Dissecting and aligning the regulatory and effector mechanisms shaping murine M2 macrophages  Page description

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Details of project

 
Identifier
116855
Type K
Principal investigator Nagy, László
Title in Hungarian Alternativan aktivált makrofágok szabályozása és végrehajtó funkciói
Title in English Dissecting and aligning the regulatory and effector mechanisms shaping murine M2 macrophages
Keywords in Hungarian veleszületett immunitás, alternativan aktivát makrofág, IL4, STAT6, transzkripció, angiogenesis,
Keywords in English innate immunity, alternatively activated macrophage, IL4, STAT6, transcription, angiogenesis
Discipline
Immunology (Council of Medical and Biological Sciences)80 %
Ortelius classification: Immunology
Cell differentiation, physiology and dynamics (Council of Medical and Biological Sciences)10 %
Genomics, comparative genomics, functional genomics (Council of Medical and Biological Sciences)10 %
Panel Genetics, Genomics, Bioinformatics and Systems Biology
Department or equivalent Department of Biochemistry and Molecular Biology (University of Debrecen)
Participants Pap, Attila
Póliska, Szilárd
Tzerpos, Petros
Starting date 2016-01-01
Closing date 2019-12-31
Funding (in million HUF) 43.999
FTE (full time equivalent) 4.82
state running project





 

Final report

 
Results in Hungarian
A projekt során a IL-4-indukált alternatív makrofág polarizációs programban résztvevő transzkripciós és poszt-transzkripciós szabályozási mechanizmusokat tanulmányoztuk transzkriptómikai, epigenomikai és immunológiai vizsgálómódszerek együttes alkalmazásával. Megállapítottuk, hogy az alternatívan polarizált makrofágokban a PPARγ transzkripciós faktor ligand-független módon képes átrendezni a sejtek kromatin szerkezetét, amely egy specifikus transzkripciós memóriát eredményez. Ennek következménye egy kizárólagosan a sejtek második IL-4 általi aktivációját követően kifejeződő, az extracelluláris mátrix átalakulásához kapcsolódó génhálózat, amely hozzájárulhat az alternatívan polarizált makrofágok szöveti regenerációban betöltött szerepéhez. Továbbá azonosítottuk az IL-4-aktivált STAT6 transzkripciós faktor egy eddig nem ismert transzkripciós represszor funkcióját, amely segítségével részben gátolja a makrofágok gyulladásos válaszát, köztük az NLRP3 inflammaszóma aktivációt, IL-1β termelődést és prioptózist. Végül azonosítottuk az IL-4/STAT6 szignálútvonal által humán és egér makrofágokban indukált miR-342-3p miRNS apoptózist elősegítő hatását, amelyet egy anti-apoptotikus funkcióval bíró génhálózat közvetlen és közvetett gátlásán keresztül ér el.
Results in English
In this project, we studied the transcriptional and post-transcriptional regulatory mechanisms in alternatively polarized macrophages combining transcriptomic, epigenomic and immunological approaches. We observed that PPARγ transcription factor can induces chromatin rearrangement in ligand-independent manner during alternative macrophage polarization leading a specific transcriptional memory. PPARγ-dependent transcriptional memory results the activation of extracellular matrix remodeling-related gene network upon IL-4 re-stimulation potentially contributing to the role of alternatively polarized macrophages in tissue regeneration. In addition, we identified a novel direct transcriptional repressor activity of IL-4-activated STAT6 transcription factor in murine macrophages resulting diminished inflammatory responsiveness including blunted NLRP3 inflammasome activation, IL-1β secretion and pyroptosis. Finally, we observed that IL-4/STAT6 signaling pathway-induced miR-342-3p has pro-apoptotic role in macrophages through direct and indirect inhibition of an anti-apoptotic gene network.
Full text https://www.otka-palyazat.hu/download.php?type=zarobeszamolo&projektid=116855
Decision
Yes





 

List of publications

 
Horvath Attila, Daniel Bence, Szeles Lajos, Cuaranta-Monroy Ixchelt, Czimmerer Zsolt, Ozgyin Lilla, Steiner Laszlo, Kiss Mate, Simandi Zoltan, Poliska Szilard, Giannakis Nikolas, Raineri Emanuele, Gut Ivo G, Nagy Benedek, Nagy Laszlo: Labelled regulatory elements are pervasive features of the macrophage genome and are dynamically utilized by classical and alternative polarization signals, NUCLEIC ACIDS RESEARCH 47: (6) pp. 2778-2792., 2019
Czimmerer Z, Horvath A, Daniel B, Nagy G, Cuaranta-Monroy I, Kiss M, Kolostyak Z, Poliska S, Steiner L, Giannakis N, Varga T, Nagy L: Dynamic transcriptional control of macrophage miRNA signature via inflammation responsive enhancers revealed using a combination of next generation sequencing-based approaches., BIOCHIM BIOPHYS ACTA x: x, 2017
Czimmerer Z, Nagy ZS, Nagy G, Horvath A, Silye-Cseh T, Kriston A, Jonas D, Sauer S, Steiner L, Daniel B, Deleuze JF, Nagy L: Extensive and functional overlap of the STAT6 and RXR cistromes in the active enhancer repertoire of human CD14+ monocyte derived differentiating macrophages., MOL CELL ENDOCRINOL 63: (4) 647-661, 2017
Kiss M, Czimmerer Z, Nagy G, Bieniasz-Krzywiec P, Ehling M, Pap A, Poliska S, Botof P, Tzerpos P, Horvath A, Kolostyak Z, Daniel B, Szatmari I, Mazzone M, Nagy L: Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism, P NATL ACAD SCI USA 114: (40) 10725-10730, 2017
Patsalos Andreas, Pap Attila, Varga Tamas, Trencsenyi Gyorgy, Contreras Gerardo Alvarado, Garai Ildiko, Papp Zoltan, Dezso Balazs, Pintye Eva, Nagy Laszlo: In situ macrophage phenotypic transition is affected by altered cellular composition prior to acute sterile muscle injury, J PHYSIOL-LONDON 595: (17) 5815-5842, 2017
Simandi Z, Horvath A, Cuaranta-Monroy I, Sauer S, Deleuze JF, Nagy L: RXR heterodimers orchestrate transcriptional control of neurogenesis and cell fate specification., MOL CELL ENDOCRINOL x: x, 2017
Andreas Patsalos, Zoltan Simandi, Tristan T. Hays, Matthew Peloquin, Matine Hajian, Isabella Restrepo, Paul M. Coen, Alan J. Russell, Laszlo Nagy: In vivo GDF3 administration abrogates aging related muscle regeneration delay following acute sterile injury, AGING CELL 17 : 5 Paper: e12815, 2018
Bence Daniel,Gergely Nagy, Zsolt Czimmerer, Attila Horvath, David W.Hammers, Ixchelt Cuaranta-Monroy, Szilard Poliska, Petros Tzerpos, Zsuzsanna Kolostyak, Tristan T.Hays, Andreas Patsalos, René Houtman, Sascha Sauer, Jean Francois-Deleuze, Fraydoon Rastinejad, Balint L.Balint, Lee Sweeney, Laszlo Nagy: The Nuclear Receptor PPARγ Controls Progressive Macrophage Polarization as a Ligand-Insensitive Epigenomic Ratchet of Transcriptional Memory, Immunity 49: (4) pp. 615-626, 2018
Czimmerer Z, Daniel B, Horvath A, Ruckerl D, Nagy G, Kiss M, Peloquin M, Budai MM, Cuaranta-Monroy I, Simandi Z, Steiner L, Nagy B Jr, Poliska S, Banko C, Bacso Z, Schulman IG, Sauer S, Deleuze JF, Allen JE, Benko S, Nagy L: The Transcription Factor STAT6 Mediates Direct Repression of Inflammatory Enhancers and Limits Activation of Alternatively Polarized Macrophages., IMMUNITY 48: (1) pp. 75-90., 2018
Daniel B, Nagy G, Horvath A, Czimmerer Z, Cuaranta-Monroy I, Poliska S, Hays TT, Sauer S, Francois-Deleuze J, Nagy L: The IL-4/STAT6/PPARgamma signaling axis is driving the expansion of the RXR heterodimer cistrome, providing complex ligand responsiveness in macrophages, NUCLEIC ACIDS RES 46: (9) pp. 4425-4439., 2018
Zsolt Czimmerer, Attila Horvath, Bence Daniel, Gergely Nagy, Ixchelt Cuaranta-Monroy, Mate Kiss, Zsuzsanna Kolostyak, Szilard Poliska, Laszlo Steiner, Nikolas Giannakis, Tamas Varga, Laszlo Nagy: Dynamic transcriptional control of macrophage miRNA signature via inflammation responsive enhancers revealed using a combination of next generation sequencing-based appro, Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 1861 pp. 14-28., 2018
Zsolt Czimmerer, Zsuzsanna S.Nagy, Gergely Nagy, Attila Horvath, Timea Silye-Cseh, Agnes Kriston, David Jonas, Sascha Sauer, Laszlo Steiner, Bence Daniel, Jean-Francois Deleuze, Laszlo Nagy: Extensive and functional overlap of the STAT6 and RXR cistromes in the active enhancer repertoire of human CD14+ monocyte derived differentiating macrophages, Molecular and Cellular Endocrinology (471): 63-74., 2018
Tamas Varga, Rémi Mounier, Attila Horváth, Sylvain Cuvellier, Florent Dumont, Szilárd Póliska, Hamida Ardjoune, Gaëtan Juban, László Nagy, Bénédicte Chazaud: Highly dynamic transcriptional signature of distinct macrophage subsets during sterile inflammation, resolution, and tissue repair, J IMMUNOL 196: (11) 4771-4782, 2016
Czimmerer Z, Varga T, Kiss M, Ovando Vázquez C, Doan-Xuan QM, Rückerl D, Tattikota SG, Yan X, S Nagy Z, Daniel B, Poliska S, Horvath A, Nagy G, Varallyay E, Poy MN, Allen JA, Bacso Z, Abreu-Goodger C, Nagy L: The IL4-STAT6 signaling axis establishes a conserved microRNA signature in human and mouse macrophages regulating cell survival via miR-342-3p, GENOME MED 8: (1) 63, 2016
Simandi Z, Horvath A, Nagy G P, Nagy L: Prediction and Validation of Gene Regulatory Elements Activated During Retinoic Acid Induced Embryonic Stem Cell Differentiation, JOVE-J VIS EXP :, 2016
Attila Pap, Ixchelt Cuaranta-Monroy, Matt Peloquin, László Nagy: Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases?, INT J MOL SCI 17: (8), 2016
Simandi Z, Horvath A, Wright L C, Cuaranta-Monroy I, De Luca I, Karolyi K, Sauer S, Deleuze JF, Gudas L J, Cowley S M, Nagy L: Oct4 acts as an integrator of pluripotency and signal-induced differentiation, MOL CELL 63: 647-661, 2016
Tamas Varga, Remi Mounier, Andreas Patsalos, Peter Gogolak, Matthew Peloquin, Attila Horvath, Attila Pap, Bence Daniel, Gergely Nagy, Eva Pintye, Szilard Poliska, Sylvain Cuvellier, Sabrina Ben Larbi, Brian E Sansbury, Matthew Spite, Chester W Brown, Benedicte Chazaud, Laszlo Nagy: Macrophage PPARg , a Lipid Activated Transcription Factor Controls the Growth Factor GDF3 and Skeletal Muscle Regeneration, IMMUNITY 45: 1038-1051, 2016
Patsalos Andreas, Pap Attila, Varga Tamas, Trencsenyi Gyorgy, Contreras Gerardo Alvarado, Garai Ildiko, Papp Zoltan, Dezso Balazs, Pintye Eva, Nagy Laszlo: In situ macrophage phenotypic transition is affected by altered cellular composition prior to acute sterile muscle injury, J PHYSIOL-LONDON 595: (17) 5815-5842, 2017
Kiss M, Czimmerer Z, Nagy G, Bieniasz-Krzywiec P, Ehling M, Pap A, Poliska S, Botof P, Tzerpos P, Horvath A, Kolostyak Z, Daniel B, Szatmari I, Mazzone M, Nagy L: Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism, P NATL ACAD SCI USA 114: (40) 10725-10730, 2017
Czimmerer Z, Horvath A, Daniel B, Nagy G, Cuaranta-Monroy I, Kiss M, Kolostyak Z, Poliska S, Steiner L, Giannakis N, Varga T, Nagy L: Dynamic transcriptional control of macrophage miRNA signature via inflammation responsive enhancers revealed using a combination of next generation sequencing-based approaches., BIOCHIM BIOPHYS ACTA x: x, 2017
Simandi Z, Horvath A, Cuaranta-Monroy I, Sauer S, Deleuze JF, Nagy L: RXR heterodimers orchestrate transcriptional control of neurogenesis and cell fate specification., MOL CELL ENDOCRINOL x: x, 2017
Attila Pap, Ixchelt Cuaranta-Monroy, Matt Peloquin, László Nagy: Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases?, INT J MOL SCI 17: (8) , 2016
Dozsa A, Mihaly J, Dezso B, Csizmadia E, Keresztessy T, Marko L, Rühl R, Remenyik E, Nagy L: Decreased peroxisome proliferator-activated receptor y level and signalling in sebaceous glands of patients with acne vulgaris, CLIN EXP DERMATOL 41: (5) 547-551, 2016
Kiss M, Nagy L: Nuclear Receptors in Immune Function, In: Michael J H Ratcliffe (szerk.) (szerk.) Encyclopedia of Immunobiology: Volume 3: Activation of the Immune System. Oxford: Elsevier, 2016. pp. 145-156., 2016
Nagy G, Czipa E, Steiner L, Nagy T, Pongor S, Nagy L, Barta E: Motif oriented high-resolution analysis of ChIP-seq data reveals the topological order of CTCF and cohesin proteins on DNA., BMC GENOMICS 17: (1) , 2016
Simandi Z, Horvath A, Nagy G P, Nagy L: Prediction and Validation of Gene Regulatory Elements Activated During Retinoic Acid Induced Embryonic Stem Cell Differentiation, JOVE-J VIS EXP : , 2016
Simandi Z, Horvath A, Wright L C, Cuaranta-Monroy I, De Luca I, Karolyi K, Sauer S, Deleuze JF, Gudas L J, Cowley S M, Nagy L: Oct4 acts as an integrator of pluripotency and signal-induced differentiation, MOL CELL 63: 647-661, 2016
Tamas Varga, Remi Mounier, Andreas Patsalos, Peter Gogolak, Matthew Peloquin, Attila Horvath, Attila Pap, Bence Daniel, Gergely Nagy, Eva Pintye, Szilard Poliska, Sylvain Cuvellier, Sabrina Ben Larbi, Brian E Sansbury, Matthew Spite, Chester W Brown, Benedicte Chazaud, Laszlo Nagy: Macrophage PPARg , a Lipid Activated Transcription Factor Controls the Growth Factor GDF3 and Skeletal Muscle Regeneration, IMMUNITY 45: 1038-1051, 2016
Tamas Varga, Rémi Mounier, Attila Horváth, Sylvain Cuvellier, Florent Dumont, Szilárd Póliska, Hamida Ardjoune, Gaëtan Juban, László Nagy, Bénédicte Chazaud: Highly dynamic transcriptional signature of distinct macrophage subsets during sterile inflammation, resolution, and tissue repair, J IMMUNOL 196: (11) 4771-4782, 2016
Czimmerer Z, Varga T, Kiss M, Ovando Vázquez C, Doan-Xuan QM, Rückerl D, Tattikota SG, Yan X, S Nagy Z, Daniel B, Poliska S, Horvath A, Nagy G, Varallyay E, Poy MN, Allen JA, Bacso Z, Abreu-Goodger C, Nagy L: The IL4-STAT6 signaling axis establishes a conserved microRNA signature in human and mouse macrophages regulating cell survival via miR-342-3p, GENOME MED 8: (1) 63, 2016





 

Events of the project

 
2019-07-01 17:49:34
Résztvevők változása
2016-09-30 07:29:02
Résztvevők változása




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