Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
WAVE1 mediates suppression of phagocytosis by phospholipid-derived DAMPs
Ulrich Matt, … , John D. Scott, Sylvia Knapp
Ulrich Matt, … , John D. Scott, Sylvia Knapp
Published June 24, 2013
Citation Information: J Clin Invest. 2013;123(7):3014-3024. https://doi.org/10.1172/JCI60681.
View: Text | PDF | Erratum
Research Article Immunology Article has an altmetric score of 30

WAVE1 mediates suppression of phagocytosis by phospholipid-derived DAMPs

  • Text
  • PDF
Abstract

Clearance of invading pathogens is essential to preventing overwhelming inflammation and sepsis that are symptomatic of bacterial peritonitis. Macrophages participate in this innate immune response by engulfing and digesting pathogens, a process called phagocytosis. Oxidized phospholipids (OxPL) are danger-associated molecular patterns (DAMPs) generated in response to infection that can prevent the phagocytic clearance of bacteria. We investigated the mechanism underlying OxPL action in macrophages. Exposure to OxPL induced alterations in actin polymerization, resulting in spreading of peritoneal macrophages and diminished uptake of E. coli. Pharmacological and cell-based studies showed that an anchored pool of PKA mediates the effects of OxPL. Gene silencing approaches identified the A-kinase anchoring protein (AKAP) WAVE1 as an effector of OxPL action in vitro. Chimeric Wave1–/– mice survived significantly longer after infection with E. coli and OxPL treatment in vivo. Moreover, we found that endogenously generated OxPL in human peritoneal dialysis fluid from end-stage renal failure patients inhibited phagocytosis via WAVE1. Collectively, these data uncover an unanticipated role for WAVE1 as a critical modulator of the innate immune response to severe bacterial infections.

Authors

Ulrich Matt, Omar Sharif, Rui Martins, Tanja Furtner, Lorene Langeberg, Riem Gawish, Immanuel Elbau, Ana Zivkovic, Karin Lakovits, Olga Oskolkova, Bianca Doninger, Andreas Vychytil, Thomas Perkmann, Gernot Schabbauer, Christoph J. Binder, Valery N. Bochkov, John D. Scott, Sylvia Knapp

×

Figure 1

Oxidation of lipids occurs in E. coli peritonitis in vivo and leads to an actin-dependent change in cell shape in vitro.

Options: View larger image (or click on image) Download as PowerPoint
Oxidation of lipids occurs in E. coli peritonitis in vivo and leads to a...
(A) Endogenous levels of oxidized phosphatidylcholine were measured in PLF of mice infected with E. coli after 8 or 16 hours, respectively, compared with supernatants of RAW 264.7 cells after adding 5 or 10 μg/ml of OxPAPC, respectively. Co, control. (B) RAW 267.4 cells were incubated with indicated doses of OxPAPC or DMPC for 15 minutes, and phagocytosis of E. coli was assessed after 60 and 120 minutes (triplicates, representative of 3 independent experiments). (C) FACS histogram showing uptake of FITC-labeled E. coli by resident peritoneal macrophages pretreated with 10 μg/ml of OxPAPC or DMPC after 60 minutes. (D) Mice (n = 8/group) were infected with 104 CFU E. coli i.p. and treated with 2.5 mg/kg DMPC or OxPAPC i.p. Peritoneal CFU counts were enumerated 10 hours after infection. Data (A–D) are presented as mean ± SEM; *P < 0.05; **P < 0.01 versus controls. ***P < 0.001. (E) RAW 264.7 cells were incubated with carrier, DMPC, or OxPAPC (10 μg/ml; 30 minutes) alone or following incubation with 2 μM cytochalasin D (30 minutes). Cells were subsequently stained for F-actin using phalloidin (green) and PI for nuclei (red). Scale bar: 30 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 3 news outlets
Blogged by 1
50 readers on Mendeley
See more details