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Increased mitochondrial arginine metabolism supports bioenergetics in asthma
- Source :
- The Journal of clinical investigation, vol 126, iss 7
- Publication Year :
- 2016
- Publisher :
- American Society for Clinical Investigation, 2016.
-
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.
- Subjects :
- 0301 basic medicine
Eotaxin
Adult
Male
medicine.medical_specialty
Arginine
Cellular respiration
Immunology
Nitric Oxide Synthase Type II
Inflammation
Medical and Health Sciences
03 medical and health sciences
Mice
Th2 Cells
Internal medicine
medicine
2.1 Biological and endogenous factors
Animals
Humans
Aetiology
Phosphorylation
ARG2
Lung
Electron Transport Complex I
Interleukin-13
biology
Interleukin-17
General Medicine
respiratory system
Asthma
respiratory tract diseases
Mitochondria
Arginase
Nitric oxide synthase
030104 developmental biology
Endocrinology
biology.protein
Respiratory
Female
medicine.symptom
Bronchial Hyperreactivity
Energy Metabolism
STAT6 Transcription Factor
Research Article
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- The Journal of clinical investigation, vol 126, iss 7
- Accession number :
- edsair.doi.dedup.....855bb3e3dd753b9b19dcb48478b24e71