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

Arne Ittner, Helena Block, Christoph A. Reichel, Markku Varjosalo, Helmuth Gehart, Grzegorz Sumara, Matthias Gstaiger, Fritz Krombach, Alexander Zarbock, Romeo Ricci*

*Corresponding author for this work

Research output: Contribution to journalArticle

50 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2229-2246
Number of pages18
JournalJournal of Experimental Medicine
Volume209
Issue number12
DOIs
Publication statusPublished - 1 Nov 2012
Externally publishedYes

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