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 journalArticlepeer-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-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

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

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