Epigenetic Regulation of CXCL12 Plays a Critical Role in Mediating Tumor Progression and the Immune Response In Osteosarcoma

DNA methylation plays crucial roles in responses to environmental stimuli. Modification of DNA methylation during development and abiotic stress responses has been confirmed in increasing numbers of plants, mainly annual plants. However, the epigenetic regulation mechanism underlying the immune response to pathogens remains largely unknown in plants, especially trees. To investigate whether DNA methylation is involved in the response to infection process or is related to the resistance differences among poplars, we performed comprehensive whole-genome bisulfite sequencing of the infected stem of the susceptible type Populus × euramerican ‘74/76’ and resistant type Populus tomentosa ‘henan’ upon Lonsdalea populi infection. The results revealed that DNA methylation changed dynamically in poplars during the infection process with a remarkable decrease seen in the DNA methylation ratio. Intriguingly, the resistant P. tomentosa ‘henan’ had a much lower basal DNA methylation ratio than the susceptible P. × euramerican ‘74/76’. Compared to mock-inoculation, both poplar types underwent post-inoculation CHH hypomethylation; however, significant decreases in mC and mCHH proportions were found in resistant poplar. In addition, most differentially CHH-hypomethylated regions were distributed in repeat and promoter regions. Based on comparison of DNA methylation modification with the expression profiles of genes, DNA methylation occurred in resistance genes, pathogenesis-related genes, and phytohormone genes in poplars during pathogen infection. Additionally, transcript levels of genes encoding methylation-related enzymes changed during pathogen infection. Interestingly, small-regulator miRNAs were subject to DNA methylation in poplars experiencing pathogen infection. This investigation highlights the critical role of DNA methylation in the poplar immune response to pathogen infection and provides new insights into epigenetic regulation in perennial plants in response to biotic stress.

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Bmi1 Augments Proliferation and Survival of Cortical Bone-Derived Stem Cells after Injury through Novel Epigenetic Signaling via Histone 3 Regulation

International Journal of Molecular Sciences ◽

10.3390/ijms22157813 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7813

Author(s):

Lindsay Kraus ◽

Chris Bryan ◽

Marcus Wagner ◽

Tabito Kino ◽

Melissa Gunchenko ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Dna Damage ◽

Stem Cell ◽

Histone Modification ◽

Epigenetic Regulation ◽

Critical Role ◽

Proliferative Potential ◽

Therapeutic Effects ◽

Histone 3

Ischemic heart disease can lead to myocardial infarction (MI), a major cause of morbidity and mortality worldwide. Multiple stem cell types have been safely transferred into failing human hearts, but the overall clinical cardiovascular benefits have been modest. Therefore, there is a dire need to understand the basic biology of stem cells to enhance therapeutic effects. Bmi1 is part of the polycomb repressive complex 1 (PRC1) that is involved in different processes including proliferation, survival and differentiation of stem cells. We isolated cortical bones stem cells (CBSCs) from bone stroma, and they express significantly high levels of Bmi1 compared to mesenchymal stem cells (MSCs) and cardiac-derived stem cells (CDCs). Using lentiviral transduction, Bmi1 was knocked down in the CBSCs to determine the effect of loss of Bmi1 on proliferation and survival potential with or without Bmi1 in CBSCs. Our data show that with the loss of Bmi1, there is a decrease in CBSC ability to proliferate and survive during stress. This loss of functionality is attributed to changes in histone modification, specifically histone 3 lysine 27 (H3K27). Without the proper epigenetic regulation, due to the loss of the polycomb protein in CBSCs, there is a significant decrease in cell cycle proteins, including Cyclin B, E2F, and WEE as well as an increase in DNA damage genes, including ataxia-telangiectasia mutated (ATM) and ATM and Rad3-related (ATR). In conclusion, in the absence of Bmi1, CBSCs lose their proliferative potential, have increased DNA damage and apoptosis, and more cell cycle arrest due to changes in epigenetic modifications. Consequently, Bmi1 plays a critical role in stem cell proliferation and survival through cell cycle regulation, specifically in the CBSCs. This regulation is associated with the histone modification and regulation of Bmi1, therefore indicating a novel mechanism of Bmi1 and the epigenetic regulation of stem cells.

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NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment

Cancers ◽

10.3390/cancers13122999 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2999

Author(s):

Deborah Reynaud ◽

Roland Abi Nahed ◽

Nicolas Lemaitre ◽

Pierre-Adrien Bolze ◽

Wael Traboulsi ◽

...

Keyword(s):

Immune Response ◽

Tumor Cells ◽

Major Gene ◽

Critical Role ◽

Orthotopic Model ◽

Independent Manner ◽

Maternal Immune Response ◽

The Impact

The inflammatory gene NLRP7 is the major gene responsible for recurrent complete hydatidiform moles (CHM), an abnormal pregnancy that can develop into gestational choriocarcinoma (CC). However, the role of NLRP7 in the development and immune tolerance of CC has not been investigated. Three approaches were employed to define the role of NLRP7 in CC development: (i) a clinical study that analyzed human placenta and sera collected from women with normal pregnancies, CHM or CC; (ii) an in vitro study that investigated the impact of NLRP7 knockdown on tumor growth and organization; and (iii) an in vivo study that used two CC mouse models, including an orthotopic model. NLRP7 and circulating inflammatory cytokines were upregulated in tumor cells and in CHM and CC. In tumor cells, NLRP7 functions in an inflammasome-independent manner and promoted their proliferation and 3D organization. Gravid mice placentas injected with CC cells invalidated for NLRP7, exhibited higher maternal immune response, developed smaller tumors, and displayed less metastases. Our data characterized the critical role of NLRP7 in CC and provided evidence of its contribution to the development of an immunosuppressive maternal microenvironment that not only downregulates the maternal immune response but also fosters the growth and progression of CC.

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Why Does SARS-CoV-2 Infection Induce Autoantibody Production?

Pathogens ◽

10.3390/pathogens10030380 ◽

2021 ◽

Vol 10 (3) ◽

pp. 380

Author(s):

Ales Macela ◽

Klara Kubelkova

Keyword(s):

Immune Response ◽

Immune System ◽

Host Cell ◽

Critical Role ◽

Cell Interaction ◽

Immune Recognition ◽

Autoantibody Production ◽

Host Cell Interaction ◽

Primary Virus

SARS-CoV-2 infection induces the production of autoantibodies, which is significantly associated with complications during hospitalization and a more severe prognosis in COVID-19 patients. Such a response of the patient’s immune system may reflect (1) the dysregulation of the immune response or (2) it may be an attempt to regulate itself in situations where the non-infectious self poses a greater threat than the infectious non-self. Of significance may be the primary virus-host cell interaction where the surface-bound ACE2 ectoenzyme plays a critical role. Here, we present a brief analysis of recent findings concerning the immune recognition of SARS-CoV-2, which, we believe, favors the second possibility as the underlying reason for the production of autoantibodies during COVID-19.

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Immune System Efficiency in Cancer and the Microbiota Influence

Pathobiology ◽

10.1159/000512326 ◽

2021 ◽

pp. 1-17

Author(s):

Ana Margarida Barbosa ◽

Alexandra Gomes-Gonçalves ◽

António G. Castro ◽

Egídio Torrado

Keyword(s):

Immune Response ◽

Immune System ◽

Immune Checkpoint Inhibitors ◽

Therapeutic Response ◽

Checkpoint Inhibitors ◽

Critical Role ◽

Antitumor Immune Response ◽

System Efficiency ◽

Novel Targets ◽

Cancer Immunosurveillance

The immune system plays a critical role in preventing cancer development and progression. However, the complex network of cells and soluble factor that form the tumor microenvironment (TME) can dictate the differentiation of tumor-infiltrating leukocytes and shift the antitumor immune response into promoting tumor growth. With the advent of cancer immunotherapy, there has been a reinvigorated interest in defining how the TME shapes the antitumor immune response. This interest brought to light the microbiome as a novel player in shaping cancer immunosurveillance. Indeed, accumulating evidence now suggests that the microbiome may confer susceptibility or resistance to certain cancers and may influence response to therapeutics, particularly immune checkpoint inhibitors. As we move forward into the age of precision medicine, it is vital that we define the factors that influence the interplay between the triad immune system-microbiota-cancer. This knowledge will contribute to improve the therapeutic response to current approaches and will unravel novel targets for immunotherapy.

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Hypoxia and the Tumor Microenvironment

Technology in Cancer Research & Treatment ◽

10.1177/15330338211036304 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110363

Author(s):

Yue Li ◽

Long Zhao ◽

Xiao-Feng Li

Keyword(s):

Immune Response ◽

Cell Proliferation ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Poor Prognosis ◽

Tumor Biology ◽

Metastatic Potential ◽

Tumor Detection ◽

Tumor Aggressiveness

Hypoxia is an important feature of the tumor microenvironment, and is closely associated with cell proliferation, angiogenesis, metabolism and the tumor immune response. All these factors can further promote tumor progression, increase tumor aggressiveness, enhance tumor metastatic potential and lead to poor prognosis. In this review, these effects of hypoxia on tumor biology will be discussed, along with their significance for tumor detection and treatment.

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Loss of Nckx3 Exacerbates Experimental DSS-Induced Colitis in Mice through p53/NF-κB Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms22052645 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2645

Author(s):

Dinh Nam Tran ◽

Seon Myeong Go ◽

Seon-Mi Park ◽

Eui-Man Jung ◽

Eui-Bae Jeung

Keyword(s):

Immune Response ◽

Cellular Proliferation ◽

Intestinal Inflammation ◽

Critical Role ◽

Experimental Colitis ◽

Innate Immune ◽

Inflammatory Conditions ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Microarray Analyses

Inflammatory bowel diseases (IBDs) comprises a range of chronic inflammatory conditions of the intestinal tract. The incidence and prevalence of IBDs are increasing worldwide, but the precise etiology of these diseases is not completely understood. Calcium signaling plays a regulatory role in cellular proliferation. Nckx3, a potassium-dependent Na+/Ca2+ exchanger, is not only expressed in the brain but also in the aortic, uterine, and intestinal tissues, which contain abundant smooth muscle cells. This study investigated the role of Nckx3 in intestinal inflammation. Microarray analyses revealed the upregulation of the innate immune response-associated genes in the duodenum of Nckx3 knockout (KO) mice. The Nckx3 KO mice also showed an increase in IBD- and tumorigenesis-related genes. Using dextran sodium sulfate (DSS)-induced experimental colitis mice models, the Nckx3 KO mice showed severe colitis. Furthermore, the pathways involving p53 and NF-κB signaling were significantly upregulated by the absence of Nckx3. Overall, Nckx3 plays a critical role in the innate immune and immune response and may be central to the pathogenesis of IBD.

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TLR4 regulates rabies virus-induced humoral immunity through recruitment of cDC2 to lymph organs

Journal of Virology ◽

10.1128/jvi.00829-21 ◽

2021 ◽

Author(s):

Chen Chen ◽

Chengguang Zhang ◽

Haoqi Li ◽

Zongmei Wang ◽

Yueming Yuan ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Rabies Virus ◽

Humoral Immunity ◽

Humoral Immune Response ◽

Critical Role ◽

Wild Type ◽

Humoral Immune ◽

Specific Igg ◽

Molecular Patterns

Rabies, caused by rabies virus (RABV), is fatal to both humans and animals around the world. Effective clinical therapy for rabies has not been achieved, and vaccination is the most effective means of preventing and controlling rabies. Although different vaccines, such as live attenuated and inactivated vaccines, can induce different immune responses, different expression of pattern recognition receptors (PRRs) also causes diverse immune responses. Toll-like receptor 4 (TLR4) is a pivotal PRR that induces cytokine production and bridges innate and adaptive immunity. Importantly, TLR4 recognizes various virus-derived pathogen-associated molecular patterns (PAMPs) and virus-induced damage-associated molecular patterns (DAMPs), usually leading to the activation of immune cells. However, the role of TLR4 in the humoral immune response induced by RABV has not been revealed yet. Based on TLR4-deficient ( TLR4 -/- ) and wild-type (WT) mouse models, we report that TLR4-dependent recruitment of the conventional type-2 dendritic cells (CD8α - CD11b + cDC2) into secondary lymph organs (SLOs) is critical for antigen presentation. cDC2-initiated differentiation of Tfh cells promotes the proliferation of germinal centre (GC) B cells, the formation of GCs, and the production of plasma cells (PCs), all of which contribute to the production of RABV-specific IgG and virus-neutralizing antibodies (VNAs). Collectively, our work demonstrates that TLR4 is necessary for the recruitment of cDC2 and for the induction of RABV-induced humoral immunity, which is regulated by the cDC2-Tfh-GC B axis. IMPORTANCE Vaccination is the most efficient method to prevent rabies. TLR4, a well-known immune sensor, plays a critical role in initiating innate immune response. Here, we found that TLR4 deficiency ( TLR4 -/- ) mice suppressed the induction of humoral immune response after immunization with rabies virus (RABV), including reduced production of VNAs and RABV-specific IgG, compared with that occurred in wild-type (WT) mice. As a consequence, TLR4 -/- mice exhibited higher mortality than WT mice after challenge with virulent RABV. Importantly, further investigation found that TLR4 signaling promoted the recruitment of cDC2 (CD8α + CD11b - ), a subset of cDCs known to induce CD4 + T cell immunity through their MHC-II presentation machinery. Our results imply that TLR4 is indispensable for an efficient humoral response to rabies vaccine, which provides new insight into the development of novel rabies vaccines.

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5-Bromo-2-deoxyuridine regulates invasiveness and expression of integrins and matrix-degrading proteinases in a differentiated hamster melanoma cell

Journal of Cell Science ◽

10.1242/jcs.105.1.191 ◽

1993 ◽

Vol 105 (1) ◽

pp. 191-201 ◽

Cited By ~ 3

Author(s):

L. Thomas ◽

P.W. Chan ◽

S. Chang ◽

C. Damsky

Keyword(s):

Extracellular Matrix ◽

Tumor Progression ◽

Melanoma Cell ◽

Critical Role ◽

Terminal Differentiation ◽

Cell System ◽

Melanocyte Stimulating Hormone ◽

Complex Processes ◽

Differentiation Marker ◽

Stimulating Hormone

Cell interactions with the extracellular matrix play a critical role in regulating complex processes such as terminal differentiation and tumor progression. In these studies we describe a melanoma cell system that should be useful in addressing the regulation of cell-matrix interactions and the roles they play in regulating differentiation and cell invasiveness. CS (suspension)-1 melanoma cells are relatively well differentiated: they are melanotic, responsive to melanocyte-stimulating hormone, and express TA99, a melanosome membrane differentiation marker. Their repertoire of integrin receptors for extracellular matrix ligands is limited; in particular, they lack receptors for vitronectin, accounting for the observation that they are nonadherent when cultured in the presence of serum. CS-1 cells are noninvasive as well, and express low levels of both metalloproteinases and activated plasminogen activators. Treatment of these cells with melanocyte-stimulating hormone causes them to increase melanin production and assume an arborized phenotype, suggesting that it promotes their further differentiation. In contrast, treatment of CS-1 with the thymidine analog 5-bromodeoxyuridine, converts them to a highly invasive cell population (termed BCS-1) that loses its differentiated properties and responsiveness to melanocyte-stimulating hormone, acquires a broad integrin repertoire (including vitronectin receptors), and expresses elevated levels of metalloproteinases and activated urokinase. From these observations and findings of others on BrdU treatment of other developmental lineages, we hypothesize that BrdU both suppresses differentiation and promotes invasiveness of CS-1 cells. The demonstrated manipulability of CS-1 cells should make them extremely useful for studying the regulation of both terminal differentiation and tumor progression in the melanocyte lineage.

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Phagocytes from Mice Lacking the Sts Phosphatases Have an Enhanced Antifungal Response to Candida albicans

mBio ◽

10.1128/mbio.00782-18 ◽

2018 ◽

Vol 9 (4) ◽

Cited By ~ 8

Author(s):

David Frank ◽

Shamoon Naseem ◽

Gian Luigi Russo ◽

Cindy Li ◽

Kaustubh Parashar ◽

...

Keyword(s):

Bone Marrow ◽

Immune Response ◽

Candida Albicans ◽

Tyrosine Kinase ◽

Critical Role ◽

Inflammasome Activation ◽

Wild Type ◽

Content Type ◽

Enhanced Production ◽

Immunological Mechanisms

ABSTRACT Mice lacking expression of the homologous phosphatases Sts-1 and Sts-2 (Sts−/− mice) are resistant to disseminated candidiasis caused by the fungal pathogen Candida albicans. To better understand the immunological mechanisms underlying the enhanced resistance of Sts−/− mice, we examined the kinetics of fungal clearance at early time points. In contrast to the rapid C. albicans growth seen in normal kidneys during the first 24 h postinfection, we observed a reduction in kidney fungal CFU within Sts−/− mice beginning at 12 to 18 h postinfection. This corresponds to the time period when large numbers of innate leukocytes enter the renal environment to counter the infection. Because phagocytes of the innate immune system are important for host protection against pathogenic fungi, we evaluated responses of bone marrow leukocytes. Relative to wild-type cells, Sts−/− marrow monocytes and bone marrow-derived dendritic cells (BMDCs) displayed a heightened ability to inhibit C. albicans growth ex vivo. This correlated with significantly enhanced production of reactive oxygen species (ROS) by Sts−/− BMDCs downstream of Dectin-1, a C-type lectin receptor that plays a critical role in stimulating host responses to fungi. We observed no visible differences in the responses of other antifungal effector pathways, including cytokine production and inflammasome activation, despite enhanced activation of the Syk tyrosine kinase downstream of Dectin-1 in Sts−/− cells. Our results highlight a novel mechanism regulating the immune response to fungal infections. Further understanding of this regulatory pathway could aid the development of therapeutic approaches to enhance protection against invasive candidiasis. IMPORTANCE Systemic candidiasis caused by fungal Candida species is becoming an increasingly serious medical problem for which current treatment is inadequate. Recently, the Sts phosphatases were established as key regulators of the host antifungal immune response. In particular, genetic inactivation of Sts significantly enhanced survival of mice infected intravenously with Candida albicans. The Sts−/− in vivo resistance phenotype is associated with reduced fungal burden and an absence of inflammatory lesions. To understand the underlying mechanisms, we studied phagocyte responses. Here, we demonstrate that Sts−/− phagocytes have heightened responsiveness to C. albicans challenge relative to wild-type cells. Our data indicate the Sts proteins negatively regulate phagocyte activation via regulating selective elements of the Dectin-1–Syk tyrosine kinase signaling axis. These results suggest that phagocytes lacking Sts respond to fungal challenge more effectively and that this enhanced responsiveness partially underlies the profound resistance of Sts−/− mice to systemic fungal challenge.

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