Mitochondrial respiratory complex III sustains IL-10 production in activated macrophages and promotes tumor-mediated immune evasion

  • Sci Adv. 2025 Jan 24;11(4):eadq7307. doi: 10.1126/sciadv.adq7307.
Alessia Zotta  1 ,  Juliana Toller-Kawahisa  1 ,  Eva M Palsson-McDermott  1 ,  Shane M O'Carroll  1 ,  Órlaith C Henry  1 ,  Emily A Day  1  2 ,  Anne F McGettrick  1 ,  Ross W Ward  1 ,  Dylan G Ryan  3 ,  Mark A Watson  4 ,  Martin D Brand  4 ,  Marah C Runtsch  5 ,  Kathrin Maitz  5 ,  Anna Lueger  5 ,  Julia Kargl  5 ,  Jan L Miljkovic  3 ,  Ed C Lavelle  1 ,  Luke A J O'Neill  1
Affiliations
  • 1. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
  • 2. Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada.
  • 3. Mitochondria Biology Unit, University of Cambridge, Cambridge, UK.
  • 4. Buck Institute for Research on Aging, Novato, CA, USA.
  • 5. Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria.
PMID: 39841829 DOI: 10.1126/sciadv.adq7307
Abstract

The cytokine interleukin-10 (IL-10) limits the immune response and promotes resolution of acute inflammation. Because of its immunosuppressive effects, IL-10 up-regulation is a common feature of tumor progression and metastasis. Recently, IL-10 regulation has been shown to depend on mitochondria and redox-sensitive signals. We have found that Suppressor of site IIIQo Electron Leak 1.2 (S3QEL 1.2), a specific inhibitor of Reactive Oxygen Species (ROS) production from mitochondrial complex III, and myxothiazol, a complex III inhibitor, decrease IL-10 in lipopolysaccharide (LPS)-activated macrophages. IL-10 down-regulation is likely to be mediated by suppression of c-Fos, which is a subunit of activator protein 1 (AP1), a transcription factor required for IL-10 gene expression. S3QEL 1.2 impairs IL-10 production in vivo after LPS challenge and promotes the survival of mice bearing B16F10 melanoma by lowering tumor growth. Our data identify a link between complex III-dependent ROS generation and IL-10 production in macrophages, the targeting of which could have potential in boosting antitumor immunity.

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