IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction

Claudia A Nold-Petry; Camden Y Lo; Ina Rudloff; Kirstin D Elgass; Suzhao Li; Michael P Gantier; Amelie S Lotz-Havla; Søren W Gersting; Steven X Cho; Jason C Lao; Andrew M Ellisdon; Björn Rotter; Tania Azam; Niamh E Mangan; Fernando J Rossello; James C Whisstock; Philip Bufler; Cecilia Garlanda; Alberto Mantovani; Charles A Dinarello; Marcel F Nold

doi:10.1038/ni.3103

IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction

Nat Immunol. 2015 Apr;16(4):354-65. doi: 10.1038/ni.3103. Epub 2015 Mar 2.

Authors

Claudia A Nold-Petry¹, Camden Y Lo², Ina Rudloff¹, Kirstin D Elgass³, Suzhao Li⁴, Michael P Gantier⁵, Amelie S Lotz-Havla⁶, Søren W Gersting⁶, Steven X Cho¹, Jason C Lao¹, Andrew M Ellisdon⁷, Björn Rotter⁸, Tania Azam⁴, Niamh E Mangan⁹, Fernando J Rossello¹⁰, James C Whisstock⁷, Philip Bufler¹¹, Cecilia Garlanda¹², Alberto Mantovani¹³, Charles A Dinarello¹⁴, Marcel F Nold¹⁵

Affiliations

¹ 1] Ritchie Centre, MIMR-PHI Institute of Medical Research, Melbourne, Victoria, Australia. [2] Department of Paediatrics, Monash University, Melbourne, Australia.
² 1] Ritchie Centre, MIMR-PHI Institute of Medical Research, Melbourne, Victoria, Australia. [2] Monash Micro Imaging, Monash University, Melbourne, Australia.
³ Monash Micro Imaging, Monash University, Melbourne, Australia.
⁴ Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
⁵ 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.
⁶ Molecular Pediatrics, Ludwig-Maximilians University, Munich, Germany.
⁷ 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.
⁸ GenXPro, Frankfurt, Germany.
⁹ 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.
¹⁰ Victorian Bioinformatics Consortium, Monash University, Melbourne, Australia.
¹¹ Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, Munich, Germany.
¹² Humanitas Clinical and Research Center, Rozzano, Italy.
¹³ 1] Humanitas Clinical and Research Center, Rozzano, Italy. [2] Humanitas University, Rozzano, Italy.
¹⁴ 1] Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA. [2] Radboud University Medical Centre, Nijmegen, the Netherlands.
¹⁵ 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.

PMID: 25729923
DOI: 10.1038/ni.3103

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Gene Expression Regulation
Humans
Immunity, Innate
Inflammation / genetics
Inflammation / immunology
Inflammation / pathology
Interleukin-1 / genetics
Interleukin-1 / immunology*
Interleukin-18 Receptor alpha Subunit / antagonists & inhibitors
Interleukin-18 Receptor alpha Subunit / genetics
Interleukin-18 Receptor alpha Subunit / immunology*
Leukocytes, Mononuclear / drug effects
Leukocytes, Mononuclear / immunology*
Leukocytes, Mononuclear / pathology
Lipopolysaccharides / pharmacology
MAP Kinase Kinase Kinases / genetics
MAP Kinase Kinase Kinases / immunology
Mice
Mice, Transgenic
NF-kappa B / genetics
NF-kappa B / immunology
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / immunology
Protein Binding
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / immunology
Proto-Oncogene Proteins c-fyn / genetics
Proto-Oncogene Proteins c-fyn / immunology
RNA, Small Interfering / genetics
RNA, Small Interfering / immunology
RNA-Binding Proteins / genetics
RNA-Binding Proteins / immunology
Receptor Protein-Tyrosine Kinases / genetics
Receptor Protein-Tyrosine Kinases / immunology
Receptors, Interleukin-1 / antagonists & inhibitors
Receptors, Interleukin-1 / deficiency
Receptors, Interleukin-1 / genetics
Receptors, Interleukin-1 / immunology*
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / immunology
Signal Transduction / immunology*
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / immunology
c-Mer Tyrosine Kinase

Substances

IL37 protein, human
Interleukin-1
Interleukin-18 Receptor alpha Subunit
Lipopolysaccharides
NF-kappa B
P62 protein, human
Proto-Oncogene Proteins
RNA, Small Interfering
RNA-Binding Proteins
Receptors, Interleukin-1
SIGIRR protein, human
STAT3 Transcription Factor
STAT3 protein, human
MTOR protein, human
MERTK protein, human
Receptor Protein-Tyrosine Kinases
c-Mer Tyrosine Kinase
FYN protein, human
Proto-Oncogene Proteins c-fyn
TOR Serine-Threonine Kinases
MAP Kinase Kinase Kinases
MAP kinase kinase kinase 7
PTEN Phosphohydrolase
PTEN protein, human

Associated data

SRA/SRP051714

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding