TY - JOUR
T1 - The oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages
AU - Chu, Lan H.
AU - Indramohan, Mohanalaxmi
AU - Ratsimandresy, Rojo A.
AU - Gangopadhyay, Anu
AU - Morris, Emily P.
AU - Monack, Denise M.
AU - Dorfleutner, Andrea
AU - Stehlik, Christian
N1 - Funding Information:
We thank Dr Bo Shi for support with the elutriation of human primary macrophages, Drs Carla M. Cuda and Qi-Quan Huang for advice in BMDC differentiation, Dr. Joan M. Cook-Mills for the MULTIVAP nitrogen evaporator, and members of the Stehlik lab for helpful discussions. Casp1–/–, Asc–/–, and Nlrp3–/– mice were kindly provided by Dr Vishva M. Dixit (Genentech, USA), Gsdmd–/– femurs by Dr Thirumala-Devi Kanneganti (St. Jude Children’s Research Hospital, USA), mutant S. typhimurium strains by Drs Edward A. Miao (University of North Carolina at Chapel Hill, USA), Samuel I. Miller (University of Washington, USA), and Denise M. Monack (Stanford University, USA), Plasmids pMD2.G and psPAX2 by Didier Trono (École Polytechnique Fédérale de Lausanne, Switzerland), and CMG 14-12 cells by Sunao Takeshita (National Center for Geriatrics and Gerontology Japan). This work was supported by the National Institutes of Health (AI099009, AR064349, and AI120618 to C.S., AI120625 to C.S. and A.D., and AR066739 to A.D.), a Cancer Center Support Grant (CA060553), and the Skin Disease Research Center (AR057216) to C.S. L.H.C. was supported by the Vietnam Education Foundation Fellowship and the American Heart Association (AHA, 15PRE25700116), and M.I. was supported by the AHA (15POST25690052).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Lipopolysaccharide (LPS) of Gram-negative bacteria can elicit a strong immune response. Although extracellular LPS is sensed by TLR4 at the cell surface and triggers a transcriptional response, cytosolic LPS binds and activates non-canonical inflammasome caspases, resulting in pyroptotic cell death, as well as canonical NLRP3 inflammasome-dependent cytokine release. Contrary to the highly regulated multiprotein platform required for caspase-1 activation in the canonical inflammasomes, the non-canonical mouse caspase-11 and the orthologous human caspase-4 function simultaneously as innate sensors and effectors, and their regulation is unclear. Here we show that the oxidized phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) inhibits the non-canonical inflammasome in macrophages, but not in dendritic cells. Aside from a TLR4 antagonistic role, oxPAPC binds directly to caspase-4 and caspase-11, competes with LPS binding, and consequently inhibits LPS-induced pyroptosis, IL-1β release and septic shock. Therefore, oxPAPC and its derivatives might provide a basis for therapies that target non-canonical inflammasomes during Gram-negative bacterial sepsis.
AB - Lipopolysaccharide (LPS) of Gram-negative bacteria can elicit a strong immune response. Although extracellular LPS is sensed by TLR4 at the cell surface and triggers a transcriptional response, cytosolic LPS binds and activates non-canonical inflammasome caspases, resulting in pyroptotic cell death, as well as canonical NLRP3 inflammasome-dependent cytokine release. Contrary to the highly regulated multiprotein platform required for caspase-1 activation in the canonical inflammasomes, the non-canonical mouse caspase-11 and the orthologous human caspase-4 function simultaneously as innate sensors and effectors, and their regulation is unclear. Here we show that the oxidized phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) inhibits the non-canonical inflammasome in macrophages, but not in dendritic cells. Aside from a TLR4 antagonistic role, oxPAPC binds directly to caspase-4 and caspase-11, competes with LPS binding, and consequently inhibits LPS-induced pyroptosis, IL-1β release and septic shock. Therefore, oxPAPC and its derivatives might provide a basis for therapies that target non-canonical inflammasomes during Gram-negative bacterial sepsis.
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U2 - 10.1038/s41467-018-03409-3
DO - 10.1038/s41467-018-03409-3
M3 - Article
C2 - 29520027
AN - SCOPUS:85047770496
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 996
ER -