title: Epigenetic Modulation of Microglial Inflammatory Gene Loci in Helminth-Induced Immune Suppression: Implications for Immune Regulation in Neurocysticercosis.
abstract: In neurocysticercosis, parasite-induced immune suppressive effects are thought to play an important role in enabling site-specific inhibition of inflammatory responses to infections. It is axiomatic that microglia-mediated (M1 proinflammatory) response causes central nervous system inflammation; however, the mechanisms by which helminth parasites modulate microglia activation remain poorly understood. Here, we show that microglia display a diminished expression of M1-inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nitric oxide synthase 2 (NOS2) in murine neurocysticercosis. Microglia also exhibited a lack of myeloid cell maturation marker major histocompatibility complex (MHC)-II in these parasite-infected brains. Treatment of microglia with helminth soluble/secreted factors (HSFs) in vitro did not induce expression of M1-inflammatory signature molecule NOS2 as well as MHC-II in primary microglia. However, HSF treatment completely inhibited lipopolysaccharide-induced increase in expression of MHC-II, NOS2 and nitric oxide production in these cells. As epigenetic modulation of chromatin states that regulates recruitment of RNA polymerase II (Pol-II) is a key regulatory step in determining gene expression and functional outcome, we next evaluated whether HSF induced modulation of these phenomenon in microglia in vitro. Indeed, HSF downregulated Pol-II recruitment to the promoter region of TNF-α, IL-6, NOS2, MHC-II, and transcription factor CIITA (a regulator of MHC-II expression), by itself. Moreover, HSF suppressed the lipopolysaccharide-induced increase in Pol-II recruitment as well. In addition, HSF exposure reduced the positive histone marks H3K4Me3 and H3K9/14Ac at the promoter of TNF-α, IL-6, NOS2, MHC-II, and CIITA. These studies provide a novel mechanistic insight into helminth-mediated immune suppression in microglia via modulation of epigenetic processes.
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, The University of North Dakota, Grand Forks, ND, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Chauhan
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, The University of North Dakota, Grand Forks, ND, USA.
authors.forename: Fredice Z
authors.initials: FZ
authors.lastname: Quenum
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, The University of North Dakota, Grand Forks, ND, USA.
authors.forename: Ata
authors.initials: A
authors.lastname: Abbas
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, The University of North Dakota, Grand Forks, ND, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Bradley
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, The University of North Dakota, Grand Forks, ND, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Nechaev
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, The University of North Dakota, Grand Forks, ND, USA.
authors.forename: Brij B
authors.initials: BB
authors.lastname: Singh
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, The University of North Dakota, Grand Forks, ND, USA.
authors.forename: Jyotika
authors.initials: J
authors.lastname: Sharma
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, The University of North Dakota, Grand Forks, ND, USA bibhuti.mishra@med.und.edu.
authors.forename: Bibhuti B
authors.initials: BB
authors.lastname: Mishra
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology*; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000276:immunology*; D006373:Helminthiasis / Q000276:immunology* / Q000473:pathology*; D006376:Helminths / Q000378:metabolism / Q000472:pathogenicity*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011134:Polysaccharides / Q000494:pharmacology; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D006657:Histones; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D011134:Polysaccharides; D015534:Trans-Activators; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D012319:RNA Polymerase II
keywords: epigenetics; helminth; immune suppression; microglia; neurocysticercosis