title: Arabinosylated lipoarabinomannan skews Th2 phenotype towards Th1 during Leishmania infection by chromatin modification: involvement of MAPK signaling.
abstract: The parasitic protozoan Leishmania donovani is the causative organism for visceral leishmaniasis (VL) which persists in the host macrophages by deactivating its signaling machinery resulting in a critical shift from proinflammatory (Th1) to an anti-inflammatory (Th2) response. The severity of this disease is mainly determined by the production of IL-12 and IL-10 which could be reversed by use of effective immunoprophylactics. In this study we have evaluated the potential of Arabinosylated Lipoarabinomannan (Ara-LAM), a cell wall glycolipid isolated from non pathogenic Mycobacterium smegmatis, in regulating the host effector response via effective regulation of mitogen-activated protein kinases (MAPK) signaling cascades in Leishmania donovani infected macrophages isolated from BALB/C mice. Ara-LAM, a Toll-like receptor 2 (TLR2) specific ligand, was found to activate p38 MAPK signaling along with subsequent abrogation of extracellular signal-regulated kinase (ERKs) signaling. The use of pharmacological inhibitors of p38MAPK and ERK signaling showed the importance of these signaling pathways in the regulation of IL-10 and IL-12 in Ara-LAM pretreated parasitized macrophages. Molecular characterization of this regulation of IL-10 and IL-12 was revealed by chromatin immunoprecipitation assay (CHIP) which showed that in Ara-LAM pretreated parasitized murine macrophages there was a significant induction of IL-12 by selective phosphorylation and acetylation of histone H3 residues at its promoter region. While, IL-10 production was attenuated by Ara-LAM pretreatment via abrogation of histone H3 phosphorylation and acetylation at its promoter region. This Ara-LAM mediated antagonistic regulations in the induction of IL-10 and IL-12 genes were further correlated to changes in the transcriptional regulators Signal transducer and activator of transcription 3 (STAT3) and Suppressor of cytokine signaling 3 (SOCS3). These results demonstrate the crucial role played by Ara-LAM in regulating the MAPK signaling pathway along with subsequent changes in host effector response during VL which might provide crucial clues in understanding the Ara-LAM mediated protection during Leishmania induced pathogenesis.
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, India.
authors.forename: Parna
authors.initials: P
authors.lastname: Bhattacharya
authors.forename: Gaurav
authors.initials: G
authors.lastname: Gupta
authors.forename: Saikat
authors.initials: S
authors.lastname: Majumder
authors.forename: Anupam
authors.initials: A
authors.lastname: Adhikari
authors.forename: Sayantan
authors.initials: S
authors.lastname: Banerjee
authors.forename: Kuntal
authors.initials: K
authors.lastname: Halder
authors.forename: Suchandra Bhattacharya
authors.initials: SB
authors.lastname: Majumdar
authors.forename: Moumita
authors.initials: M
authors.lastname: Ghosh
authors.forename: Shubho
authors.initials: S
authors.lastname: Chaudhuri
authors.forename: Syamal
authors.initials: S
authors.lastname: Roy
authors.forename: Subrata
authors.initials: S
authors.lastname: Majumdar
mesh_terms: D000818:Animals; D001089:Arabinose / Q000737:chemistry*; D002843:Chromatin / Q000737:chemistry*; D006657:Histones / Q000378:metabolism; D006825:Hybridomas / Q000378:metabolism; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007893:Leishmania donovani / Q000378:metabolism*; D008024:Ligands; D008070:Lipopolysaccharides / Q000737:chemistry*; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D018417:Th1 Cells / Q000166:cytology*; D018418:Th2 Cells / Q000166:cytology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D008024:Ligands; D008070:Lipopolysaccharides; D050796:STAT3 Transcription Factor; C050016:lipoarabinomannan; D016753:Interleukin-10; D018664:Interleukin-12; D001089:Arabinose; D048051:p38 Mitogen-Activated Protein Kinases