Platelet IP6K1 regulates neutrophil extracellular trap–microparticle complex formation in acute pancreatitis
Raeh Madhi, Milladur Rahman, Dler Taha, Johan Linders, Mohammed Merza, Yongzhi Wang, Matthias Mörgelon, and Henrik Thorlacius
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Published December 5, 2019 - More info
JCI Insight. 2019;4(23):e135102. https://doi.org/10.1172/jci.insight.135102.
© 2019 American Society for Clinical Investigation
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Abstract
Platelet inositol hexakisphosphate kinase 1 (IP6K1) has been shown to control systemic inflammation. Herein, we examined if platelets and IP6K1 regulate pancreatic tissue injury via formation of NETs in experimental models of acute pancreatitis (AP) in mice. By use of electron microscopy abundant NET formation was observed in the inflamed pancreas. These NETs contained numerous microparticles (MP) expressing CD41 or Mac-1. Platelet depletion reduced deposition of NET-MP complexes in the inflamed pancreas. Circulating platelet-neutrophil aggregates (PNA) were increased and inhibition of P-selectin not only disrupted PNA formation but also reduced NETs formation in the inflamed pancreas. NETs depleted of MPs had lower capacity to provoke amylase secretion and STAT-3 phosphorylation in acinar cells. Taurocholate-induced NETs formation, inflammation and tissue damage in the pancreas were decreased in IP6K1-deficient mice. Thrombin stimulation of mixtures of wild-type platelets and neutrophils resulted in NETs formation but not when IP6K1-deficient platelets were incubated with wild-type neutrophils. Polyphosphate rescue restored thrombin-induced NET formation in mixtures of IP6K1-deficient platelets and wild-type neutrophils. Platelet IP6K1 regulates NET-MP complex formation in the pancreas of mice during induction of AP. Targeting platelet IP6K1 might useful to decrease NET-dependent pancreatic tissue inflammation and tissue injury in patients with AP.
Authors
Raed Madhi, Milladur Rahman, Dler Taha, Johan Linders, Mohammed Merza, Yongzhi Wang, Matthias Mörgelin, Henrik Thorlacius
Original citation: JCI Insight. https://doi.org/10.1172/jci.insight.129270
Citation for this expression of concern: JCI Insight. https://doi.org/10.1172/jci.insight.135102
Following publication, the Editors became aware of irregularities in the pseudocoloring of microparticles in scanning electron microscopy images in Figures 1–4 and 6 and Supplemental Figure 7. The Editors have requested an institutional investigation into this matter, and we will inform our readers of the outcome when the investigation is complete.
