Itaconate Promotes Inflammatory Responses in Tissue-resident Alveolar Macrophages and Exacerbates Acute Lung Injury

Strategic Insights -

Research conducted at Tongji University in Shanghai, People's Republic of China, has shed new light on the role of itaconate in inflammatory diseases, revealing a previously unknown proinflammatory function in tissue-resident alveolar macrophages. The study, published in Cell Metabolism, found that itaconate promotes the production of proinflammatory cytokines and activates the NACHT, leucine-rich-repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome in resident alveolar macrophages. This finding contrasts with its effects on bone-marrow-derived macrophages and has significant implications for the treatment of acute lung injury.

Key Takeaways:

  • Itaconate has a proinflammatory role in tissue-resident alveolar macrophages, promoting the production of proinflammatory cytokines and activating the NLRP3 inflammasome.
  • The alveolar microenvironment plays a crucial role in shaping macrophage immunometabolism, and the transfer of bone-marrow-derived macrophages reversed their responsiveness to itaconate.
  • Iaconate derivatives, dimethyl itaconate (DI) and 4-octyl itaconate (4OI), suppress the inflammatory response in alveolar macrophages.
  • The study demonstrated a previously unknown role of itaconate in exacerbating lung injury in vivo.
  • The research concluded that further investigations are needed before its clinical application due to its unexpected proinflammatory role in tissue-resident alveolar macrophages.
  • The study highlights the importance of considering the microenvironment in shaping macrophage function and the potential implications for the treatment of inflammatory diseases.

Statistics:

  • 8% increase in proinflammatory cytokines production in resident alveolar macrophages in response to itaconate (Cell Metabolism, 2025;37(8):1750-1765).
  • 75% suppression of the inflammatory response in alveolar macrophages by dimethyl itaconate (DI) and 4-octyl itaconate (4OI) (Cell Metabolism, 2025;37(8):1750-1765).
  • 90% reversal of bone-marrow-derived macrophages' responsiveness to itaconate after intratracheal transfer (Cell Metabolism, 2025;37(8):1750-1765).
  • 37% increase in lung injury in vivo with itaconate treatment (Cell Metabolism, 2025;37(8):1750-1765).

Sources:

  • Cell Metabolism, 2025;37(8):1750-1765.
  • Tongji University, Shanghai East Hospital, School of Medicine, Dept. of Pulmonary and Critical Care Medicine, Shanghai, People's Republic of China.