Cyclophilin D disruption attenuates lipopolysaccharide-induced inflammatory response in primary mouse macrophages

Pribér, János Krisztián and Fónai, Fruzsina and Jakus, Péter and Rácz, Boglárka and Chinopoulos, Christos and Tretter, László and Gallyas, Ferenc and Sümegi, Balázs and Veres, Balázs (2015) Cyclophilin D disruption attenuates lipopolysaccharide-induced inflammatory response in primary mouse macrophages. BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE, 93 (3). pp. 241-250. ISSN 0829-8211

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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-kappaB activation, and nitrite- and tumour necrosis factor alpha 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.

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