title: Ac2PIM-responsive miR-150 and miR-143 target receptor-interacting protein kinase 2 and transforming growth factor beta-activated kinase 1 to suppress NOD2-induced immunomodulators.
abstract: Specific and coordinated regulation of innate immune receptor-driven signaling networks often determines the net outcome of the immune responses. Here, we investigated the cross-regulation of toll-like receptor (TLR)2 and nucleotide-binding oligomerization domain (NOD)2 pathways mediated by Ac2PIM, a tetra-acylated form of mycobacterial cell wall component and muramyl dipeptide (MDP), a peptidoglycan derivative respectively. While Ac2PIM treatment of macrophages compromised their ability to induce NOD2-dependent immunomodulators like cyclooxygenase (COX)-2, suppressor of cytokine signaling (SOCS)-3, and matrix metalloproteinase (MMP)-9, no change in the NOD2-responsive NO, TNF-α, VEGF-A, and IL-12 levels was observed. Further, genome-wide microRNA expression profiling identified Ac2PIM-responsive miR-150 and miR-143 to target NOD2 signaling adaptors, RIP2 and TAK1, respectively. Interestingly, Ac2PIM was found to activate the SRC-FAK-PYK2-CREB cascade via TLR2 to recruit CBP/P300 at the promoters of miR-150 and miR-143 and epigenetically induce their expression. Loss-of-function studies utilizing specific miRNA inhibitors establish that Ac2PIM, via the miRNAs, abrogate NOD2-induced PI3K-PKCδ-MAPK pathway to suppress β-catenin-mediated expression of COX-2, SOCS-3, and MMP-9. Our investigation has thus underscored the negative regulatory role of Ac2PIM-TLR2 signaling on NOD2 pathway which could broaden our understanding on vaccine potential or adjuvant utilities of Ac2PIM and/or MDP.
authors.affiliation: From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India and.
authors.forename: Praveen
authors.initials: P
authors.lastname: Prakhar
authors.affiliation: From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India and.
authors.forename: Sahana
authors.initials: S
authors.lastname: Holla
authors.affiliation: From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India and.
authors.forename: Devram Sampat
authors.initials: DS
authors.lastname: Ghorpade
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS and Université de Toulouse, 31077 Toulouse, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Gilleron
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS and Université de Toulouse, 31077 Toulouse, France.
authors.forename: Germain
authors.initials: G
authors.lastname: Puzo
authors.affiliation: From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India and.
authors.forename: Vibha
authors.initials: V
authors.lastname: Udupa
authors.affiliation: From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, Karnataka, India and balaji@mcbl.iisc.ernet.in.
authors.forename: Kithiganahalli Narayanaswamy
authors.initials: KN
authors.lastname: Balaji
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D044127:Epigenesis, Genetic; D007113:Immunity, Innate; D007155:Immunologic Factors / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases; D009569:Nitric Oxide / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011135:Polysaccharides, Bacterial / Q000494:pharmacology; D011485:Protein Binding; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000119:Acetylmuramyl-Alanyl-Isoglutamine; D051546:Cyclooxygenase 2; D007155:Immunologic Factors; D020930:MAP Kinase Kinase Kinases; D020780:Matrix Metalloproteinase 9; D035683:MicroRNAs; D020928:Mitogen-Activated Protein Kinases; D009569:Nitric Oxide; D053473:Nod2 Signaling Adaptor Protein; D019869:Phosphatidylinositol 3-Kinases; D011135:Polysaccharides, Bacterial; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051195:Toll-Like Receptor 2; D000099151:MAP Kinase Kinase Kinase 7; C532884:MIRN143 microRNA, mouse; C529101:Mirn150 microRNA, mouse; C495945:Nod2 protein, mouse; C491411:Socs3 protein, mouse; C493486:Tlr2 protein, mouse; C077623:Ptgs2 protein, mouse; C506255:Ripk2 protein, mouse; C501830:Mmp9 protein, mouse
keywords: Nod-like receptor (NLR); innate immunity; macrophage; microRNA (miRNA); signal transduction; toll-like receptor (TLR)