title: Myeloid-Restricted AMPKα1 Promotes Host Immunity and Protects against IL-12/23p40-Dependent Lung Injury during Hookworm Infection.
abstract: How the metabolic demand of parasitism affects immune-mediated resistance is poorly understood. Immunity against parasitic helminths requires M2 cells and IL-13, secreted by CD4(+) Th2 and group 2 innate lymphoid cells (ILC2), but whether certain metabolic enzymes control disease outcome has not been addressed. This study demonstrates that AMP-activated protein kinase (AMPK), a key driver of cellular energy, regulates type 2 immunity and restricts lung injury following hookworm infection. Mice with a selective deficiency in the AMPK catalytic α1 subunit in alveolar macrophages and conventional dendritic cells produced less IL-13 and CCL17 and had impaired expansion of ILC2 in damaged lung tissue compared with wild-type controls. Defective type 2 responses were marked by increased intestinal worm burdens, exacerbated lung injury, and increased production of IL-12/23p40, which, when neutralized, restored IL-13 production and improved lung recovery. Taken together, these data indicate that defective AMPK activity in myeloid cells negatively impacts type 2 responses through increased IL-12/23p40 production. These data support an emerging concept that myeloid cells and ILC2 can coordinately regulate tissue damage at mucosal sites through mechanisms dependent on metabolic enzyme function.
authors.affiliation: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA 94110;
authors.forename: Wildaliz
authors.identifier: 0000-0001-9687-8333
authors.initials: W
authors.lastname: Nieves
authors.affiliation: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA 94110;
authors.forename: Li-Yin
authors.initials: LY
authors.lastname: Hung
authors.affiliation: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA 94110;
authors.forename: Taylor K
authors.initials: TK
authors.lastname: Oniskey
authors.affiliation: EPIRUS Biopharmaceuticals Netherlands BV, 3584 CM Utrecht, the Netherlands;
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: Institut National de la Santé et de la Recherché Médicale U1016, Institut Cochin, 75014 Paris, France; CNRS, UMR 8104, 75014 Paris, France; and Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.affiliation: Institut National de la Santé et de la Recherché Médicale U1016, Institut Cochin, 75014 Paris, France; CNRS, UMR 8104, 75014 Paris, France; and Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Benoit
authors.identifier: 0000-0002-0121-0224
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA 94110; debroski@vet.upenn.edu.
authors.forename: De'Broski R
authors.identifier: 0000-0002-2449-5365
authors.initials: DR
authors.lastname: Herbert
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D006725:Hookworm Infections / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology*; D053759:Interleukin-23 / Q000276:immunology*; D055370:Lung Injury / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D053759:Interleukin-23; D018664:Interleukin-12; C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases