IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction.
Interleukin 37 (IL-37) and IL-1R8 (SIGIRR or TIR8) are anti-inflammatory orphan members of the IL-1 ligand family and IL-1 receptor family, respectively. Here we demonstrate formation and function of the endogenous ligand-receptor complex IL-37-IL-1R8-IL-18Rα. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Rα impaired the anti-inflammatory activity of IL-37. Whereas mice with transgenic expression of IL-37 (IL-37tg mice) with intact IL-1R8 were protected from endotoxemia, IL-1R8-deficient IL-37tg mice were not. Proteomic and transcriptomic investigations revealed that IL-37 used IL-1R8 to harness the anti-inflammatory properties of the signaling molecules Mer, PTEN, STAT3 and p62(dok) and to inhibit the kinases Fyn and TAK1 and the transcription factor NF-κB, as well as mitogen-activated protein kinases. Furthermore, IL-37-IL-1R8 exerted a pseudo-starvational effect on the metabolic checkpoint kinase mTOR. IL-37 thus bound to IL-18Rα and exploited IL-1R8 to activate a multifaceted intracellular anti-inflammatory program.
1] Ritchie Centre, MIMR-PHI Institute of Medical Research, Melbourne, Victoria, Australia. [2] Department of Paediatrics, Monash University, Melbourne, Australia.
Claudia A
CA
Nold-Petry
1] Ritchie Centre, MIMR-PHI Institute of Medical Research, Melbourne, Victoria, Australia. [2] Monash Micro Imaging, Monash University, Melbourne, Australia.
Camden Y
CY
Lo
1] Ritchie Centre, MIMR-PHI Institute of Medical Research, Melbourne, Victoria, Australia. [2] Department of Paediatrics, Monash University, Melbourne, Australia.
Ina
I
Rudloff
Monash Micro Imaging, Monash University, Melbourne, Australia.
Kirstin D
KD
Elgass
Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
Suzhao
S
Li
1] Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Melbourne, Victoria, Australia. [2] Department of Molecular and Translational Science, Monash University, Melbourne, Australia.
Michael P
000000033740698X
MP
Gantier
Molecular Pediatrics, Ludwig-Maximilians University, Munich, Germany.
Amelie S
AS
Lotz-Havla
Molecular Pediatrics, Ludwig-Maximilians University, Munich, Germany.
Søren W
SW
Gersting
1] Ritchie Centre, MIMR-PHI Institute of Medical Research, Melbourne, Victoria, Australia. [2] Department of Paediatrics, Monash University, Melbourne, Australia.
Steven X
SX
Cho
1] Ritchie Centre, MIMR-PHI Institute of Medical Research, Melbourne, Victoria, Australia. [2] Department of Paediatrics, Monash University, Melbourne, Australia.
Jason C
JC
Lao
1] Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia. [2] Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, Australia.
Andrew M
AM
Ellisdon
GenXPro, Frankfurt, Germany.
Björn
B
Rotter
Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
Tania
T
Azam
1] Department of Molecular and Translational Science, Monash University, Melbourne, Australia. [2] Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Melbourne, Australia.
Niamh E
NE
Mangan
Victorian Bioinformatics Consortium, Monash University, Melbourne, Australia.
Fernando J
0000000338858777
FJ
Rossello
1] Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia. [2] Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, Australia.
James C
JC
Whisstock
Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, Munich, Germany.
Philip
P
Bufler
Humanitas Clinical and Research Center, Rozzano, Italy.
Cecilia
C
Garlanda
1] Humanitas Clinical and Research Center, Rozzano, Italy. [2] Humanitas University, Rozzano, Italy.
Alberto
A
Mantovani
1] Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA. [2] Radboud University Medical Centre, Nijmegen, the Netherlands.
Charles A
CA
Dinarello
1] Ritchie Centre, MIMR-PHI Institute of Medical Research, Melbourne, Victoria, Australia. [2] Department of Paediatrics, Monash University, Melbourne, Australia. [3] Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
Marcel F
MF
Nold
D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology*; D053727:Interleukin-18 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000276:immunology; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D000076202:c-Mer Tyrosine Kinase; D000099151:MAP Kinase Kinase Kinase 7
D007375:Interleukin-1; D053727:Interleukin-18 Receptor alpha Subunit; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D011518:Proto-Oncogene Proteins; D051076:Proto-Oncogene Proteins c-fyn; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D020794:Receptor Protein-Tyrosine Kinases; D017472:Receptors, Interleukin-1; D050796:STAT3 Transcription Factor; D058570:TOR Serine-Threonine Kinases; D000076202:c-Mer Tyrosine Kinase; D000099151:MAP Kinase Kinase Kinase 7; C508587:IL37 protein, human; C118585:P62 protein, human; C546891:SIGIRR protein, human; C494086:STAT3 protein, human; C546842:MTOR protein, human; C097072:MERTK protein, human; C494957:FYN protein, human; C494929:PTEN protein, human