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

  • Cytokine. 2026 Jun:202:157142. doi: 10.1016/j.cyto.2026.157142.
Lingjiang Zhu  1 ,  Liuqing Wang  2 ,  Yuqi Wang  3 ,  Jundi Wang  4 ,  Dawei Cui  5 ,  Yiwen Wang  6 ,  Lei Liu  7 ,  Jing Xue  8
Affiliations
  • 1. Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Zhejiang 310009, PR China.
  • 2. Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Zhejiang 310009, PR China; Department of Rheumatology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Zhejiang 321000, PR China.
  • 3. Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Zhejiang 310009, PR China; Department of Rheumatology, Affiliated Hangzhou First People's Hospital of Westlake University, School of Medicine, Zhejiang 310006, PR China.
  • 4. Department of Rheumatology, Affiliated Hangzhou First People's Hospital of Westlake University, School of Medicine, Zhejiang 310006, PR China.
  • 5. Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang 310006, PR China.
  • 6. Department of Rheumatology and Immunology, The Affiliated Hospital of Jiaxing University (The First Hospital of Jiaxing), No. 1882 Zhonghuan South Road, Jiaxing, Zhejiang 314000, PR China. Electronic address: [email protected].
  • 7. Department of Rheumatology, Affiliated Hangzhou First People's Hospital of Westlake University, School of Medicine, Zhejiang 310006, PR China. Electronic address: [email protected].
  • 8. Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Zhejiang 310009, PR China. Electronic address: [email protected].
PMID: 41931855 DOI: 10.1016/j.cyto.2026.157142
Abstract

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.

Keywords
GLUT1; Glycolysis; Gout; IL-38; NLRP3.
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