Epigenetic Modulation of Microglial Inflammatory Gene Loci in Helminth-Induced Immune Suppression: Implications for Immune Regulation in Neurocysticercosis.
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.
['Chauhan|Arun|A|', 'Quenum|Fredice Z|FZ|', 'Abbas|Ata|A|', 'Bradley|David S|DS|', 'Nechaev|Sergei|S|', 'Singh|Brij B|BB|', 'Sharma|Jyotika|J|', 'Mishra|Bibhuti B|BB|']
D000818:Animals D000831:Animals, Newborn D002478:Cells, Cultured D002490:Central Nervous System D047369:Chromatin Immunoprecipitation D016207:Cytokines D004195:Disease Models, Animal D044127:Epigenesis, Genetic D006373:Helminthiasis D006376:Helminths D000949:Histocompatibility Antigens Class II D006657:Histones D051379:Mice D008810:Mice, Inbred C57BL D017628:Microglia D052247:Nitric Oxide Synthase Type II D009687:Nuclear Proteins D011134:Polysaccharides D012319:RNA Polymerase II D015534:Trans-Activators
epigenetics immune suppression neurocysticercosis helminth microglia