Mitochondrial respiratory complex III sustains IL-10 production in activated macrophages and promotes tumor-mediated immune evasion
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 III<sub>Qo</sub> 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 <i>IL-10</i> 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.
Authors
- Juliana E. Toller-Kawahisa (ORCID: https://orcid.org/0000-0001-7323-5036)
- Mark A. Watson
- Martin D. Brand (ORCID: https://orcid.org/0000-0003-4418-6153)
- Eva M. Pålsson‐McDermott (ORCID: https://orcid.org/0009-0005-0201-5171)
- Shane M. O’Carroll
- Julia Kargl (ORCID: https://orcid.org/0000-0002-0870-0816)
- Emily A. Day (ORCID: https://orcid.org/0000-0003-3245-5715)
- Anna Lueger (ORCID: https://orcid.org/0009-0007-9644-4763)
- Ross W. Ward (ORCID: https://orcid.org/0000-0001-5242-4022)
- Kathrin Maitz (ORCID: https://orcid.org/0009-0006-8180-3906)
- Anne F. McGettrick (ORCID: https://orcid.org/0000-0001-6887-7229)
- Marah C. Runtsch (ORCID: https://orcid.org/0000-0002-9059-9269)
- Jan Lj. Miljković (ORCID: https://orcid.org/0000-0002-1910-9677)
- Luke O'neill (ORCID: https://orcid.org/0000-0002-4333-2748)
- Dylan G. Ryan (ORCID: https://orcid.org/0000-0003-4553-9192)
- Ed C. Lavelle (ORCID: https://orcid.org/0000-0002-3167-1080)
- Alessia Zotta (ORCID: https://orcid.org/0009-0004-0158-3241)
- Órlaith C. Henry (ORCID: https://orcid.org/0009-0008-7233-2852)
Institutions
- Western University (CA)
- Buck Institute for Research on Aging (US)
- Medical University of Graz (AT)
- Trinity College Dublin (IE)
- MRC Mitochondrial Biology Unit (GB)
Publication Details
- Journal
- Science Advances
- Published
- 2025-01-22
- DOI
- https://doi.org/10.1126/sciadv.adq7307
- Citations
- 19
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 15.15
Funders
- Buck Institute for Research on Aging