title: Regulation of PTEN activity by p38δ-PKD1 signaling in neutrophils confers inflammatory responses in the lung.
abstract: Despite their role in resolving inflammatory insults, neutrophils trigger inflammation-induced acute lung injury (ALI), culminating in acute respiratory distress syndrome (ARDS), a frequent complication with high mortality in humans. Molecular mechanisms underlying recruitment of neutrophils to sites of inflammation remain poorly understood. Here, we show that p38 MAP kinase p38δ is required for recruitment of neutrophils into inflammatory sites. Global and myeloid-restricted deletion of p38δ in mice results in decreased alveolar neutrophil accumulation and attenuation of ALI. p38δ counteracts the activity of its downstream target protein kinase D1 (PKD1) in neutrophils and myeloid-restricted inactivation of PKD1 leads to exacerbated lung inflammation. Importantly, p38δ and PKD1 conversely regulate PTEN activity in neutrophils, thereby controlling their extravasation and chemotaxis. PKD1 phosphorylates p85α to enhance its interaction with PTEN, leading to polarized PTEN activity, thereby regulating neutrophil migration. Thus, aberrant p38δ-PKD1 signaling in neutrophils may underlie development of ALI and life-threatening ARDS in humans.
authors.affiliation: Institute of Cell Biology, Eidgenössische Technische Hochschule Zurich, 8006 Zurich, Switzerland.
authors.forename: Arne
authors.initials: A
authors.lastname: Ittner
authors.forename: Helena
authors.initials: H
authors.lastname: Block
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Reichel
authors.forename: Markku
authors.initials: M
authors.lastname: Varjosalo
authors.forename: Helmuth
authors.initials: H
authors.lastname: Gehart
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Sumara
authors.forename: Matthias
authors.initials: M
authors.lastname: Gstaiger
authors.forename: Fritz
authors.initials: F
authors.lastname: Krombach
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
authors.forename: Romeo
authors.initials: R
authors.lastname: Ricci
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D006652:Histological Techniques; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D048292:Mitogen-Activated Protein Kinase 13 / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017931:DNA Primers; D048292:Mitogen-Activated Protein Kinase 13; C089212:protein kinase D; D011493:Protein Kinase C; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse