Publications by authors named "Matthew Schaller"

68 Publications

Dysregulation of intercellular signaling by MOF deletion leads to liver injury.

J Biol Chem 2020 Dec 29. Epub 2020 Dec 29.

Medicine; Biochemistry and Molecular Medicine, University of Southern California, United States.

Epigenetic mechanisms that alter heritable gene expression and chromatin structure play an essential role in many biological processes, including liver function. Human MOF (males absent on the first) is a histone acetyltransferase that is globally downregulated in human steatohepatitis. However, the function of MOF in the liver remains unclear. Here, we report that MOF plays an essential role in adult liver. Genetic deletion of Mof by Mx1-Cre in liver leads to acute liver injury, with increase of lipid deposition and fibrosis akin to human steatohepatitis. Surprisingly, hepatocyte specific Mof deletion had no overt liver abnormality. Using the in vitro co-culturing experiment, we show that Mof deletion-induced liver injury requires coordinated changes and reciprocal signaling between hepatocytes and Kupffer cells, which enables feedforward regulation to augment inflammation and apoptotic responses. At the molecular level, Mof deletion induced characteristic changes in metabolic gene programs, which bore noticeable similarity to the molecular signature of human steatohepatitis. Simultaneous deletion of Mof in both hepatocytes and macrophages results in enhanced expression of inflammatory genes and NO signaling in vitro. These changes, in turn, lead to apoptosis of hepatocytes and lipotoxicity. Our work highlights the importance of histone acetyltransferase MOF in maintaining metabolic liver homeostasis and sheds light on the epigenetic dysregulation in liver pathogenesis.
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http://dx.doi.org/10.1074/jbc.RA120.016079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948572PMC
December 2020

NOTCH1 and DLL4 are involved in the human tuberculosis progression and immune response activation.

Tuberculosis (Edinb) 2020 09 8;124:101980. Epub 2020 Aug 8.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo - FCFRP/USP, Ribeirão Preto, São Paulo, Brazil. Electronic address:

Tuberculosis (TB) is the leading cause of mortality among infectious diseases worldwide. The study of molecular targets for therapy and diagnosis suggested that Notch signaling is an important pathway for the maintenance of the immune response during Mycobacterium tuberculosis (Mtb) infection. We evaluated the participation of the Notch pathway in the modulation of immune response during Mtb infection, and observed that patients with active TB had increased DLL4 expression in intermediate and non-classic monocytes. Further, patients with moderate and advanced lung injury have higher Notch1 expression in CD4 T cells when compared to patients with a minimal lung injury. When we considered the severity of disease in active TB patients, the expression of the DLL4 in intermediate monocytes and the expression of Notch1 in CD4 T cells are positively correlated with the degree of lung injury. In vitro, PBMCs treated with the Notch pharmacological inhibitor reduced the production of IL-17A and IL-2, whereas anti-hDLL4 treatment promoted a significant increase in TNF-α and phagocytosis. We suggest that Notch1 and DLL4 are associated with immune response activation in human tuberculosis, and can be a novel target to be exploited in the future in the searching of biomarkers.
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http://dx.doi.org/10.1016/j.tube.2020.101980DOI Listing
September 2020

Pneumococcal conjugate vaccine modulates macrophage-mediated innate immunity in pneumonia caused by Streptococcus pneumoniae following influenza.

Microbes Infect 2020 09 17;22(8):312-321. Epub 2020 Jan 17.

Department of Microbiology and Infectious Diseases, Faculty of Medicine, Toho University Graduate School of Medicine, Tokyo, 143-8540, Japan.

Pneumococcal conjugate vaccination (PCV) may prevent influenza-related pneumonia, including Streptococcus pneumoniae pneumonia. To investigate PCV efficacy against secondary pneumococcal pneumonia following influenza, PCV was administered intramuscularly 2 and 5 weeks before S. pneumoniae serotype-3 colonization of murine nasopharynges followed by intranasal challenge with a sublethal dose of influenza A virus. Bacterial and viral loads, including innate immune responses were compared across conditions. PCV vaccination improved the survival of mice with secondary pneumococcal pneumonia and significantly reduced the pulmonary bacterial burden. Increased monocyte/macrophage influx into the lungs, alleviated loss of alveolar macrophages and decreased neutrophil influx into the lungs occurred in PCV-treated mice irrespective of pneumococcal colonization. Higher monocyte chemoattractant protein 1 levels and lower levels of CXCL1, interferon-γ, interleukin-17A, and IL-10, were detected in PCV-treated mice. Additionally, PCV treatment activated the macrophage intracellular killing of S. pneumoniae. Collectively, PCV potentially modulates the host's innate immunity and specific antibodies induction. Macrophage-related innate immunity should be further explored to elucidate the efficacy and mechanisms of PCV versus influenza-related life-threatening diseases.
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http://dx.doi.org/10.1016/j.micinf.2019.12.005DOI Listing
September 2020

Ly6CLo Monocyte/Macrophages are Essential for Thrombus Resolution in a Murine Model of Venous Thrombosis.

Thromb Haemost 2020 Feb 30;120(2):289-299. Epub 2019 Dec 30.

Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan, Ann Arbor, Michigan, United States.

Venous thrombosis (VT) resolution is a complex process, resembling sterile wound healing. Infiltrating blood-derived monocyte/macrophages (Mo/MΦs) are essential for the regulation of inflammation in tissue repair. These cells differentiate into inflammatory (CD11bLy6C) or proreparative (CD11bLy6C) subtypes. Previous studies have shown that infiltrating Mo/MΦs are important for VT resolution, but the precise roles of different Mo/MΦs subsets are not well understood. Utilizing murine models of stasis and stenosis inferior vena cava thrombosis in concert with a Mo/MΦ depletion model (CD11b-diphtheria toxin receptor [DTR]-expressing mice), we examined the effect of Mo/MΦ depletion on thrombogenesis and VT resolution. In the setting of an 80 to 90% reduction in circulating CD11bMo/MΦs, we demonstrated that Mo/MΦs are not essential for thrombogenesis, with no difference in thrombus size, neutrophil recruitment, or neutrophil extracellular traps found. Conversely, CD11bMo/MΦ are essential for VT resolution. Diphtheria toxoid (DTx)-mediated depletion after thrombus creation depleted primarily CD11bLy6C Mo/MΦs and resulted in larger thrombi. DTx-mediated depletion did not alter CD11bLy6C Mo/MΦ recruitment, suggesting a protective effect of CD11bLy6C Mo/MΦs in VT resolution. Confirmatory Mo/MΦ depletion with clodronate lysosomes showed a similar phenotype, with failure to resolve VT. Adoptive transfer of CD11bLy6C Mo/MΦs into Mo/MΦ-depleted mice reversed the phenotype, restoring normal thrombus resolution. These findings suggest that CD11bLy6C Mo/MΦs are essential for normal VT resolution, consistent with the known proreparative function of this subset, and that further study of Mo/MΦ subsets may identify targets for immunomodulation to accelerate and improve thrombosis resolution.
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http://dx.doi.org/10.1055/s-0039-3400959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365023PMC
February 2020

Upregulation of H3K27 Demethylase KDM6 During Respiratory Syncytial Virus Infection Enhances Proinflammatory Responses and Immunopathology.

J Immunol 2020 01 20;204(1):159-168. Epub 2019 Nov 20.

Department of Pathology, University of Michigan, Ann Arbor, MI 48109;

Severe disease following respiratory syncytial virus (RSV) infection has been linked to enhanced proinflammatory cytokine production that promotes a Th2-type immune environment. Epigenetic regulation in immune cells following viral infection plays a role in the inflammatory response and may result from upregulation of key epigenetic modifiers. In this study, we show that RSV-infected bone marrow-derived dendritic cells (BMDC) as well as pulmonary dendritic cells (DC) from RSV-infected mice upregulated the expression of and , H3K27 demethylases. KDM6-specific chemical inhibition (GSK J4) in BMDC led to decreased production of chemokines and cytokines associated with the inflammatory response during RSV infection (i.e., CCL-2, CCL-3, CCL-5, IL-6) as well as decreased MHC class II and costimulatory marker (CD80/86) expression. RSV-infected BMDC treated with GSK J4 altered coactivation of T cell cytokine production to RSV as well as a primary OVA response. Airway sensitization of naive mice with RSV-infected BMDCs exacerbate a live challenge with RSV infection but was inhibited when BMDCs were treated with GSK J4 prior to sensitization. Finally, in vivo treatment with the KDM6 inhibitor, GSK J4, during RSV infection reduced inflammatory DC in the lungs along with IL-13 levels and overall inflammation. These results suggest that KDM6 expression in DC enhances proinflammatory innate cytokine production to promote an altered Th2 immune response following RSV infection that leads to more severe immunopathology.
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http://dx.doi.org/10.4049/jimmunol.1900741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920528PMC
January 2020

Inhibition of the stem cell factor 248 isoform attenuates the development of pulmonary remodeling disease.

Am J Physiol Lung Cell Mol Physiol 2020 01 20;318(1):L200-L211. Epub 2019 Nov 20.

Department of Pathology, University of Michigan, Ann Arbor, Michigan.

Stem cell factor (SCF) and its receptor c-kit have been implicated in inflammation, tissue remodeling, and fibrosis. Ingenuity Integrated Pathway Analysis of gene expression array data sets showed an upregulation of SCF transcripts in idiopathic pulmonary fibrosis (IPF) lung biopsies compared with tissue from nonfibrotic lungs that are further increased in rapid progressive disease. SCF248, a cleavable isoform of SCF, was abundantly and preferentially expressed in human lung fibroblasts and fibrotic mouse lungs relative to the SCF220 isoform. In fibroblast-mast cell coculture studies, blockade of SCF248 using a novel isoform-specific anti-SCF248 monoclonal antibody (anti-SCF248), attenuated the expression of , and transcripts in cocultured IPF but not normal lung fibroblasts. Administration of anti-SCF248 on days 8 and 12 after bleomycin instillation in mice significantly reduced fibrotic lung remodeling and , , and transcript expression. In addition, bleomycin increased numbers of c-kit+ mast cells, eosinophils, and ILC2 in lungs of mice, whereas they were not significantly increased in anti-SCF248-treated animals. Finally, mesenchymal cell-specific deletion of SCF significantly attenuated bleomycin-mediated lung fibrosis and associated fibrotic gene expression. Collectively, these data demonstrate that SCF is upregulated in diseased IPF lungs and blocking SCF248 isoform significantly ameliorates fibrotic lung remodeling in vivo suggesting that it may be a therapeutic target for fibrotic lung diseases.
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http://dx.doi.org/10.1152/ajplung.00114.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985874PMC
January 2020

Sepsis Induces Prolonged Epigenetic Modifications in Bone Marrow and Peripheral Macrophages Impairing Inflammation and Wound Healing.

Arterioscler Thromb Vasc Biol 2019 11 5;39(11):2353-2366. Epub 2019 Sep 5.

From the Section of Vascular Surgery, Department of Surgery (F.M.D., A.D., A.D.J., A.S.K., A.T.O., W.J.M., K.A.G.), University of Michigan, Ann Arbor.

Objective: Sepsis represents an acute life-threatening disorder resulting from a dysregulated host response. For patients who survive sepsis, there remains long-term consequences, including impaired inflammation, as a result of profound immunosuppression. The mechanisms involved in this long-lasting deficient immune response are poorly defined. Approach and Results: Sepsis was induced using the murine model of cecal ligation and puncture. Following a full recovery period from sepsis physiology, mice were subjected to our wound healing model and wound macrophages (CD11b+, CD3-, CD19-, Ly6G-) were sorted. Post-sepsis mice demonstrated impaired wound healing and decreased reepithelization in comparison to controls. Further, post-sepsis bone marrow-derived macrophages and wound macrophages exhibited decreased expression of inflammatory cytokines vital for wound repair (IL [interleukin]-1β, IL-12, and IL-23). To evaluate if decreased inflammatory gene expression was secondary to epigenetic modification, we conducted chromatin immunoprecipitation on post-sepsis bone marrow-derived macrophages and wound macrophages. This demonstrated decreased expression of , an epigenetic enzyme, and impaired histone 3 lysine 4 trimethylation (activation mark) at NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells)-binding sites on inflammatory gene promoters in bone marrow-derived macrophages and wound macrophages from postcecal ligation and puncture mice. Bone marrow transplantation studies demonstrated epigenetic modifications initiate in bone marrow progenitor/stem cells following sepsis resulting in lasting impairment in peripheral macrophage function. Importantly, human peripheral blood leukocytes from post-septic patients demonstrate a significant reduction in compared with nonseptic controls.

Conclusions: These data demonstrate that severe sepsis induces stable mixed-lineage leukemia 1-mediated epigenetic modifications in the bone marrow, which are passed to peripheral macrophages resulting in impaired macrophage function and deficient wound healing persisting long after sepsis recovery.
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http://dx.doi.org/10.1161/ATVBAHA.119.312754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818743PMC
November 2019

Formyl peptide receptor 2 regulates monocyte recruitment to promote intestinal mucosal wound repair.

FASEB J 2019 12 4;33(12):13632-13643. Epub 2019 Oct 4.

Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.

Mucosal wound repair is coordinated by dynamic crosstalk between endogenous and exogenous mediators and specific receptors on epithelial cells and infiltrating immune cells. One class of such receptor-ligand pairs involves formyl peptide receptors (FPRs) that have been shown to influence inflammatory response and repair. Here we explored the role of murine Fpr2/3, an ortholog of human FPR2/receptor for lipoxin A4 (ALX), in orchestrating intestinal mucosal repair. Compared with wild-type (WT) mice, mice exhibited delayed recovery from acute experimental colitis and perturbed repair after biopsy-induced colonic mucosal injury. Decreased numbers of infiltrating monocytes were observed in healing wounds from mice compared with WT animals. Bone marrow transplant experiments revealed that monocytes showed a competitive disadvantage when infiltrating colonic wounds. Moreover, monocytes were defective in chemotactic responses to the chemokine CC chemokine ligand (CCL)20, which is up-regulated during early phases of inflammation. Analysis of monocytes revealed altered expression of the CCL20 receptor CC chemokine receptor (CCR)6, suggesting that Fpr2/3 regulates CCL20-CCR6-mediated monocyte chemotaxis to sites of mucosal injury in the gut. These findings demonstrate an important contribution of Fpr2/3 in facilitating monocyte recruitment to sites of mucosal injury to influence wound repair.-Birkl, D., O'Leary, M. N., Quiros, M., Azcutia, V., Schaller, M., Reed, M., Nishio, H., Keeney, J., Neish, A. S., Lukacs, N. W., Parkos, C. A., Nusrat, A. Formyl peptide receptor 2 regulates monocyte recruitment to promote intestinal mucosal wound repair.
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http://dx.doi.org/10.1096/fj.201901163RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894067PMC
December 2019

The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair.

Immunity 2019 08 23;51(2):258-271.e5. Epub 2019 Jul 23.

Department of Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Macrophage plasticity is critical for normal tissue repair to ensure transition from the inflammatory to the proliferative phase of healing. We examined macrophages isolated from wounds of patients afflicted with diabetes and of healthy controls and found differential expression of the methyltransferase Setdb2. Myeloid-specific deletion of Setdb2 impaired the transition of macrophages from an inflammatory phenotype to a reparative one in normal wound healing. Mechanistically, Setdb2 trimethylated histone 3 at NF-κB binding sites on inflammatory cytokine gene promoters to suppress transcription. Setdb2 expression in wound macrophages was regulated by interferon (IFN) β, and under diabetic conditions, this IFNβ-Setdb2 axis was impaired, leading to a persistent inflammatory macrophage phenotype in diabetic wounds. Setdb2 regulated the expression of xanthine oxidase and thereby the uric acid (UA) pathway of purine catabolism in macrophages, and pharmacologic targeting of Setdb2 or the UA pathway improved healing. Thus, Setdb2 regulates macrophage plasticity during normal and pathologic wound repair and is a target for therapeutic manipulation.
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http://dx.doi.org/10.1016/j.immuni.2019.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703945PMC
August 2019

SIRT3 Regulates Macrophage-Mediated Inflammation in Diabetic Wound Repair.

J Invest Dermatol 2019 12 15;139(12):2528-2537.e2. Epub 2019 Jun 15.

Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA. Electronic address:

Control of inflammation is critical for the treatment of nonhealing wounds, but a delicate balance exists between early inflammation that is essential for normal tissue repair and the pathologic inflammation that can occur later in the repair process. This necessitates the development of novel therapies that can target inflammation at the appropriate time during repair. Here, we found that SIRT3 is essential for normal healing and regulates inflammation in wound macrophages after injury. Under prediabetic conditions, SIRT3 was decreased in wound macrophages and resulted in dysregulated inflammation. In addition, we found that FABP4 regulates SIRT3 in human blood monocytes, and inhibition of FABP4 in wound macrophages decreases inflammatory cytokine expression, making FABP4 a viable target for the regulation of excess inflammation and wound repair in diabetes. Using a series of ex vivo and in vivo studies with genetically engineered mouse models and diabetic human monocytes, we showed that FABP4 expression is epigenetically upregulated in diabetic wound macrophages and, in turn, diminishes SIRT3 expression, thereby promoting inflammation. These findings have significant implications for controlling inflammation and promoting tissue repair in diabetic wounds.
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http://dx.doi.org/10.1016/j.jid.2019.05.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185380PMC
December 2019

The Role of Iron in the Susceptibility of Neonatal Mice to Escherichia coli K1 Sepsis.

J Infect Dis 2019 08;220(7):1219-1229

Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Michigan Medicine, Ann Arbor.

Sepsis from Escherichia coli expressing the K1 antigen is a leading cause of death in neonates. In a murine model, E. coli K1 grew rapidly in the peritoneal cavity of neonatal mice, causing fatal disease. In contrast, adult mice cleared the infection. Neonatal mice mounted a rapid and equivalent antimicrobial immune response compared to adult mice. Interestingly, peritoneal fluid from neonatal mice contained significantly more total iron than that of adult mice, which was sufficient to support enhanced E. coli growth. Transient iron overload in adult mice infected with E. coli resulted in 100% mortality. Maternal diet-induced mild iron deficiency decreased offspring peritoneal iron, decreased bacterial growth, and conferred protection against sepsis. Taken together, neonatal susceptibility to E. coli K1 sepsis is enhanced by a localized excess of peritoneal iron that allows for unchecked bacterial growth. Targeting this excess iron may provide a new therapeutic target in human patients.
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http://dx.doi.org/10.1093/infdis/jiz282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325330PMC
August 2019

Chorioamnionitis exposure remodels the unique histone modification landscape of neonatal monocytes and alters the expression of immune pathway genes.

FEBS J 2019 01 22;286(1):82-109. Epub 2018 Dec 22.

Department of Pathology, Michigan Medicine, Ann Arbor, MI, USA.

Chorioamnionitis is an intrauterine infection involving inflammation of the chorion, amnion, and placenta. It leads to a fetal systemic inflammatory response that can alter the transcription of neonatal immune genes. We have previously shown that neonatal monocytes gain the activating histone tail modification H3K4me3 at promoter sites of immunologically important genes as development progresses from preterm neonate to adult. In this study, we applied ChIP-seq and RNA-seq to evaluate the impact of chorioamnionitis on the neonatal monocyte H3K4me3 histone modification landscape over the course of fetal and neonatal immune system development. Chorioamnionitis exposure in neonatal monocytes resulted in a net increase in total monocyte H3K4me3, primarily in introns and intergenic regions. Immune gene expression was decreased in chorioamnionitis-exposed monocytes, with the majority of enriched transcripts falling into pathways that are not linked to the immune system. Over half of all neonatal monocyte H3K4me3 peaks, independent of their location, were associated with active gene transcription. Overall, chorioamnionitis exposure resulted in the global remodeling of the neonatal monocyte H3K4me3 landscape and changes in the expression of known immune genes. These changes resulted in a less robust inflammatory response upon exposure to a secondary challenge, which may explain why chorioamnionitis-exposed neonates have an increased risk of sepsis. DATABASE: ChIP-seq data for U30/O30/Term: GEO GSE81957 ChIP-seq data for U30C/O30C/TermC: GEO GSE111873 RNA-seq data for U/L/CU/CL: GEO GSE111927.
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http://dx.doi.org/10.1111/febs.14728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326865PMC
January 2019

Notch ligand Delta-like 4 induces epigenetic regulation of Treg cell differentiation and function in viral infection.

Mucosal Immunol 2018 09 23;11(5):1524-1536. Epub 2018 Jul 23.

Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.

Notch ligand Delta-like ligand 4 (DLL4) has been shown to regulate CD4 T-cell differentiation, including regulatory T cells (T). Epigenetic alterations, which include histone modifications, are critical in cell differentiation decisions. Recent genome-wide studies demonstrated that T have increased trimethylation on histone H3 at lysine 4 (H3K4me3) around the T master transcription factor, Foxp3 loci. Here we report that DLL4 dynamically increased H3K4 methylation around the Foxp3 locus that was dependent upon upregulated SET and MYDN domain containing protein 3 (SMYD3). DLL4 promoted Smyd3 through the canonical Notch pathway in iT differentiation. DLL4 inhibition during pulmonary respiratory syncytial virus (RSV) infection decreased Smyd3 expression and Foxp3 expression in T leading to increased Il17a. On the other hand, DLL4 supported Il10 expression in vitro and in vivo, which was also partially dependent upon SMYD3. Using genome-wide unbiased mRNA sequencing, novel sets of DLL4- and Smyd3-dependent differentially expressed genes were discovered, including lymphocyte-activation gene 3 (Lag3), a checkpoint inhibitor that has been identified for modulating Th cell activation. Together, our data demonstrate a novel mechanism of DLL4/Notch-induced Smyd3 epigenetic pathways that maintain regulatory CD4 T cells in viral infections.
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http://dx.doi.org/10.1038/s41385-018-0052-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160345PMC
September 2018

Chorioamnionitis exposure dampens the preterm monocyte response to subsequent challenges.

Immunol Cell Biol 2018 09 21;96(8):789-791. Epub 2018 Jun 21.

Department of Pathology, Michigan Medicine, 4710 BSRB, 109 Zina Pitcher Drive, Ann Arbor, MI, 48109-2200, USA.

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http://dx.doi.org/10.1111/imcb.12174DOI Listing
September 2018

Ly6C Blood Monocyte/Macrophage Drive Chronic Inflammation and Impair Wound Healing in Diabetes Mellitus.

Arterioscler Thromb Vasc Biol 2018 05 1;38(5):1102-1114. Epub 2018 Mar 1.

From the Department of Surgery (A.K., A.J., F.M.D., A.D., A.B., A.O., P.K.H., K.A.G.)

Objective: Wound monocyte-derived macrophage plasticity controls the initiation and resolution of inflammation that is critical for proper healing, however, in diabetes mellitus, the resolution of inflammation fails to occur. In diabetic wounds, the kinetics of blood monocyte recruitment and the mechanisms that control in vivo monocyte/macrophage differentiation remain unknown.

Approach And Results: Here, we characterized the kinetics and function of Ly6C [Lin (CD3CD19NK1.1Ter-119) Ly6GCD11b] and Ly6C [Lin (CD3CD19NK1.1Ter-119) Ly6GCD11b] monocyte/macrophage subsets in normal and diabetic wounds. Using flow-sorted -labeled Ly6C monocyte/macrophages, we show Ly6C cells transition to a Ly6C phenotype in normal wounds, whereas in diabetic wounds, there is a late, second influx of Ly6C cells that fail transition to Ly6C. The second wave of Ly6C cells in diabetic wounds corresponded to a spike in MCP-1 (monocyte chemoattractant protein-1) and selective administration of anti-MCP-1 reversed the second Ly6C influx and improved wound healing. To examine the in vivo phenotype of wound monocyte/macrophages, RNA-seq-based transcriptome profiling was performed on flow-sorted Ly6C [LinLy6GCD11b] and Ly6C [LinLy6GCD11b] cells from normal and diabetic wounds. Gene transcriptome profiling of diabetic wound Ly6C cells demonstrated differences in proinflammatory and profibrotic genes compared with controls.

Conclusions: Collectively, these data identify kinetic and functional differences in diabetic wound monocyte/macrophages and demonstrate that selective targeting of CD11bLy6C monocyte/macrophages is a viable therapeutic strategy for inflammation in diabetic wounds.
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http://dx.doi.org/10.1161/ATVBAHA.118.310703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920725PMC
May 2018

The STAT4/MLL1 Epigenetic Axis Regulates the Antimicrobial Functions of Murine Macrophages.

J Immunol 2017 09 21;199(5):1865-1874. Epub 2017 Jul 21.

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.

Macrophages are critical immune cells for the clearance of microbial pathogens and cellular debris from peripheral tissues. Macrophage inflammatory responses are governed by gene expression patterns, and these patterns are often subject to epigenetic control. Chromatin modifications, such as histone methylation, regulate gene accessibility in macrophages, and macrophage polarization is governed in part by the expression and function of chromatin-modifying enzymes. The histone methyltransferase mixed-lineage leukemia 1 (MLL1) preferentially modifies lysine residue 4 on the unstructured protein tail of histone H3. MLL1 expression and function have been shown to be governed by signal transduction pathways that are activated by inflammatory stimuli, such as NF-κB. Therefore, we sought to investigate the role of MLL1 in mediating macrophage inflammatory responses. Bone marrow-derived macrophages from mice with a targeted MLL1 gene knockout (Lys2-Cre MLL1) exhibited decreased proinflammatory gene expression with concurrent decreases in activating histone methylation. However, MLL1-deficient macrophages also exhibited increased phagocytic and bacterial killing activity in vitro. RNA profiling of MLL1-knockout macrophages identified numerous genes involved with inflammatory responses whose expression was altered in response to TLR ligands or proinflammatory cytokines, including STAT4. STAT4-dependent cytokines, such as type I IFNs were able to drive MLL1 expression in macrophages, and MLL1-knockout macrophages exhibited decreased activating histone methylation in the STAT4 promoter. These results implicate an important role for MLL1-dependent epigenetic regulation of macrophage antimicrobial functions.
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http://dx.doi.org/10.4049/jimmunol.1601272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568492PMC
September 2017

The Histone Methyltransferase MLL1 Directs Macrophage-Mediated Inflammation in Wound Healing and Is Altered in a Murine Model of Obesity and Type 2 Diabetes.

Diabetes 2017 09 29;66(9):2459-2471. Epub 2017 Jun 29.

Department of Surgery, University of Michigan, Ann Arbor, MI

Macrophages are critical for the initiation and resolution of the inflammatory phase of wound repair. In diabetes, macrophages display a prolonged inflammatory phenotype in late wound healing. Mixed-lineage leukemia-1 (MLL1) has been shown to direct gene expression by regulating nuclear factor-κB (NF-κB)-mediated inflammatory gene transcription. Thus, we hypothesized that MLL1 influences macrophage-mediated inflammation in wound repair. We used a myeloid-specific knockout ( ) to determine the function of MLL1 in wound healing. mice display delayed wound healing and decreased wound macrophage inflammatory cytokine production compared with control animals. Furthermore, wound macrophages from mice demonstrated decreased histone H3 lysine 4 trimethylation (H3K4me3) (activation mark) at NF-κB binding sites on inflammatory gene promoters. Of note, early wound macrophages from prediabetic mice displayed similarly decreased MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines compared with controls. Late wound macrophages from prediabetic mice demonstrated an increase in MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines. Prediabetic macrophages treated with an MLL1 inhibitor demonstrated reduced inflammation. Finally, monocytes from patients with type 2 diabetes had increased compared with control subjects without diabetes. These results define an important role for MLL1 in regulating macrophage-mediated inflammation in wound repair and identify a potential target for the treatment of chronic inflammation in diabetic wounds.
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http://dx.doi.org/10.2337/db17-0194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566299PMC
September 2017

Notch Regulates Macrophage-Mediated Inflammation in Diabetic Wound Healing.

Front Immunol 2017 1;8:635. Epub 2017 Jun 1.

Department of Surgery, University of Michigan, Ann Arbor, MI, United States.

Macrophages are essential immune cells necessary for regulated inflammation during wound healing. Recent studies have identified that Notch plays a role in macrophage-mediated inflammation. Thus, we investigated the role of Notch signaling on wound macrophage phenotype and function during normal and diabetic wound healing. We found that Notch receptor and ligand expression are dynamic in wound macrophages during normal healing. Mice with a myeloid-specific Notch signaling defect ( ) demonstrated delayed early healing (days 1-3) and wound macrophages had decreased inflammatory gene expression. In our physiologic murine model of type 2 diabetes (T2D), Notch receptor expression was significantly increased in wound macrophages on day 6, following the initial inflammatory phase of wound healing, corresponding to increased inflammatory cytokine expression. This increase in and was also observed in human monocytes from patients with T2D. Further, in prediabetic mice with a genetic Notch signaling defect ( on a high-fat diet), improved wound healing was seen at late time points (days 6-7). These findings suggest that Notch is critical for the early inflammatory phase of wound healing and directs production of macrophage-dependent inflammatory mediators. These results identify that canonical Notch signaling is important in directing macrophage function in wound repair and define a translational target for the treatment of non-healing diabetic wounds.
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http://dx.doi.org/10.3389/fimmu.2017.00635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451506PMC
June 2017

Paralogous Genes Modulate Th2 Cell Function during Chronic Allergic Inflammation via Regulation of .

J Immunol 2017 07 2;199(2):501-509. Epub 2017 Jun 2.

Department of Pathology, University of Michigan, Ann Arbor, MI 48109; and.

Allergic asthma is a significant health burden in western countries, and continues to increase in prevalence. Th2 cells contribute to the development of disease through release of the cytokines IL-4, IL-5, and IL-13, resulting in increased airway eosinophils and mucus hypersecretion. The molecular mechanisms behind the disease pathology remain largely unknown. In this study we investigated a potential regulatory role for the gene family, , , and , genes known to be important in lung development within mesenchymal cell populations. We found that -mutant mice show exacerbated pathology compared with wild-type controls in a chronic allergen model, with an increased Th2 response and exacerbated lung tissue pathology. Bone marrow chimera experiments indicated that the observed enhanced pathology was mediated by immune cell function independent of mesenchymal cell Hox5 family function. Examination of T cells grown in Th2 polarizing conditions showed increased proliferation, enhanced expression, and elevated production of IL-4, IL-5, and IL-13 in -deficient T cells compared with wild-type controls. Overexpression of FLAG-tagged HOX5 proteins in Jurkat cells demonstrated HOX5 binding to the locus and decreased and IL-4 expression, supporting a role for HOX5 proteins in direct transcriptional control of Th2 development. These results reveal a novel role for genes as developmental regulators of Th2 immune cell function that demonstrates a redeployment of mesenchyme-associated developmental genes.
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http://dx.doi.org/10.4049/jimmunol.1601826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508748PMC
July 2017

Histone methylation is critical in monocyte to macrophage differentiation.

FEBS J 2017 05;284(9):1306-1308

Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI, USA.

Monocyte derived macrophages contribute to many human diseases, and a prescribed set of transcription factors control the differentiation of monocytes into macrophages. In this issue of The FEBS Journal, Jin and colleagues demonstrate that histone methylation changes in monocytes alter chromatin structure and ultimately direct the expression of numerous transcription factors crucial in this differentiation process.
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http://dx.doi.org/10.1111/febs.14074DOI Listing
May 2017

Notch Ligand Delta-like 4 Promotes Regulatory T Cell Identity in Pulmonary Viral Infection.

J Immunol 2017 02 11;198(4):1492-1502. Epub 2017 Jan 11.

Department of Pathology, University of Michigan, Ann Arbor, MI 48109;

Regulatory T (T) cells establish tolerance, prevent inflammation at mucosal surfaces, and regulate immunopathology during infectious responses. Recent studies have shown that Delta-like ligand 4 (Dll4) was upregulated on APC after respiratory syncytial virus (RSV) infection, and its inhibition leads to exaggerated immunopathology. In the present study, we outline the role of Dll4 in T cell differentiation, stability, and function in RSV infection. We found that Dll4 was expressed on CD11b pulmonary dendritic cells in the lung and draining lymph nodes in wild-type BALB/c mice after RSV infection. Dll4 neutralization exacerbated RSV-induced disease pathology, mucus production, group 2 innate lymphoid cell infiltration, IL-5 and IL-13 production, as well as IL-17A CD4 T cells. Dll4 inhibition decreased the abundance of CD62LCD44Foxp3 central T cells in draining lymph nodes. The RSV-induced disease was accompanied by an increase in Th17-like effector phenotype in Foxp3 T cells and a decrease in granzyme B expression after Dll4 blockade. Finally, Dll4-exposed induced T cells maintained the CD62LCD44 central T cell phenotype, had increased Foxp3 expression, became more suppressive, and were resistant to Th17 skewing in vitro. These results suggest that Dll4 activation during differentiation sustained T cell phenotype and function to control RSV infection.
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http://dx.doi.org/10.4049/jimmunol.1601654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296281PMC
February 2017

IL-17RB granulocytes are associated with airflow obstruction in asthma.

Ann Allergy Asthma Immunol 2016 12;117(6):674-679

Division of Allergy and Immunology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan. Electronic address:

Background: Interleukin (IL)-25 (IL-17E) is a proinflammatory cytokine that plays an important role in the T-helper type 2 cell pathway. The effects of IL-25 are mediated by its specific receptor, IL-17RB. Previous studies have defined an IL-17RB granulocyte population known as type 2 myeloid (T2M) cells that express T-helper type 2 cell cytokines. The correlation of IL-17RB granulocytes, T2M cells, and asthma parameters is unknown.

Objective: To investigate the relation of IL-17RB granulocytes (and its subset, T2M cells) in patients with asthma with clinical parameters including spirometric values and the Asthma Control Test (ACT).

Methods: Peripheral blood from subjects with asthma and healthy controls was collected and analyzed by flow cytometry. Granulocytes were gated for IL-17RB, T2M (CD11bCD16CD177IL-17RB), and eosinophil (CD16) populations. Spirometry testing was performed on subjects with asthma. ACT scores and medical histories were collected by questionnaire and chart review. Correlations of IL-17RB cells and T2M cells with spirometry and ACT score were analyzed.

Results: Percentages of IL-17RB granulocytes and T2M cells were larger in subjects with asthma than in controls. Furthermore, percentages of the 2 cell populations were negatively correlated with degree of airway obstruction as measured by the ratio of percentage-predicted forced expiratory volume in 1 second to force vital capacity (r = -0.17, P = .043 for IL-17RB granulocytes; r = -0.32, P = .03 for T2M cells). There was no correlation with ACT score. The percentage of eosinophils was increased in subjects with asthma. However, IL-17RB eosinophil percentages were similar between subjects with asthma and controls and did not correlate with any clinical parameter.

Conclusion: IL-17RB granulocytes and T2M cells from peripheral blood were increased in subjects with asthma, and the 2 cell types correlated with degree of airflow obstruction.
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http://dx.doi.org/10.1016/j.anai.2016.09.448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5172383PMC
December 2016

Systemic Expression of Notch Ligand Delta-Like 4 during Mycobacterial Infection Alters the T Cell Immune Response.

Front Immunol 2016 24;7:527. Epub 2016 Nov 24.

Department of Pathology, University of Michigan Medical School , Ann Arbor, MI , USA.

The Notch ligand delta-like 4 (DLL4) is known to fine-tune the CD4 T cell cytokine response. DLL4 is expressed on the surface of antigen-presenting cells (APCs) in a MyD88-dependent manner. We found that DLL4 expression was upregulated on bone marrow progenitor cells and APCs in mice infected with BCG . Transfer of DLL4 progenitor cells from infected hosts resulted in an increase DLL4 myeloid cells in the spleen, indicating that expression of the gene is propagated throughout hematopoiesis. We also found an increase in DLL4 monocytes from individuals who were infected with . In latent individuals, DLL4 expression correlated with increased cytokine production from T cells in response to PPD stimulation. Finally, antibody blockade of DLL4 reduced T cell cytokine production from naïve T cells stimulated with antigen. These results demonstrate that the Notch ligand DLL4 can influence T cell cytokine production in both humans and mice, and further reveal that expression of DLL4 is upregulated on early hematopoietic progenitors in response to chronic mycobacterial infection. These data suggest that widespread DLL4 expression may occur as a result of mycobacterial infection, and that this expression may alter CD4 T cell responses to both previously encountered and novel antigens.
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http://dx.doi.org/10.3389/fimmu.2016.00527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121470PMC
November 2016

Neonatal monocytes exhibit a unique histone modification landscape.

Clin Epigenetics 2016 20;8:99. Epub 2016 Sep 20.

Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI 48109 USA.

Background: Neonates have dampened expression of pro-inflammatory cytokines and difficulty clearing pathogens. This makes them uniquely susceptible to infections, but the factors regulating neonatal-specific immune responses are poorly understood. Epigenetics, including histone modifications, can activate or silence gene transcription by modulating chromatin structure and stability without affecting the DNA sequence itself and are potentially modifiable. Histone modifications are known to regulate immune cell differentiation and function in adults but have not been well studied in neonates.

Results: To elucidate the role of histone modifications in neonatal immune function, we performed chromatin immunoprecipitation on mononuclear cells from 45 healthy neonates (gestational ages 23-40 weeks). As gestation approached term, there was increased activating H3K4me3 on the pro-inflammatory , , , and cytokine promoters ( < 0.01) with no change in repressive H3K27me3, suggesting that these promoters in preterm neonates are less open and accessible to transcription factors than in term neonates. Chromatin immunoprecipitation with massively parallel DNA sequencing (ChIP-seq) was then performed to establish the H3K4me3, H3K9me3, H3K27me3, H3K4me1, H3K27ac, and H3K36me3 landscapes in neonatal and adult CD14+ monocytes. As development progressed from neonate to adult, monocytes lost the poised enhancer mark H3K4me1 and gained the activating mark H3K4me3, without a change in additional histone modifications. This decreased H3K4me3 abundance at immunologically important neonatal monocyte gene promoters, including , , , , and was associated with reduced gene expression.

Conclusions: These results provide evidence that neonatal immune cells exist in an epigenetic state that is distinctly different from adults and that this state contributes to neonatal-specific immune responses that leaves them particularly vulnerable to infections.
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http://dx.doi.org/10.1186/s13148-016-0265-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028999PMC
April 2017

Identification of promising plasma immune biomarkers to differentiate active pulmonary tuberculosis.

Cytokine 2016 12 31;88:99-107. Epub 2016 Aug 31.

Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP, Brazil. Electronic address:

Although much research has been done related to biomarker discovery for tuberculosis infection, a set of biomarkers that can discriminate between active and latent TB diseases remains elusive. In the current study we correlate clinical aspects of TB disease with changes in the immune response as determined by biomarkers detected in plasma. Our study measured 18 molecules in human plasma in 17 patients with active disease (APTB), 14 individuals with latent tuberculosis infection (LTBI) and 16 uninfected controls (CTRL). We found that active tuberculosis patients have increased plasma levels of IL-6, IP-10, TNF-α, sCD163 and sCD14. Statistical analysis of these biomarkers indicated that simultaneous measurement of sCD14 and IL-6 was able to diagnose active tuberculosis infection with 83% accuracy. We also demonstrated that TNF-α and sCD163 were correlated with tuberculosis severity. We showed that the simultaneous detection of both plasma sCD14 and IL-6 is a promising diagnostic approach to identify APTB, and further, measurement of TNF-α and sCD163 can identify the most severe cases of tuberculosis.
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http://dx.doi.org/10.1016/j.cyto.2016.08.030DOI Listing
December 2016

Type I Interferon Induced Epigenetic Regulation of Macrophages Suppresses Innate and Adaptive Immunity in Acute Respiratory Viral Infection.

PLoS Pathog 2015 Dec 28;11(12):e1005338. Epub 2015 Dec 28.

Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States of America.

Influenza A virus (IAV) is an airborne pathogen that causes significant morbidity and mortality each year. Macrophages (Mϕ) are the first immune population to encounter IAV virions in the lungs and are required to control infection. In the present study, we explored the mechanism by which cytokine signaling regulates the phenotype and function of Mϕ via epigenetic modification of chromatin. We have found that type I interferon (IFN-I) potently upregulates the lysine methyltransferase Setdb2 in murine and human Mϕ, and in turn Setdb2 regulates Mϕ-mediated immunity in response to IAV. The induction of Setdb2 by IFN-I was significantly impaired upon inhibition of the JAK-STAT signaling cascade, and chromatin immunoprecipitation revealed that both STAT1 and interferon regulatory factor 7 bind upstream of the transcription start site to induce expression. The generation of Setdb2LacZ reporter mice revealed that IAV infection results in systemic upregulation of Setdb2 in myeloid cells. In the lungs, alveolar Mϕ expressed the highest level of Setdb2, with greater than 70% lacZ positive on day 4 post-infection. Silencing Setdb2 activity in Mϕ in vivo enhanced survival in lethal IAV infection. Enhanced host protection correlated with an amplified antiviral response and less obstruction to the airways. By tri-methylating H3K9, Setdb2 silenced the transcription of Mx1 and Isg15, antiviral effectors that inhibit IAV replication. Accordingly, a reduced viral load in knockout mice on day 8 post-infection was linked to elevated Isg15 and Mx1 transcript in the lungs. In addition, Setdb2 suppressed the expression of a large number of other genes with proinflammatory or immunomodulatory function. This included Ccl2, a chemokine that signals through CCR2 to regulate monocyte recruitment to infectious sites. Consistently, knockout mice produced more CCL2 upon IAV infection and this correlated with a 2-fold increase in the number of inflammatory monocytes and alveolar Mϕ in the lungs. Finally, Setdb2 expression by Mϕ suppressed IL-2, IL-10, and IFN-γ production by CD4+ T cells in vitro, as well as proliferation in IAV-infected lungs. Collectively, these findings identify Setdb2 as a novel regulator of the immune system in acute respiratory viral infection.
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http://dx.doi.org/10.1371/journal.ppat.1005338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692439PMC
December 2015

Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sézary syndrome.

Nat Commun 2015 09 29;6:8470. Epub 2015 Sep 29.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Sézary syndrome (SS) is an aggressive leukaemia of mature T cells with poor prognosis and limited options for targeted therapies. The comprehensive genetic alterations underlying the pathogenesis of SS are unknown. Here we integrate whole-genome sequencing (n=6), whole-exome sequencing (n=66) and array comparative genomic hybridization-based copy-number analysis (n=80) of primary SS samples. We identify previously unknown recurrent loss-of-function aberrations targeting members of the chromatin remodelling/histone modification and trithorax families, including ARID1A in which functional loss from nonsense and frameshift mutations and/or targeted deletions is observed in 40.3% of SS genomes. We also identify recurrent gain-of-function mutations targeting PLCG1 (9%) and JAK1, JAK3, STAT3 and STAT5B (JAK/STAT total ∼11%). Functional studies reveal sensitivity of JAK1-mutated primary SS cells to JAK inhibitor treatment. These results highlight the complex genomic landscape of SS and a role for inhibition of JAK/STAT pathways for the treatment of SS.
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http://dx.doi.org/10.1038/ncomms9470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4598843PMC
September 2015

Sirtuin 1 Regulates Dendritic Cell Activation and Autophagy during Respiratory Syncytial Virus-Induced Immune Responses.

J Immunol 2015 Aug 8;195(4):1637-46. Epub 2015 Jul 8.

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in children worldwide. Sirtuin 1 (SIRT1), an NAD(+)-dependent deacetylase, has been associated with the induction of autophagy and the regulation of inflammatory mediators. We found that Sirt1 was upregulated in mouse lung after RSV infection. Infected animals that received EX-527, a selective SIRT1 inhibitor, displayed exacerbated lung pathology, with increased mucus production, elevated viral load, and enhanced Th2 cytokine production. Gene expression analysis of isolated cell populations revealed that Sirt1 was most highly upregulated in RSV-treated dendritic cells (DCs). Upon RSV infection, EX-527-treated DCs, Sirt1 small interfering RNA-treated DCs, or DCs from conditional knockout (Sirt1(f/f)-CD11c-Cre(+)) mice showed downregulated inflammatory cytokine gene expression and attenuated autophagy. Finally, RSV infection of Sirt1(f/f)-CD11c-Cre(+) mice resulted in altered lung and lymph node cytokine responses, leading to exacerbated pathology. These data indicate that SIRT1 promotes DC activation associated with autophagy-mediated processes during RSV infection, thereby directing efficient antiviral immune responses.
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http://dx.doi.org/10.4049/jimmunol.1500326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530059PMC
August 2015

Epigenetic regulation of IL-12-dependent T cell proliferation.

J Leukoc Biol 2015 Oct 9;98(4):601-13. Epub 2015 Jun 9.

*Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Immunology, Nara Medical University, Nara, Japan; and Dermatology Research, Almirall, S.A., St Feliu de Llobregat, Spain.

It is well established that the cytokine IL-12 and the transcription factor STAT4, an essential part of the IL-12 signaling pathway, are critical components of the Th1 differentiation process in T cells. In response to pathogenic stimuli, this process causes T cells to proliferate rapidly and secrete high amounts of the cytokine IFN-γ, leading to the Th1 proinflammatory phenotype. However, there are still unknown components of this differentiation pathway. We here demonstrated that the expression of the histone methyltransferase Mll1 is driven by IL-12 signaling through STAT4 in humans and mice and is critical for the proper differentiation of a naïve T cell to a Th1 cell. Once MLL1 is up-regulated by IL-12, it regulates the proliferation of Th1 cells. As evidence of this, we show that Th1 cells from Mll1(+/-) mice are unable to proliferate rapidly in a Th1 environment in vitro and in vivo. Additionally, upon restimulation with cognate antigen Mll1(+/-), T cells do not convert to a Th1 phenotype, as characterized by IFN-γ output. Furthermore, we observed a reduction in IFN-γ production and proliferation in human peripheral blood stimulated with tetanus toxoid by use of a specific inhibitor of the MLL1/menin complex. Together, our results demonstrate that the MLL1 gene plays a previously unrecognized but essential role in Th1 cell biology and furthermore, describes a novel pathway through which Mll1 expression is regulated.
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http://dx.doi.org/10.1189/jlb.1A0814-375RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763868PMC
October 2015

Epigenetic changes in bone marrow progenitor cells influence the inflammatory phenotype and alter wound healing in type 2 diabetes.

Diabetes 2015 Apr 3;64(4):1420-30. Epub 2014 Nov 3.

Department of Pathology, University of Michigan, Ann Arbor, MI.

Classically activated (M1) macrophages are known to play a role in the development of chronic inflammation associated with impaired wound healing in type 2 diabetes (T2D); however, the mechanism responsible for the dominant proinflammatory (M1) macrophage phenotype in T2D wounds is unknown. Since epigenetic enzymes can direct macrophage phenotypes, we assessed the role of histone methylation in bone marrow (BM) stem/progenitor cells in the programming of macrophages toward a proinflammatory phenotype. We have found that a repressive histone methylation mark, H3K27me3, is decreased at the promoter of the IL-12 gene in BM progenitors and this epigenetic signature is passed down to wound macrophages in a murine model of glucose intolerance (diet-induced obese). These epigenetically "preprogrammed" macrophages result in poised macrophages in peripheral tissue and negatively impact wound repair. We found that in diabetic conditions the H3K27 demethylase Jmjd3 drives IL-12 production in macrophages and that IL-12 production can be modulated by inhibiting Jmjd3. Using human T2D tissue and murine models, we have identified a previously unrecognized mechanism by which macrophages are programmed toward a proinflammatory phenotype, establishing a pattern of unrestrained inflammation associated with nonhealing wounds. Hence, histone demethylase inhibitor-based therapy may represent a novel treatment option for diabetic wounds.
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http://dx.doi.org/10.2337/db14-0872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375075PMC
April 2015