IL-38 reprograms macrophage metabolism to restrain NLRP3 inflammasome assembly and attenuate monosodium urate crystals induced inflammation.

OBJECTIVE

Although interleukin (IL)-38 is recognized as an anti-inflammatory cytokine, its precise mechanism in monosodium urate (MSU) crystals induced inflammation remains undefined, and its impact on macrophages metabolism during MSU crystals induced inflammation has not been explored.

METHOD: RAW264.7 cells, THP-1 cells and mouse peritoneal macrophages were stimulated with MSU crystals with or without recombinant IL-38. Glucose uptake, Glucose Transporter Type 1 (GLUT1) expression, Reactive Oxygen Species (ROS) levels and NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome activation and assembly were assessed by quantitative real-time PCR, immunofluorescence and western blot. In vivo, C57BL/6 mice received daily intraperitoneal injection of recombinant mouse IL-38(rmIL-38) or vehicle for 5 days, followed by MSU crystals intraperitoneal injection. Lavage cytokines and inflammasome proteins were quantified.

RESULTS

IL-38 attenuated MSU crystals induced up-regulation of NLRP3 inflammasome. MSU crystals rapidly up-regulated GLUT1, increased glucose uptake and ROS production, and promoted NLRP3-apoptosis-associated speck-like protein containing a CARD(ASC)-caspase-1 speck formation. In vivo, IL-38 pretreatment reduced lavage IL-1β and CC motif chemokine ligand 2 and suppressed NLRP3/caspase-1/ASC expression in peritoneal macrophages. Treatment with rmIL-38 alleviated arthritis by MSU crystals.

CONCLUSION

IL-38 acts as a metabolic regulatory cytokine that restraints GLUT1-mediated glycolysis and ROS production, thereby preventing NLRP3 inflammasome assembly and activation. These findings position IL-38 as a promising upstream therapeutic for acute gout.