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. DinarelloMarcel F. Nold

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)354-365
Number of pages12
JournalNature Immunology
Volume16
Issue number4
DOIs
Publication statusPublished - Mar 19 2015

Fingerprint

Interleukins
Signal Transduction
Anti-Inflammatory Agents
Phosphotransferases
Interleukin Receptors
Ligands
Endotoxemia
Interleukin-1 Receptors
Mitogen-Activated Protein Kinases
Interleukin-1
Proteomics
Transgenic Mice
Lipopolysaccharides
Blood Cells
Transcription Factors

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. / Nold-Petry, Claudia A.; Lo, Camden Y.; Rudloff, Ina; Elgass, Kirstin D.; Li, Suzhao; Gantier, Michael P.; Lotz-Havla, Amelie S.; Gersting, Søren W.; Cho, Steven X.; Lao, Jason C.; Ellisdon, Andrew M.; Rotter, Björn; Azam, Tania; Mangan, Niamh E.; Rossello, Fernando J.; Whisstock, James C.; Bufler, Philip; Garlanda, Cecilia; Mantovani, Alberto; Dinarello, Charles A.; Nold, Marcel F.

In: Nature Immunology, Vol. 16, No. 4, 19.03.2015, p. 354-365.

Research output: Contribution to journalArticle

Nold-Petry, CA, Lo, CY, Rudloff, I, Elgass, KD, Li, S, Gantier, MP, Lotz-Havla, AS, Gersting, SW, Cho, SX, Lao, JC, Ellisdon, AM, Rotter, B, Azam, T, Mangan, NE, Rossello, FJ, Whisstock, JC, Bufler, P, Garlanda, C, Mantovani, A, Dinarello, CA & Nold, MF 2015, 'IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction', Nature Immunology, vol. 16, no. 4, pp. 354-365. https://doi.org/10.1038/ni.3103
Nold-Petry, Claudia A. ; Lo, Camden Y. ; Rudloff, Ina ; Elgass, Kirstin D. ; Li, Suzhao ; Gantier, Michael P. ; Lotz-Havla, Amelie S. ; Gersting, Søren W. ; Cho, Steven X. ; Lao, Jason C. ; Ellisdon, Andrew M. ; Rotter, Björn ; Azam, Tania ; Mangan, Niamh E. ; Rossello, Fernando J. ; Whisstock, James C. ; Bufler, Philip ; Garlanda, Cecilia ; Mantovani, Alberto ; Dinarello, Charles A. ; Nold, Marcel F. / IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. In: Nature Immunology. 2015 ; Vol. 16, No. 4. pp. 354-365.
@article{e99a2b4fd69041978b11207779f58663,
title = "IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction",
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.",
author = "Nold-Petry, {Claudia A.} and Lo, {Camden Y.} and Ina Rudloff and Elgass, {Kirstin D.} and Suzhao Li and Gantier, {Michael P.} and Lotz-Havla, {Amelie S.} and Gersting, {S{\o}ren W.} and Cho, {Steven X.} and Lao, {Jason C.} and Ellisdon, {Andrew M.} and Bj{\"o}rn Rotter and Tania Azam and Mangan, {Niamh E.} and Rossello, {Fernando J.} and Whisstock, {James C.} and Philip Bufler and Cecilia Garlanda and Alberto Mantovani and Dinarello, {Charles A.} and Nold, {Marcel F.}",
year = "2015",
month = "3",
day = "19",
doi = "10.1038/ni.3103",
language = "English",
volume = "16",
pages = "354--365",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction

AU - Nold-Petry, Claudia A.

AU - Lo, Camden Y.

AU - Rudloff, Ina

AU - Elgass, Kirstin D.

AU - Li, Suzhao

AU - Gantier, Michael P.

AU - Lotz-Havla, Amelie S.

AU - Gersting, Søren W.

AU - Cho, Steven X.

AU - Lao, Jason C.

AU - Ellisdon, Andrew M.

AU - Rotter, Björn

AU - Azam, Tania

AU - Mangan, Niamh E.

AU - Rossello, Fernando J.

AU - Whisstock, James C.

AU - Bufler, Philip

AU - Garlanda, Cecilia

AU - Mantovani, Alberto

AU - Dinarello, Charles A.

AU - Nold, Marcel F.

PY - 2015/3/19

Y1 - 2015/3/19

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84925671141&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84925671141&partnerID=8YFLogxK

U2 - 10.1038/ni.3103

DO - 10.1038/ni.3103

M3 - Article

C2 - 25729923

AN - SCOPUS:84925671141

VL - 16

SP - 354

EP - 365

JO - Nature Immunology

JF - Nature Immunology

SN - 1529-2908

IS - 4

ER -