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

doi:10.1038/ni.3103

. 2015 Apr;16(4):354-65.

doi: 10.1038/ni.3103. Epub 2015 Mar 2.

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-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

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 et al. Nat Immunol. 2015 Apr.

. 2015 Apr;16(4):354-65.

doi: 10.1038/ni.3103. Epub 2015 Mar 2.

Authors

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.

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References

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[1] Immunity. 2013 Dec 12;39(6):1003-18 - PubMed

[2] Immunity. 2013 Dec 12;39(6):1003-18 - PubMed

[3] Trends Immunol. 2009 Sep;30(9):439-46 - PubMed

[4] Trends Immunol. 2009 Sep;30(9):439-46 - PubMed

[5] Immunity. 2010 Jan 29;32(1):54-66 - PubMed

[6] Immunity. 2010 Jan 29;32(1):54-66 - PubMed

[7] J Am Soc Nephrol. 2005 Oct;16(10 ):2897-905 - PubMed

[8] J Am Soc Nephrol. 2005 Oct;16(10 ):2897-905 - PubMed

[9] Cytokine. 2001 Jan 7;13(1):1-7 - PubMed

[10] Cytokine. 2001 Jan 7;13(1):1-7 - PubMed

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

Affiliations

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

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