An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells.
Dendritic cells (DCs) use pattern recognition receptors to detect microorganisms and activate protective immunity. These cells and receptors are thought to operate in an all-or-nothing manner, existing in an immunologically active or inactive state. Here, we report that encounters with microbial products and self-encoded oxidized phospholipids (oxPAPC) induce an enhanced DC activation state, which we call "hyperactive." Hyperactive DCs induce potent adaptive immune responses and are elicited by caspase-11, an enzyme that binds oxPAPC and bacterial lipopolysaccharide (LPS). oxPAPC and LPS bind caspase-11 via distinct domains and elicit different inflammasome-dependent activities. Both lipids induce caspase-11-dependent interleukin-1 release, but only LPS induces pyroptosis. The cells and receptors of the innate immune system can therefore achieve different activation states, which may permit context-dependent responses to infection.
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA. Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy. Unit of Cell Signalling and Innate Immunity, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
Ivan
I
Zanoni
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA.
Yunhao
Y
Tan
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA.
Marco
M
Di Gioia
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA.
Achille
A
Broggi
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Jianbin
J
Ruan
National Institute of Biological Sciences, Beijing 102206, China.
Jianjin
J
Shi
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA.
Carlos A
CA
Donado
National Institute of Biological Sciences, Beijing 102206, China.
Feng
F
Shao
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
Hao
H
Wu
Department of Chemical and Paper Engineering, Western Michigan University, Kalamazoo, MI, USA.
James R
JR
Springstead
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA. jonathan.kagan@childrens.harvard.edu.
Jonathan C
JC
Kagan
D056704:Adaptive Immunity; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000276:immunology*; D053471:Caspases, Initiator; D016923:Cell Death / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010743:Phospholipids / Q000378:metabolism*; D051192:Receptors, Pattern Recognition / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism
D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D010743:Phospholipids; D051192:Receptors, Pattern Recognition; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator