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Cyclophilin D disruption attenuates lipopolysaccharide-induced inflammatory response in primary mouse macrophages
Janos Priber1, Fruzsina Fonai, Peter Balazs Jakus
1Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 12 Szigeti St., H-7624 Pecs, Hungary.
Abstract:
According to recent results, various mitochondrial processes can actively regulate the immune response. In the present report, we studied whether mitochondrial permeability transition (mPT) has such a role. To this end, we compared bacterial lipopolysaccharide (LPS)-induced inflammatory response in cyclophilin D (CypD) knock-out and wild-type mouse resident peritoneal macrophages. CypD is a regulator of mPT; therefore, mPT is damaged in CypD(-/-) cells. We chose this genetic modification-based model because the mPT inhibitor cyclosporine A regulates inflammatory processes by several pathways unrelated to the mitochondria. The LPS increased mitochondrial depolarisation, cellular and mitochondrial reactive oxygen species production, nuclear factor-κB activation, and nitrite- and tumour necrosis factor α accumulation in wild-type cells, but these changes were diminished or absent in the CypD-deficient macrophages. Additionally, LPS enhanced Akt phosphorylation/activation as well as FOXO1 and FOXO3a phosphorylation/inactivation both in wild-type and CypD(-/-) cells. However, Akt and FOXO phosphorylation was significantly more pronounced in CypD-deficient compared to wild-type macrophages. These results provide the first pieces of experimental evidence for the functional regulatory role of mPT in the LPS-induced early inflammatory response of macrophages.
Insights
Mitochondrial permeability transition (mPT) regulates the early inflammatory response. Blocking mPT in macrophages via CypD deficiency significantly reduces lipopolysaccharide (LPS)-induced inflammation and alters key signaling pathways.
Area of Science:
- Immunology
- Mitochondrial Biology
- Cellular Signaling
Background:
- Mitochondria play a crucial role in regulating immune responses.
- The involvement of mitochondrial permeability transition (mPT) in inflammation is not fully understood.
Purpose of the Study:
- To investigate the role of mPT in the inflammatory response mediated by macrophages.
- To determine if mPT regulates lipopolysaccharide (LPS)-induced inflammation.
Main Methods:
- Comparison of LPS-induced inflammatory responses in wild-type and cyclophilin D (CypD) knock-out mouse macrophages.
- Assessment of mitochondrial depolarization, reactive oxygen species (ROS) production, NF-κB activation, and cytokine/nitrite accumulation.
- Analysis of Akt and FOXO signaling pathway activation.
Main Results:
- CypD deficiency diminished LPS-induced mitochondrial depolarization, ROS production, NF-κB activation, and TNF-α/nitrite accumulation.
- LPS induced greater Akt and FOXO phosphorylation/inactivation in CypD-deficient macrophages compared to wild-type.
- These findings indicate a regulatory role for mPT in macrophage inflammatory responses.
Conclusions:
- Mitochondrial permeability transition (mPT) is a functional regulator of the early inflammatory response in macrophages.
- mPT modulates key signaling pathways, including NF-κB, Akt, and FOXO, during LPS stimulation.
