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

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.

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.

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.

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.