title: Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens.
abstract: Toll-like receptor (TLR) signaling in macrophages is required for antipathogen responses, including the biosynthesis of nitric oxide from arginine, and is essential for immunity to Mycobacterium tuberculosis, Toxoplasma gondii and other intracellular pathogens. Here we report a 'loophole' in the TLR pathway that is advantageous to these pathogens. Intracellular pathogens induced expression of the arginine hydrolytic enzyme arginase 1 (Arg1) in mouse macrophages through the TLR pathway. In contrast to diseases dominated by T helper type 2 responses in which Arg1 expression is greatly increased by interleukin 4 and 13 signaling through the transcription factor STAT6, TLR-mediated Arg1 induction was independent of the STAT6 pathway. Specific elimination of Arg1 in macrophages favored host survival during T. gondii infection and decreased lung bacterial load during tuberculosis infection.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38015, USA.
authors.forename: Karim C
authors.initials: KC
authors.lastname: El Kasmi
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Qualls
authors.forename: John T
authors.initials: JT
authors.lastname: Pesce
authors.forename: Amber M
authors.initials: AM
authors.lastname: Smith
authors.forename: Robert W
authors.initials: RW
authors.lastname: Thompson
authors.forename: Marcela
authors.initials: M
authors.lastname: Henao-Tamayo
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Basaraba
authors.forename: Till
authors.initials: T
authors.lastname: König
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schleicher
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Koo
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Elaine I
authors.initials: EI
authors.lastname: Tuomanen
authors.forename: Ian M
authors.initials: IM
authors.lastname: Orme
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
authors.forename: Christian
authors.initials: C
authors.lastname: Bogdan
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wynn
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Murray
mesh_terms: D000818:Animals; D001119:Arginase / Q000276:immunology* / Q000378:metabolism; D001424:Bacterial Infections / Q000276:immunology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000276:immunology / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D053594:Myeloid Differentiation Factor 88; D050800:STAT6 Transcription Factor; D051193:Toll-Like Receptors; D001119:Arginase