IL-37 requires IL-18Rα and SIGIRR to carry out its multi-faceted anti-inflammatory program on innate signal transduction — ASN Events
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  3. IL-37 requires IL-18Rα and SIGIRR to carry out its multi-faceted anti-inflammatory program on innate signal transduction

IL-37 requires IL-18Rα and SIGIRR to carry out its multi-faceted anti-inflammatory program on innate signal transduction (#308)

Claudia A Nold 1 2 , Camden Y Lo 3 , Ina Rudloff 1 2 , Suzhao Li 4 , Michael P Gantier 3 , Bjoern M Rotter 5 , Amelie S Lotz 6 , Soeren W Gersting 6 , Tania Azam 4 , Steven X Cho 1 2 , Philip Bufler 6 , Cecilia Garlanda 7 , Alberto Mantovani 7 , Charles A Dinarello 4 , Marcel F Nold 1 2
  1. Department of Paediatrics, Monash University, Melbourne, VIC, Australia
  2. Ritchie Centre, MIMR-PHI Institute of Medical Research, Melbourne, VIC, Australia
  3. MIMR-PHI Institute of Medical Research, Clayton, VIC, Australia
  4. Department of Medicine, University of Colorado Denver, Aurora, CO, USA
  5. GenXPro, Frankfurt, Germany
  6. Department of Pediatrics, Ludwig-Maximilians University, Munich, Germany
  7. Humanitas Clinical and Research Center, Rozzano, Italy

Aims. Both IL‑37 and SIGIRR (TIR8, IL‑1R8) are anti-inflammatory orphan IL‑1 ligand and receptor family members. Association of recombinant IL-37 with IL-18 receptor alpha (IL-18Rα) was reported, but no biological activity was observed. Therefore, we investigated the interactions between IL-37, SIGIRR and IL-18Rα, and their effects on intracellular signaling.

Methods and results. In IL-37-transfected THP-1 macrophages, we observed an 83% reduction in IL-1β, but only 34% when endogenous SIGIRR was silenced. A similar attenuation of IL-37-induced anti-inflammation was demonstrated in LPS-stimulated human PBMC, and by IL-18Rα silencing. By immunoprecipitation and immunofluorescence, IL-37 associates with SIGIRR and IL-18Rα in A549 epithelial cells and RAW macrophages, both transfected with IL-37. 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 demonstrated each pair’s sub-40nm co-localization. These cell surface-interactions were maximal 30min after LPS. Formation of the three-component ligand-receptor complex was confirmed by BRET and super-resolution microscopy. We next generated a strain of SIGIRR-KO mice transgenic for IL-37 (IL-37tg-SIGIRR-KO). As expected, IL-37tg mice were protected from endotoxic shock; however, IL-37tg-SIGIRR-KO mice were not: LPS induced severe hypothermia (trough 25°C) and acidosis (pH7.16) in wild-type, but not in IL-37tg mice (29°C, pH7.32). In IL-37tg-SIGIRR-KO mice, these protective effects were considerably weaker. Mechanistical exploration of the effects of the IL-37 receptor complex on intracellular signaling by proteomic and transcriptomic methods revealed that, via SIGIRR, IL‑37 exploits the activities of anti-inflammatory mediators, e.g. Dok1, and inhibits not only NF-κB and MAPKs, but also mTor and Tak1.

Conclusions. IL-37 engages in a cell surface-complex with IL-18Rα and SIGIRR to limit the severity of inflammation by activating an intracellular anti-inflammatory program. As it blocks mTor, IL-37 may function as an endogenous rapamycin. SIGIRR utilizes an unexpected second mechanism of action in addition to the known decoy functions.