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.
Nold-Petry, C. A.
, Lo, C. Y-W., Rudloff, I., Elgass, K.
, Li, S., Gantier, M. P. M.
, Lotz-Havla, A. S., Gersting, S. W., Cho, S., Lao, C. W. J., Ellisdon, A. M.
, Rotterd, B., Azam, T., Mangan, N., Rossello, F. J., Whisstock, J.
, Bufler, P., Garlanda, C., Mantovani, A. A., ... Nold, M. F.
(2015). IL-37 requires the receptors IL-18Ralpha and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction
. Nature Immunology
(4), 354 - 365. https://doi.org/10.1038/ni.3103