Regulation of PTEN activity by p38δ-PKD1 signaling in neutrophils confers inflammatory responses in the lung

• DOI: 10.1084/jem.20120677
• Publication Date: 2012-11-06T05:15:07Z
• Authors: Arne Ittner; Helena Block; Christoph A. Reichel; Markku Varjosalo; Helmuth Gehart; Grzegorz Sumara; Matthias Gstaiger; Fritz Krombach; Alexander Zarbock; Romeo Ricci
• Keywords: Mice, Knockout; 0301 basic medicine; 0303 health sciences; Neutrophils; Acute Lung Injury; Histological Techniques; PTEN Phosphohydrolase; Real-Time Polymerase Chain Reaction; Article; Mass Spectrometry; Cell Line; 3. Good health; [SDV] Life Sciences [q-bio]; Mice, Inbred C57BL; Mice; Mitogen-Activated Protein Kinase 13; 03 medical and health sciences; Microscopy, Fluorescence; Animals; Immunoprecipitation; Protein Kinase C; DNA Primers; Signal Transduction

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.