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 DinarelloMarcel Friedrich Nold

Research output: Contribution to journalArticleResearchpeer-review

180 Citations (Scopus)

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

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