LAUSR

OBJECTIVE Interleukin (IL)-37 is a natural suppressor of inflammation. Macrophages play an important role in acute gout flare by dominating the inflammation and spontaneous relief. We have reported IL-37 could limit runaway inflammation in gout. Here we focus on whether IL-37 inhibits gouty inflammation by altering macrophage functions and how it does. METHODS Macrophage functions were evaluated in terms of phagocytosis, pyroptosis, polarization, and metabolism. Phagocytosis and polarization of macrophages were detected by side scattering and double-labelling iNOS/Arg-1 using flow cytometry, respectively. Transcription of pyroptosis-related molecules was detected by qPCR. Metabolomics was performed by liquid chromatograph mass spectrometer. Human IL-37 knock-in mice and a model with point mutation (S9A) at mouse Gsk3b locus were created by CRISPR/Cas-mediated genome engineering. MSU was injected into paws and peritoneal cavity to model acute gout. Vernier caliper was used to measure the thickness of the paws. The mice paws and human synovium tissues or tophi were collected for pathological staining. Peritoneal fluid of mice was used to enrich macrophages to detect polarization. RESULTS IL-37 promoted non-inflammatory phagocytic activity of macrophages, by enhancing phagocytosis of MSU, reducing pyroptosis-related proteins transcription and inflammatory cytokines releasing, protecting mitochondrial function, and mediating metabolic reprogramming in MSU-treated THP-1 cells. These multifaceted roles of IL-37 were partly depended on the mediation of glycogen synthase kinase-3β (GSK-3β). CONCLUSIONS Our study revealed that IL-37 could shape macrophages into a "silent" non-inflammatory phagocytic fashion. IL-37 may become a potentially valuable treatment option for patients of chronic gout, especially for those with tophi.