Mitochondria contribute to LPS-induced MAPK activation via uncoupling protein UCP2 in macrophages

Yalin Emre , Corinne Hurtaud , Tobias Nübel , François Criscuolo , Daniel Ricquier , Anne-Marie Cassard-Doulcier (1)

1 Cytokines, chimiokines et immunopathologie

The mitochondrion is a major organelle contributing to energy metabolism but also a main site of reactive oxygen species (ROS) production. Lipopolysaccharide (LPS)-induced ROS signaling is a critical event in macrophage activation. We report here that part of LPS-mediated ROS signaling comes from mitochondria inside a signal amplification loop that enhances mitogen-activated protein kinase (MAPK) activation. More precisely, we identified the inner mitochondrial membrane uncoupling protein 2 (UCP2) as a physiological brake on ROS signaling. Stimulation of murine bone marrow-derived macrophages by LPS quickly downregulated UCP2 through the JNK and p38 pathways. UCP2 downregulation was shown to be necessary to increase mitochondrial ROS production in order to potentiate MAPK activation. Consistent with this, UCP2-deficient macrophages exhibit an enhanced inflammatory state characterized by increased nitric oxide production and elevated migration ability. Additionally, we found that absence of UCP2 renders macrophages more resistant to NO-induced apoptosis.

Mots clés: Life Sciences

Yalin Emre, Corinne Hurtaud, Tobias Nübel, François Criscuolo, Daniel Ricquier, et al.. Mitochondria contribute to LPS-induced MAPK activation via uncoupling protein UCP2 in macrophages. Biochemical Journal, 2006, 402 (2), pp.271-278. ⟨10.1042/BJ20061430⟩. ⟨hal-00478667⟩