title: The WNT signaling pathway contributes to dectin-1-dependent inhibition of Toll-like receptor-induced inflammatory signature.
abstract: Macrophages regulate cell fate decisions during microbial challenges by carefully titrating signaling events activated by innate receptors such as dectin-1 or Toll-like receptors (TLRs). Here, we demonstrate that dectin-1 activation robustly dampens TLR-induced proinflammatory signature in macrophages. Dectin-1 induced the stabilization of β-catenin via spleen tyrosine kinase (Syk)-reactive oxygen species (ROS) signals, contributing to the expression of WNT5A. Subsequently, WNT5A-responsive protein inhibitors of activated STAT (PIAS-1) and suppressor of cytokine signaling 1 (SOCS-1) mediate the downregulation of IRAK-1, IRAK-4, and MyD88, resulting in decreased expression of interleukin 12 (IL-12), IL-1β, and tumor necrosis factor alpha (TNF-α). In vivo activation of dectin-1 with pathogenic fungi or ligand resulted in an increased bacterial burden of Mycobacteria, Klebsiella, Staphylococcus, or Escherichia, with a concomitant decrease in TLR-triggered proinflammatory cytokines. All together, our study establishes a new role for dectin-1-responsive inhibitory mechanisms employed by virulent fungi to limit the proinflammatory environment of the host.
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Jamma
authors.initials: J
authors.lastname: Trinath
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Sahana
authors.initials: S
authors.lastname: Holla
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Kasturi
authors.initials: K
authors.lastname: Mahadik
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Praveen
authors.initials: P
authors.lastname: Prakhar
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Singh
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India balaji@mcbl.iisc.ernet.in.
authors.forename: Kithiganahalli Narayanaswamy
authors.initials: KN
authors.lastname: Balaji
mesh_terms: D000818:Animals; D001231:Aspergillus flavus / Q000472:pathogenicity; D001232:Aspergillus fumigatus / Q000472:pathogenicity; D058491:Bacterial Load / Q000276:immunology; D002176:Candida albicans / Q000472:pathogenicity; D015536:Down-Regulation; D004789:Enzyme Activation; D004925:Escherichia / Q000472:pathogenicity; D007249:Inflammation / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007709:Klebsiella / Q000472:pathogenicity; D037181:Lectins, C-Type / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009161:Mycobacterium / Q000472:pathogenicity; D053594:Myeloid Differentiation Factor 88 / Q000096:biosynthesis; D050828:Protein Inhibitors of Activated STAT / Q000096:biosynthesis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013210:Staphylococcus / Q000472:pathogenicity; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis; D000072377:Syk Kinase; D051193:Toll-Like Receptors / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D051153:Wnt Proteins / Q000096:biosynthesis; D060449:Wnt Signaling Pathway / Q000276:immunology*; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000276:immunology; D000099181:Dectin-1
chemical_list: D053592:Interleukin-1 Receptor-Associated Kinases; D018664:Interleukin-12; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D053594:Myeloid Differentiation Factor 88; D050828:Protein Inhibitors of Activated STAT; D011505:Protein-Tyrosine Kinases; D017382:Reactive Oxygen Species; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000072377:Syk Kinase; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin; D000099181:Dectin-1; C587672:IL1B protein, mouse; C507780:Myd88 protein, mouse; C494211:Pias1 protein, mouse; C491590:Socs1 protein, mouse; C438615:Wnt5a protein, mouse; C000606897:Syk protein, mouse; C507769:Irak1 protein, mouse; C507774:Irak4 protein, mouse