title: Activation of critical, host-induced, metabolic and stress pathways marks neutrophil entry into cystic fibrosis lungs.
abstract: Cystic fibrosis (CF) patients undergo progressive airway destruction caused in part by chronic neutrophilic inflammation. While opportunistic pathogens infecting CF airways can cause inflammation, we hypothesized that host-derived metabolic and stress signals would also play a role in this process. We show that neutrophils that have entered CF airways have increased phosphorylation of the eukaryotic initiation factor 4E and its partner the 4E-binding protein 1; 2 key effectors in the growth factor- and amino acid-regulated mammalian target of rapamycin (mTOR) pathway. Furthermore CF airway neutrophils display increased phosphorylation of the cAMP response element binding protein (CREB), a major transcriptional coactivator in stress signaling cascades. These active intracellular pathways are associated with increased surface expression of critical adaptor molecules, including the growth factor receptor CD114 and the receptor for advanced glycation end-products (RAGE), a CREB inducer and sensor for host-derived damage-associated molecular patterns (DAMPs). Most CF airway fluids lack any detectable soluble RAGE, an inhibitory decoy receptor for DAMPs. Concomitantly, CF airway fluids displayed high and consequently unopposed levels of S100A12; a potent mucosa- and neutrophil-derived DAMP. CF airway neutrophils also show increased surface levels of 2 critical CREB targets, the purine-recycling enzyme CD39 and the multifunctional, mTOR-inducing CXCR4 receptor. This coordinated set of events occurs in all patients, even in the context of minimal airway inflammation and well-preserved lung function. Taken together, our data demonstrate an early and sustained activation of host-responsive metabolic and stress pathways upon neutrophil entry into CF airways, suggesting potential targets for therapeutic modulation.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Megha
authors.initials: M
authors.lastname: Makam
authors.forename: Daisy
authors.initials: D
authors.lastname: Diaz
authors.forename: Julie
authors.initials: J
authors.lastname: Laval
authors.forename: Yael
authors.initials: Y
authors.lastname: Gernez
authors.forename: Carol K
authors.initials: CK
authors.lastname: Conrad
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Dunn
authors.forename: Zoe A
authors.initials: ZA
authors.lastname: Davies
authors.forename: Richard B
authors.initials: RB
authors.lastname: Moss
authors.forename: Leonore A
authors.initials: LA
authors.lastname: Herzenberg
authors.forename: Leonard A
authors.initials: LA
authors.lastname: Herzenberg
authors.forename: Rabindra
authors.initials: R
authors.lastname: Tirouvanziam
mesh_terms: D002634:Chemotaxis, Leukocyte; D017362:Cyclic AMP Response Element-Binding Protein; D003550:Cystic Fibrosis / Q000276:immunology* / Q000378:metabolism*; D017127:Glycation End Products, Advanced; D006801:Humans; D008171:Lung Diseases / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology*; D018384:Oxidative Stress; D010766:Phosphorylation; D011494:Protein Kinases; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D017127:Glycation End Products, Advanced; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases