title: Transcriptome analysis of neutrophils after endurance exercise reveals novel signaling mechanisms in the immune response to physiological stress.
abstract: Neutrophils serve as an intriguing model for the study of innate immune cellular activity induced by physiological stress. We measured changes in the transcriptome of circulating neutrophils following an experimental exercise trial (EXTRI) consisting of 1 h of intense cycling immediately followed by 1 h of intense running. Blood samples were taken at baseline, 3 h, 48 h, and 96 h post-EXTRI from eight healthy, endurance-trained, male subjects. RNA was extracted from isolated neutrophils. Differential gene expression was evaluated using Illumina microarrays and validated with quantitative PCR. Gene set enrichment analysis identified enriched molecular signatures chosen from the Molecular Signatures Database. Blood concentrations of muscle damage indexes, neutrophils, interleukin (IL)-6 and IL-10 were increased (P < 0.05) 3 h post-EXTRI. Upregulated groups of functionally related genes 3 h post-EXTRI included gene sets associated with the recognition of tissue damage, the IL-1 receptor, and Toll-like receptor (TLR) pathways (familywise error rate, P value < 0.05). The core enrichment for these pathways included TLRs, low-affinity immunoglobulin receptors, S100 calcium binding protein A12, and negative regulators of innate immunity, e.g., IL-1 receptor antagonist, and IL-1 receptor associated kinase-3. Plasma myoglobin changes correlated with neutrophil TLR4 gene expression (r = 0.74; P < 0.05). Neutrophils had returned to their nonactivated state 48 h post-EXTRI, indicating that their initial proinflammatory response was transient and rapidly counterregulated. This study provides novel insight into the signaling mechanisms underlying the neutrophil responses to endurance exercise, suggesting that their transcriptional activity was particularly induced by damage-associated molecule patterns, hypothetically originating from the leakage of muscle components into the circulation.
authors.affiliation: Emerging Field Oxidative Stress and DNA Stability, and Research Platform Active Aging, Department of Nutritional Sciences, Faculty of Life Sciences, University of Vienna, Vienna, Austria. oliver.neubauer@univie.ac.at
authors.forename: Oliver
authors.initials: O
authors.lastname: Neubauer
authors.forename: Surendran
authors.initials: S
authors.lastname: Sabapathy
authors.forename: Ross
authors.initials: R
authors.lastname: Lazarus
authors.forename: Jeremy B M
authors.initials: JB
authors.lastname: Jowett
authors.forename: Ben
authors.initials: B
authors.lastname: Desbrow
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Peake
authors.forename: David
authors.initials: D
authors.lastname: Cameron-Smith
authors.forename: Luke J
authors.initials: LJ
authors.lastname: Haseler
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Wagner
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Bulmer
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D003165:Complement System Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015444:Exercise / Q000502:physiology*; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D010807:Physical Endurance / Q000235:genetics / Q000276:immunology*; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013312:Stress, Physiological / Q000235:genetics / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: D015415:Biomarkers; D016207:Cytokines; C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; C495345:TLR4 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D003165:Complement System Proteins; D006854:Hydrocortisone
keywords: counterregulation of inflammation; endurance exercise; muscle-derived damage-associated molecule patterns; neutrophil transcriptome; systemic inflammatory response