WAVE1 mediates suppression of phagocytosis by phospholipid-derived DAMPs.
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.
Research Center for Molecular Medicine of Austrian Academy of Sciences, Vienna, Austria.
Ulrich
U
Matt
Omar
O
Sharif
Rui
R
Martins
Tanja
T
Furtner
Lorene
L
Langeberg
Riem
R
Gawish
Immanuel
I
Elbau
Ana
A
Zivkovic
Karin
K
Lakovits
Olga
O
Oskolkova
Bianca
B
Doninger
Andreas
A
Vychytil
Thomas
T
Perkmann
Gernot
G
Schabbauer
Christoph J
CJ
Binder
Valery N
VN
Bochkov
John D
JD
Scott
Sylvia
S
Knapp
D000818:Animals; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004134:Dimyristoylphosphatidylcholine / Q000494:pharmacology; D004789:Enzyme Activation; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D007113:Immunity, Innate; D007676:Kidney Failure, Chronic / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D010530:Peritoneal Dialysis; D010538:Peritonitis / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D010587:Phagocytosis; D010713:Phosphatidylcholines / Q000494:pharmacology / Q000502:physiology; D010743:Phospholipids / Q000502:physiology*; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000235:genetics / Q000378:metabolism*
C468114:1-palmitoyl-2-arachidonyl-3-phosphorylcholine; D010713:Phosphatidylcholines; D010743:Phospholipids; D051300:Wiskott-Aldrich Syndrome Protein Family; D017868:Cyclic AMP-Dependent Protein Kinases; D004134:Dimyristoylphosphatidylcholine