Interleukin 37 employs the IL-1 family orphan receptor SIGIRR and the alpha chain of the IL-18 receptor to inhibit innate immunity (P6293)

Abstract IL-37 is a powerful anti-inflammatory IL-1 family member with activity against a broad spectrum of inflammatory assaults. One mechanism by which this beneficial effect is mediated is via intracellular association with Smad3; however, the cell surface receptor for IL-37 remains unknown. Here, we show that to block inflammation, IL-37 requires IL-18Rα and SIGIRR, a so-far orphaned member of the IL-1R family. In PBMC, which naturally express IL-37, knockdown of SIGIRR increased IL-1β and IL-6 threefold. Silencing of SIGIRR in THP-1 cells significantly attenuated the anti-inflammation of IL-37 (83% less IL-1β with IL-37 and SIGIRR, only 34% less without SIGIRR). Similar effects were observed when IL-18Rα was depleted. To study SIGIRR’s contribution to IL-37 function in vivo, we created a strain of SIGIRR-/- mice that express IL-37. The protective effect imparted by IL-37 was markedly reduced in these crossbred mice when they (and wild-type, IL-37-transgenic and SIGIRR-/- animals) were injected with LPS. Using proximity ligation assays and FRET in PBMC, thus exploring interactions of the naturally occurring pairs IL-37-SIGIRR, IL-37-IL-18Rα and SIGIRR-IL-18Rα, we showed sub-40nm colocalization of each complex. The association peaked 30min after LPS stimulation and decreased to background by 4h. Thus, IL-37 limits inflammation by employing the properties of SIGIRR and by associating with IL-18Rα, suggesting that SIGIRR-IL-18Rα functions as the cell surface receptor for IL-37.