Bim suppresses the development of SLE by limiting myeloid inflammatory responses

The Bcl-2 family is considered the guardian of the mitochondrial apoptotic pathway. We demonstrate that Bim acts as a molecular rheostat by controlling macrophage function not only in lymphoid organs but also in end organs, thereby preventing the break in tolerance. Mice lacking Bim in myeloid cells (LysMCreBimfl/fl) develop a systemic lupus erythematosus (SLE)–like disease that mirrors aged Bim−/− mice, including loss of marginal zone macrophages, splenomegaly, lymphadenopathy, autoantibodies (including anti-DNA IgG), and a type I interferon signature. LysMCreBimfl/fl mice exhibit increased mortality attributed to glomerulonephritis (GN). Moreover, the toll-like receptor signaling adaptor protein TRIF (TIR-domain–containing adapter-inducing interferon-β) is essential for GN, but not systemic autoimmunity in LysMCreBimfl/fl mice. Bim-deleted kidney macrophages exhibit a novel transcriptional lupus signature that is conserved within the gene expression profiles from whole kidney biopsies of patients with SLE. Collectively, these data suggest that the Bim may be a novel therapeutic target in the treatment of SLE.

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Lethal Dissemination of H5N1 Influenza Virus Is Associated with Dysregulation of Inflammation and Lipoxin Signaling in a Mouse Model of Infection

Journal of Virology ◽

10.1128/jvi.00553-10 ◽

2010 ◽

Vol 84 (15) ◽

pp. 7613-7624 ◽

Cited By ~ 86

Author(s):

Cristian Cilloniz ◽

Mary J. Pantin-Jackwood ◽

Chester Ni ◽

Alan G. Goodman ◽

Xinxia Peng ◽

...

Keyword(s):

Influenza Virus ◽

Inflammatory Response ◽

Inflammatory Responses ◽

Synergistic Effects ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Influenza Viruses ◽

Type I ◽

Highly Pathogenic ◽

H5n1 Influenza

ABSTRACT Periodic outbreaks of highly pathogenic avian H5N1 influenza viruses and the current H1N1 pandemic highlight the need for a more detailed understanding of influenza virus pathogenesis. To investigate the host transcriptional response induced by pathogenic influenza viruses, we used a functional-genomics approach to compare gene expression profiles in lungs from 129S6/SvEv mice infected with either the fully reconstructed H1N1 1918 pandemic virus (1918) or the highly pathogenic avian H5N1 virus Vietnam/1203/04 (VN/1203). Although the viruses reached similar titers in the lung and caused lethal infections, the mean time of death was 6 days for VN/1203-infected animals and 9 days for mice infected with the 1918 virus. VN/1203-infected animals also exhibited an earlier and more potent inflammatory response. This response included induction of genes encoding components of the inflammasome. VN/1203 was also able to disseminate to multiple organs, including the brain, which correlated with changes in the expression of genes associated with hematological functions and lipoxin biogenesis and signaling. Both viruses elicited expression of type I interferon (IFN)-regulated genes in wild-type mice and to a lesser extent in mice lacking the type I IFN receptor, suggesting alternative or redundant pathways for IFN signaling. Our findings suggest that VN/1203 is more pathogenic in mice as a consequence of several factors, including the early and sustained induction of the inflammatory response, the additive or synergistic effects of upregulated components of the immune response, and inhibition of lipoxin-mediated anti-inflammatory responses, which correlated with the ability of VN/1203 to disseminate to extrapulmonary organs.

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Meta-analysis of gene expression profiles of peripheral blood cells in systemic lupus erythematosus

Cellular and Molecular Biology ◽

10.14715/cmb/2018.64.10.7 ◽

2018 ◽

Vol 64 (10) ◽

pp. 40 ◽

Cited By ~ 2

Author(s):

Sang-Cheol Bae ◽

Young Ho Lee

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Peripheral Blood ◽

Blood Cells ◽

Expression Profiles ◽

Meta Analysis ◽

Gene Expression Profiles ◽

Peripheral Blood Cells ◽

Systemic Lupus

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n-3 Fatty acids, inflammation and immunity: new mechanisms to explain old actions

Proceedings of The Nutrition Society ◽

10.1017/s0029665113001031 ◽

2013 ◽

Vol 72 (3) ◽

pp. 326-336 ◽

Cited By ~ 202

Author(s):

Philip C. Calder

Keyword(s):

Fatty Acids ◽

Inflammatory Responses ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Mechanisms Of Action ◽

Lipid Mediators ◽

Functional Responses ◽

New Family ◽

Epa And Dha ◽

Novel Interactions

Numerous effects of n-3 fatty acids EPA and DHA on functional responses of cells involved in inflammation and immunity have been described. Fatty acid-induced modifications in membrane order and in the availability of substrates for eicosanoid synthesis are long-standing mechanisms that are considered important in explaining the effects observed. More recently, effects on signal transduction pathways and on gene expression profiles have been identified. Over the last 10 years or so, significant advances in understanding the mechanisms of action of n-3 fatty acids have been made. These include the identification of new actions of lipid mediators that were already described and of novel interactions among those mediators and the description of an entirely new family of lipid mediators, resolvins and protectins that have anti-inflammatory actions and are critical to the resolution of inflammation. It is also recognised that EPA and DHA can inhibit activation of the prototypical inflammatory transcription factor NF-κB. Recent studies suggest three alternative mechanisms by which n-3 fatty acids might have this effect. Within T-cells, as well as other cells of relevance to immune and inflammatory responses, EPA and DHA act to disrupt very early events involving formation of the structures termed lipid rafts which bring together various proteins to form an effective signalling platform. In summary, recent research has identified a number of new mechanisms of action that help to explain previously identified effects of n-3 fatty acids on inflammation and immunity.

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Correlating cellular and molecular signatures of mucosal immunity that distinguish HIV controllers from noncontrollers

Blood ◽

10.1182/blood-2009-12-257451 ◽

2010 ◽

Vol 115 (15) ◽

pp. e20-e32 ◽

Cited By ~ 29

Author(s):

P'ng Loke ◽

David Favre ◽

Peter W. Hunt ◽

Jacqueline M. Leung ◽

Bittoo Kanwar ◽

...

Keyword(s):

Flow Cytometry ◽

T Cells ◽

Expression Profiles ◽

Transcriptional Profiling ◽

Gene Expression Profiles ◽

Principal Component ◽

Immune Deficiency Syndrome ◽

Deficiency Syndrome ◽

Type I ◽

Hiv Controllers

Abstract HIV “controllers” are persons infected with human immunodeficiency virus, type I (HIV) who maintain long-term control of viremia without antiviral therapy and who usually do not develop the acquired immune deficiency syndrome (AIDS). In this study, we have correlated results from polychromatic flow cytometry and oligonucleotide expression arrays to characterize the mucosal immune responses of these subjects in relation to untreated HIV+ persons with high viral loads and progressive disease (“noncontrollers”). Paired peripheral blood and rectosigmoid biopsies were analyzed from 9 controllers and 11 noncontrollers. Several cellular immune parameters were found to be concordant between the 2 compartments. Compared with noncontrollers, the mucosal tissues of controllers had similar levels of effector T cells and fewer regulatory T cells (Tregs). Using principal component analysis to correlate immunologic parameters with gene expression profiles, transcripts were identified that accurately distinguished between controllers and noncontrollers. Direct 2-way comparison also revealed genes that are significantly different in their expression between controllers and noncontrollers, all of which had reduced expression in controllers. In addition to providing an approach that integrates flow cytometry datasets with transcriptional profiling analysis, these results underscore the importance of the sustained inflammatory response that attends progressive HIV disease.

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Whole blood genome-wide gene expression profile in males after prolonged wakefulness and sleep recovery

Physiological Genomics ◽

10.1152/physiolgenomics.00058.2012 ◽

2012 ◽

Vol 44 (21) ◽

pp. 1003-1012 ◽

Cited By ~ 24

Author(s):

R. Pellegrino ◽

D. Y. Sunaga ◽

C. Guindalini ◽

R. C. S. Martins ◽

D. R. Mazzotti ◽

...

Keyword(s):

Gene Expression ◽

Whole Blood ◽

Inflammatory Responses ◽

Expression Profiles ◽

Killer Cell ◽

Gene Expression Profiles ◽

Sleep Loss ◽

The Body ◽

Dna Damage And Repair ◽

Peripheral Tissues

Although the specific functions of sleep have not been completely elucidated, the literature has suggested that sleep is essential for proper homeostasis. Sleep loss is associated with changes in behavioral, neurochemical, cellular, and metabolic function as well as impaired immune response. Using high-resolution microarrays we evaluated the gene expression profiles of healthy male volunteers who underwent 60 h of prolonged wakefulness (PW) followed by 12 h of sleep recovery (SR). Peripheral whole blood was collected at 8 am in the morning before the initiation of PW (Baseline), after the second night of PW, and one night after SR. We identified over 500 genes that were differentially expressed. Notably, these genes were related to DNA damage and repair and stress response, as well as diverse immune system responses, such as natural killer pathways including killer cell lectin-like receptors family, as well as granzymes and T-cell receptors, which play important roles in host defense. These results support the idea that sleep loss can lead to alterations in molecular processes that result in perturbation of cellular immunity, induction of inflammatory responses, and homeostatic imbalance. Moreover, expression of multiple genes was downregulated following PW and upregulated after SR compared with PW, suggesting an attempt of the body to re-establish internal homeostasis. In silico validation of alterations in the expression of CETN3, DNAJC, and CEACAM genes confirmed previous findings related to the molecular effects of sleep deprivation. Thus, the present findings confirm that the effects of sleep loss are not restricted to the brain and can occur intensely in peripheral tissues.

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Distinct gene expression profiles provoked by polyacrylamide beads (Biogel) during chronic and acute inflammation in mice selected for maximal and minimal inflammatory responses

Inflammation Research ◽

10.1007/s00011-016-0918-1 ◽

2016 ◽

Vol 65 (4) ◽

pp. 313-323 ◽

Cited By ~ 2

Author(s):

Jussara Gonçalves Fernandes ◽

Tatiane Canhamero ◽

Andrea Borrego ◽

José Ricardo Jensen ◽

Wafa Hanna Cabrera ◽

...

Keyword(s):

Gene Expression ◽

Acute Inflammation ◽

Inflammatory Responses ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Distinct Gene

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MR Imaging Distinguishes Tumor Hypoxia Levels of Different Prognostic and Biological Significance in Cervical Cancer

10.1101/2020.05.28.20114769 ◽

2020 ◽

Author(s):

Tiril Hillestad ◽

Tord Hompland ◽

Christina S. Fjeldbo ◽

Vilde E. Skingen ◽

Unn Beate Salberg ◽

...

Keyword(s):

Cervical Cancer ◽

Epithelial To Mesenchymal Transition ◽

Inflammatory Responses ◽

Expression Profiles ◽

Tumor Hypoxia ◽

Biological Significance ◽

Gene Expression Profiles ◽

Interferon Response ◽

Moderate Hypoxia ◽

Mesenchymal Transition

AbstractTumor hypoxia levels range from mild to severe and have different biological and therapeutical consequences, but are not easily assessable in patients. We present a method based on diagnostic dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) that visualizes a continuous range of hypoxia levels in tumors of cervical cancer patients. Hypoxia images were generated using an established approach based on pixel-wise combination of the DCE-MRI parameters νe and Ktrans, reflecting oxygen consumption and supply, respectively. An algorithm to retrieve hypoxia levels from the images was developed and validated in 28 xenograft tumors, by comparing the MRI-defined levels with hypoxia levels derived from pimonidazole stained histological sections. We further established an indicator of hypoxia levels in patient tumors based on expression of nine hypoxia responsive genes. A strong correlation was found between these indicator values and the MRI-defined hypoxia levels in 63 patients. Chemoradiotherapy outcome of 74 patients was most strongly predicted by moderate hypoxia levels, whereas more severe or milder levels were less predictive. By combining gene expression profiles and MRI-defined hypoxia levels in cancer hallmark analysis, we identified a distribution of levels associated with each hallmark; oxidative phosphorylation and G2/M checkpoint were associated with moderate hypoxia, and epithelial-to-mesenchymal transition and inflammatory responses with significantly more severe levels. At the mildest levels, interferon response hallmarks, together with stabilization of HIF1A protein by immunohistochemistry, appearred significant. Thus, our method visualizes the distribution of hypoxia levels within patient tumors and has potential to distinguish levels of different prognostic and biological significance.

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Analysis of gene expression from systemic lupus erythematosus synovium reveals myeloid cell-driven pathogenesis of lupus arthritis

Scientific Reports ◽

10.1038/s41598-020-74391-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Erika L. Hubbard ◽

Michelle D. Catalina ◽

Sarah Heuer ◽

Prathyusha Bachali ◽

Robert Robl ◽

...

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Immune Cell ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Myeloid Cell ◽

Inflammatory Cells ◽

Systemic Lupus ◽

Common Manifestation

Abstract Arthritis is a common manifestation of systemic lupus erythematosus (SLE) yet understanding of the underlying pathogenic mechanisms remains incomplete. We, therefore, interrogated gene expression profiles of SLE synovium to gain insight into the nature of lupus arthritis (LA), using osteoarthritis (OA) and rheumatoid arthritis (RA) as comparators. Knee synovia from SLE, OA, and RA patients were analyzed for differentially expressed genes (DEGs) and also by Weighted Gene Co-expression Network Analysis (WGCNA) to identify modules of highly co-expressed genes. Genes upregulated and/or co-expressed in LA revealed numerous immune/inflammatory cells dominated by a myeloid phenotype, in which pathogenic macrophages, myeloid-lineage cells, and their secreted products perpetuate inflammation, whereas OA was characterized by fibroblasts and RA of lymphocytes. Genes governing trafficking of immune cells into the synovium by chemokines were identified, but not in situ generation of germinal centers (GCs). Gene Set Variation Analysis (GSVA) confirmed activation of specific immune cell types in LA. Numerous therapies were predicted to target LA, including TNF, NFκB, MAPK, and CDK inhibitors. Detailed gene expression analysis identified a unique pattern of cellular components and physiologic pathways operative in LA, as well as drugs potentially able to target this common manifestation of SLE.

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