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

Claudia Annelie Nold-Petry, Camden Yeung-Wah Lo, Ina Rudloff, Kirstin Elgass, Suzhao Li, Michael Paul Marie Gantier, Amelie Sophia Lotz-Havla, Soren W Gersting, Steven Cho, Chun Wang Jason Lao, Andrew Malcolm Ellisdon, Bjorn Rotterd, Tania Azam, Niamh Mangan, Fernando Jaime Rossello, James Whisstock, Philip Bufler, Cecilia Garlanda, Alberto A Mantovani, Charles A Dinarello & 1 others Marcel Friedrich Nold

Research output: Contribution to journalArticleResearchpeer-review

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-18Ralpha. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Ralpha 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-kappaB, 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-18Ralpha 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 - 2015

Cite this

Nold-Petry, Claudia Annelie ; Lo, Camden Yeung-Wah ; Rudloff, Ina ; Elgass, Kirstin ; Li, Suzhao ; Gantier, Michael Paul Marie ; Lotz-Havla, Amelie Sophia ; Gersting, Soren W ; Cho, Steven ; Lao, Chun Wang Jason ; Ellisdon, Andrew Malcolm ; Rotterd, Bjorn ; Azam, Tania ; Mangan, Niamh ; Rossello, Fernando Jaime ; Whisstock, James ; Bufler, Philip ; Garlanda, Cecilia ; Mantovani, Alberto A ; Dinarello, Charles A ; Nold, Marcel Friedrich. / IL-37 requires the receptors IL-18Ralpha 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.
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title = "IL-37 requires the receptors IL-18Ralpha 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-18Ralpha. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Ralpha 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-kappaB, 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-18Ralpha and exploited IL-1R8 to activate a multifaceted intracellular anti-inflammatory program.",
author = "Nold-Petry, {Claudia Annelie} and Lo, {Camden Yeung-Wah} and Ina Rudloff and Kirstin Elgass and Suzhao Li and Gantier, {Michael Paul Marie} and Lotz-Havla, {Amelie Sophia} and Gersting, {Soren W} and Steven Cho and Lao, {Chun Wang Jason} and Ellisdon, {Andrew Malcolm} and Bjorn Rotterd and Tania Azam and Niamh Mangan and Rossello, {Fernando Jaime} and James Whisstock and Philip Bufler and Cecilia Garlanda and Mantovani, {Alberto A} and Dinarello, {Charles A} and Nold, {Marcel Friedrich}",
year = "2015",
doi = "10.1038/ni.3103",
language = "English",
volume = "16",
pages = "354 -- 365",
journal = "Nature Immunology",
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IL-37 requires the receptors IL-18Ralpha and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. / Nold-Petry, Claudia Annelie; Lo, Camden Yeung-Wah; Rudloff, Ina; Elgass, Kirstin; Li, Suzhao; Gantier, Michael Paul Marie; Lotz-Havla, Amelie Sophia; Gersting, Soren W; Cho, Steven; Lao, Chun Wang Jason; Ellisdon, Andrew Malcolm; Rotterd, Bjorn; Azam, Tania; Mangan, Niamh; Rossello, Fernando Jaime; Whisstock, James; Bufler, Philip; Garlanda, Cecilia; Mantovani, Alberto A; Dinarello, Charles A; Nold, Marcel Friedrich.

In: Nature Immunology, Vol. 16, No. 4, 2015, p. 354 - 365.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

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

AU - Nold-Petry, Claudia Annelie

AU - Lo, Camden Yeung-Wah

AU - Rudloff, Ina

AU - Elgass, Kirstin

AU - Li, Suzhao

AU - Gantier, Michael Paul Marie

AU - Lotz-Havla, Amelie Sophia

AU - Gersting, Soren W

AU - Cho, Steven

AU - Lao, Chun Wang Jason

AU - Ellisdon, Andrew Malcolm

AU - Rotterd, Bjorn

AU - Azam, Tania

AU - Mangan, Niamh

AU - Rossello, Fernando Jaime

AU - Whisstock, James

AU - Bufler, Philip

AU - Garlanda, Cecilia

AU - Mantovani, Alberto A

AU - Dinarello, Charles A

AU - Nold, Marcel Friedrich

PY - 2015

Y1 - 2015

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-18Ralpha. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Ralpha 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-kappaB, 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-18Ralpha 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-18Ralpha. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Ralpha 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-kappaB, 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-18Ralpha and exploited IL-1R8 to activate a multifaceted intracellular anti-inflammatory program.

UR - http://www.nature.com/ni/journal/v16/n4/pdf/ni.3103.pdf

U2 - 10.1038/ni.3103

DO - 10.1038/ni.3103

M3 - Article

VL - 16

SP - 354

EP - 365

JO - Nature Immunology

JF - Nature Immunology

SN - 1529-2908

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