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Mitochondria complex III-generated superoxide is essential for IL-10 secretion in macrophages

Joshua S Stoolman1, Rogan A Grant1, Leah K Billingham2

  • 1Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Science Advances
|January 22, 2025
PubMed

Insights

Mitochondrial electron transport chain complex III deficiency in macrophages increases susceptibility to infection and shock. Superoxide generation by complex III is crucial for releasing anti-inflammatory IL-10 after TLR stimulation.

Area of Science:

  • Immunology
  • Mitochondrial Biology
  • Cellular Respiration

Background:

  • Mitochondrial electron transport chain (ETC) function impacts macrophage immune responses.
  • The precise mechanisms linking ETC function to macrophage immunity are not fully elucidated.

Purpose of the Study:

  • To investigate the role of ETC complex III (CIII) in macrophage immune responses.
  • To understand how CIII deficiency affects susceptibility to viral infection and endotoxic shock.

Main Methods:

  • Generated mice with CIII-deficient macrophages.
  • Utilized bone marrow-derived macrophages (BMDMs) for in vitro studies.
  • Stimulated BMDMs with Toll-like receptor (TLR) agonists (TLR3, TLR4) and cytokines (IL-4).
  • Assessed IL-10 release and susceptibility to influenza A virus (IAV) and lipopolysaccharide (LPS).

Main Results:

  • Mice with CIII-deficient macrophages showed increased susceptibility to IAV and LPS-induced endotoxic shock.
  • CIII-deficient BMDMs produced less IL-10 following TLR3 or TLR4 stimulation.
  • Restoring respiration with alternative oxidase (AOX) did not reverse shock susceptibility or restore IL-10 release.
  • Protein kinase A (PKA) activation rescued IL-10 release in CIII-deficient BMDMs.
  • IL-4 responses remained unaffected by CIII deficiency.

Conclusions:

  • Mitochondrial CIII-generated superoxide is essential for IL-10 release in response to TLR stimulation.
  • CIII function in macrophages plays a critical role in regulating innate immune responses and host defense.

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