title: RP105 Engages Phosphatidylinositol 3-Kinase p110δ To Facilitate the Trafficking and Secretion of Cytokines in Macrophages during Mycobacterial Infection.
abstract: Cytokines are key regulators of adequate immune responses to infection with Mycobacterium tuberculosis. We demonstrate that the p110δ catalytic subunit of PI3K acts as a downstream effector of the TLR family member RP105 (CD180) in promoting mycobacteria-induced cytokine production by macrophages. Our data show that the significantly reduced release of TNF and IL-6 by RP105(-/-) macrophages during mycobacterial infection was not accompanied by diminished mRNA or protein expression. Mycobacteria induced comparable activation of NF-κB and p38 MAPK signaling in wild-type (WT) and RP105(-/-) macrophages. In contrast, mycobacteria-induced phosphorylation of Akt was abrogated in RP105(-/-) macrophages. The p110δ-specific inhibitor, Cal-101, and small interfering RNA-mediated knockdown of p110δ diminished mycobacteria-induced TNF secretion by WT but not RP105(-/-) macrophages. Such interference with p110δ activity led to reduced surface-expressed TNF in WT but not RP105(-/-) macrophages, while leaving TNF mRNA and protein expression unaffected. Activity of Bruton's tyrosine kinase was required for RP105-mediated activation of Akt phosphorylation and TNF release by mycobacteria-infected macrophages. These data unveil a novel innate immune signaling axis that orchestrates key cytokine responses of macrophages and provide molecular insight into the functions of RP105 as an innate immune receptor for mycobacteria.
authors.affiliation: The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Queensland 4102, Australia;
authors.forename: Chien-Hsiung
authors.initials: CH
authors.lastname: Yu
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia;
authors.forename: Massimo
authors.initials: M
authors.lastname: Micaroni
authors.affiliation: The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Queensland 4102, Australia;
authors.forename: Andreas
authors.initials: A
authors.lastname: Puyskens
authors.affiliation: The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Queensland 4102, Australia;
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Schultz
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia;
authors.forename: Jeremy Changyu
authors.initials: JC
authors.lastname: Yeo
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia;
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Stanley
authors.affiliation: Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523; and.
authors.forename: Megan
authors.initials: M
authors.lastname: Lucas
authors.affiliation: Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523; and.
authors.forename: Jade
authors.initials: J
authors.lastname: Kurihara
authors.affiliation: Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523; and.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Dobos
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Stow
authors.affiliation: The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Queensland 4102, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland 4072, Australia a.blumenthal@uq.edu.au.
authors.forename: Antje
authors.initials: A
authors.lastname: Blumenthal
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D011687:Purines / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology
chemical_list: D015703:Antigens, CD; D004791:Enzyme Inhibitors; C490500:Ly78 protein, mouse; D011687:Purines; D052999:Quinazolinones; D014409:Tumor Necrosis Factor-alpha; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C552946:idelalisib