despite evidence for unexpected roles of circulating fibronectin in various diseases. Using transgenic mouse models, we established that circulating fibronectin facilitates the growth of bone metastases by enhancing blood vessel formation and maturation. This effect is more relevant than that of fibronectin produced by endothelial cells and pericytes, which only exert a small additive effect on vessel maturation. Circulating fibronectin enhances its local production in tumors through a positive feedback loop and increases the amount of vascular endothelial growth factor (VEGF) retained in the matrix. Both fibronectin and VEGF then cooperate to stimulate blood vessel formation. Fibronectin content in the tumor correlates with the number of blood vessels and tumor growth in the mouse models. Consistent with these results, examination of three separate arrays from patients with breast and prostate cancers revealed that a high staining intensity for fibronectin in tumors is associated with increased mortality. These results establish that circulating fibronectin modulates blood vessel formation and tumor growth by modifying the amount of and the response to VEGF. Furthermore, determination of the fibronectin content can serve as a prognostic biomarker for breast and prostate cancers and possibly other cancers.
| S-EPMC3730044 | biostudies-literature
Project description:Preparation of sequencing libraries and sequencing analysis using Illumina HiSeq 3000 platform (50 bp single-read module) were conducted at the Genomics Core of UT Health San Antonio. Sequencing reads were preprocessed by Trim Sequences tools in CLC Genomics workbench. Remaining reads were then aligned to mouse GRCm38(mm10) reference genome using RNA-Seq Analysis module in CLC Genomics workbench. To determine differentially expressed genes, exact test were performed after filtering lowly expressed gene (counts per million < 1 in more than three samples across the dataset) using edgeR package (Robinson, McCarthy et al. 2010). Gene Ontology (GO) analysis were performed using DAVID (Dennis, Sherman et al. 2003) and then visualized by GOplot (Walter, Sanchez-Cabo et al. 2015).
2020-04-16 | GSE133140 | GEO
Project description:Chromoblastomycosis is a chronic skin infection caused by the pigmented saprophytic mould Fonsecaea pedrosoi. Chronicity of infection can be broken by a coordinated innate recognition of the spores by pattern recognition receptors. While Mincle signaling via the Syk/Card9 pathway is required for fungal recognition by host cells, it is not sufficient for host control. Exogenously applied TLR agonists are necessary to promote the induction of proinflammatory cytokines and clearance of infection in vivo. Here, we investigated whether costimulation by TLR agonists fosters the development of adaptive immune responses, by examining the development of fungus-specific T cells. Subcutaneous infection of mice with F. pedrosoi spores induced the activation, expansion, and differentiation of Ag-specific CD4(+) T cells but TLR costimulation did not further augment these T-cell responses. The Dectin-2/FcRγ/Card9 signaling pathway promoted the differentiation of fungus-specific CD4(+) T cells into Th17 cells, whereas Mincle inhibited the development of this T-helper subset in infected mice. These results indicate differential roles for Dectin-2 and Mincle in the generation of adaptive immune responses to F. pedrosoi infection.
| S-EPMC4562893 | biostudies-literature
Project description:The scaffold protein CARD9 plays an essential role in anti-fungus immunity and is implicated in mediating Dectin-1/Syk-induced NF-kappaB activation in response to Candida albicans infection. However, the molecular mechanism by which CARD9 mediates C. albicans-induced NF-kappaB activation is not fully characterized. Here we demonstrate that CARD9 is involved in mediating NF-kappaB activation induced by the hyphal form of C. albicans hyphae (Hyphae) but not by its heat-inactivated unicellular form. Our data show that inhibiting Dectin-2 expression selectively blocked Hyphae-induced NF-kappaB, whereas inhibiting Dectin-1 mainly suppressed zymosan-induced NF-kappaB, indicating that Hyphae-induced NF-kappaB activation is mainly through Dectin-2 and not Dectin-1. Consistently, we find that the hyphae stimulation induces CARD9 association with Bcl10, an adaptor protein that functions downstream of CARD9 and is also involved in C. albicans-induced NF-kappaB activation. This association is dependent on Dectin-2 but not Dectin-1 following the hyphae stimulation. Finally, we find that although both CARD9 and Syk are required for Hyphae-induced NF-kappaB activation, they regulate different signaling events in which CARD9 mediates IkappaBalpha kinase ubiquitination, whereas Syk regulates IkappaBalpha kinase phosphorylation. Together, our data demonstrated that CARD9 is selectively involved in Dectin-2-induced NF-kappaB activation in response to C. albicans hyphae challenging.
| S-EPMC2923990 | biostudies-literature
Project description:Tumor growth is modulated by crosstalk between cancer cells and the tumor microenvironment. Recent advances have shown that miRNA dysfunction in tumor cells can modulate the tumor microenvironment to indirectly determine their progression. However, this process is poorly understood in testicular germ cell tumors (TGCTs). We reported here that miR-125b was repressed in TGCT samples by epigenetic modifications rather than genetic alternations. Furthermore, miR-125b overexpression significantly alleviated the tumor growth in two NCCIT human embryonic carcinoma xenograft models in vivo, whereas miR-125b did not stimulate autonomous tumor cell growth in vitro. Notably, forced expression of miR-125b in NCCIT embryonic carcinoma cells decreased the abundance of host tumor-associated macrophages (TAMs) within tumor microenvironment. Selective deletion of host macrophages by clodronate abolished the anti-tumoral ability of miR-125b in xenograft models. By RNA profiling, Western blot and luciferase reporter assay, we further observed that miR-125b directly regulated tumor cell-derived chemokine CSF1 and CX3CL1, which are known to control the recruitment of TAMs to tumor sites. Lastly, we found that one set of miRNAs, which are under the regulation of miR-125b, might convergently target CSF1/CX3CL1 in NCCIT cells using miRNA profiling. These findings uncover the anticancer effect of miR-125b via mediating tumor-stroma crosstalk in xenograft models of TGCTs and raise the possibility of targeting miR-125b as miRNA therapeutics.
| S-EPMC6148032 | biostudies-literature
Project description:Women with low levels of vitamin D have a higher risk of developing breast cancer. Numerous studies associated the presence of a CD8+ T cell infiltration with a good prognosis. As vitamin D may play a key role in the modulation of the immune system, the objective of this work was to evaluate the impact of vitamin D on the breast cancer progression and mammary tumor microenvironment. We show that vitamin D decreases breast cancer tumor growth. Immunomonitoring of the different immune subsets in dissociated tumors revealed an increase in tumor infiltrating CD8+ T cells in the vitamin D-treated group. Interestingly, these CD8+ T cells exhibited a more active T cell (TEM/CM) phenotype. However, in high-fat diet conditions, we observed an opposite effect of vitamin D on breast cancer tumor growth, associated with a reduction of CD8+ T cell infiltration. Our data show that vitamin D is able to modulate breast cancer tumor growth and inflammation in the tumor microenvironment in vivo. Unexpectedly, this effect is reversed in high-fat diet conditions, revealing the importance of diet on tumor growth. We believe that supplementation with vitamin D can in certain conditions represent a new adjuvant in the treatment of breast cancers.
| S-EPMC6563618 | biostudies-literature