title: Increased mitochondrial arginine metabolism supports bioenergetics in asthma.
abstract: High levels of arginine metabolizing enzymes, including inducible nitric oxide synthase (iNOS) and arginase (ARG), are typical in asthmatic airway epithelium; however, little is known about the metabolic effects of enhanced arginine flux in asthma. Here, we demonstrated that increased metabolism sustains arginine availability in asthmatic airway epithelium with consequences for bioenergetics and inflammation. Expression of iNOS, ARG2, arginine synthetic enzymes, and mitochondrial respiratory complexes III and IV was elevated in asthmatic lung samples compared with healthy controls. ARG2 overexpression in a human bronchial epithelial cell line accelerated oxidative bioenergetic pathways and suppressed hypoxia-inducible factors (HIFs) and phosphorylation of the signal transducer for atopic Th2 inflammation STAT6 (pSTAT6), both of which are implicated in asthma etiology. Arg2-deficient mice had lower mitochondrial membrane potential and greater HIF-2α than WT animals. In an allergen-induced asthma model, mice lacking Arg2 had greater Th2 inflammation than WT mice, as indicated by higher levels of pSTAT6, IL-13, IL-17, eotaxin, and eosinophils and more mucus metaplasia. Bone marrow transplants from Arg2-deficient mice did not affect airway inflammation in recipient mice, supporting resident lung cells as the drivers of elevated Th2 inflammation. These data demonstrate that arginine flux preserves cellular respiration and suppresses pathological signaling events that promote inflammation in asthma.
authors.forename: Weiling
authors.initials: W
authors.lastname: Xu
authors.forename: Sudakshina
authors.initials: S
authors.lastname: Ghosh
authors.forename: Suzy A A
authors.initials: SA
authors.lastname: Comhair
authors.forename: Kewal
authors.initials: K
authors.lastname: Asosingh
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Janocha
authors.forename: Deloris A
authors.initials: DA
authors.lastname: Mavrakis
authors.forename: Carole D
authors.initials: CD
authors.lastname: Bennett
authors.forename: Lourdes L
authors.initials: LL
authors.lastname: Gruca
authors.forename: Brian B
authors.initials: BB
authors.lastname: Graham
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Queisser
authors.forename: Christina C
authors.initials: CC
authors.lastname: Kao
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Wedes
authors.forename: John M
authors.initials: JM
authors.lastname: Petrich
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
authors.forename: Satish C
authors.initials: SC
authors.lastname: Kalhan
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
mesh_terms: D000328:Adult; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001249:Asthma / Q000276:immunology* / Q000378:metabolism*; D016535:Bronchial Hyperreactivity; D042967:Electron Transport Complex I / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D007249:Inflammation; D018793:Interleukin-13 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation; D050800:STAT6 Transcription Factor / Q000378:metabolism; D018418:Th2 Cells
chemical_list: D018793:Interleukin-13; D020381:Interleukin-17; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D042967:Electron Transport Complex I