Objective: Although the pathogenesis of psoriasis is largely unknown accumulating evidences configure it as an immune-mediated disease determined through cytokines-mediated positive loops between activated lymphocytes subsets and keratinocytes. Mitochondria in addition to their role in the cell bioenergetics are now recognized as a decisional hub in controlling the immunological response. In the present study we compared mitochondria-related functions of PBMC between psoriatic patients and healthy controls. Methods: Freshly isolated PBMC from eleven psoriatic patients and nine healthy controls were subjected to mitochondria-dependent respiratory activity measurements by high-resolution oxymetry and the specific activity of respiratory chain complexes assessed by spectrophotometric assays. Quantitative RT-PCR and immunoblotting were applied to detect the level of selected transcripts and proteins respectively. Results: Respirometric analysis unveiled in patients’ cells a significant three-fold increase of oligomycinsensitive endogenous mitochondria-driven oxygen consumption, which was traceable back to a specific increased activity of the respiratory chain complex I. Analysis by quantitative RT-PCR of transcription factors regulating the mitochondrial biogenesis did not result in significant changes between patients and control cells and was confirmed by the unaffected expression of the complex I subunits. Treatment of either patients’ or control cells with isoproterenol and IBMX ruled out the involvement of a cAMP-PKA-mediated post-transcriptional modification of the respiratory complex. GRIM19 a pleiotropic protein, involved in the structural and functional stabilization of complex I and in the mitochondrial translocation of STAT3 was significantly up-regulated in patients’ cells. Phosphorylation at S727 of STAT3 was increased in patients’cells, which, in addition, unveiled a shift in the relative expression of the STAT3α/β splisoforms. Conclusion: Altogether the results obtained suggest the occurrence in circulating mononucleate cells from psoriatic patients of an altered activity of complex I likely mediated by up-regulation of GRIM19/STAT3β, which might lead to a chronic activation of T-lymphocytes thereby contributing to the development of psoriasis.

Alterations of Mitochondrial Respiration and Complex I Activity in Mononucleate Cells from Psoriatic Patients: Possible Involvement of GRIM-19-STAT3α/β

SCRIMA, ROSELLA;PICCOLI, CLAUDIA;MASTROLONARDO, MARIO;CAPITANIO, NAZZARENO
2014

Abstract

Objective: Although the pathogenesis of psoriasis is largely unknown accumulating evidences configure it as an immune-mediated disease determined through cytokines-mediated positive loops between activated lymphocytes subsets and keratinocytes. Mitochondria in addition to their role in the cell bioenergetics are now recognized as a decisional hub in controlling the immunological response. In the present study we compared mitochondria-related functions of PBMC between psoriatic patients and healthy controls. Methods: Freshly isolated PBMC from eleven psoriatic patients and nine healthy controls were subjected to mitochondria-dependent respiratory activity measurements by high-resolution oxymetry and the specific activity of respiratory chain complexes assessed by spectrophotometric assays. Quantitative RT-PCR and immunoblotting were applied to detect the level of selected transcripts and proteins respectively. Results: Respirometric analysis unveiled in patients’ cells a significant three-fold increase of oligomycinsensitive endogenous mitochondria-driven oxygen consumption, which was traceable back to a specific increased activity of the respiratory chain complex I. Analysis by quantitative RT-PCR of transcription factors regulating the mitochondrial biogenesis did not result in significant changes between patients and control cells and was confirmed by the unaffected expression of the complex I subunits. Treatment of either patients’ or control cells with isoproterenol and IBMX ruled out the involvement of a cAMP-PKA-mediated post-transcriptional modification of the respiratory complex. GRIM19 a pleiotropic protein, involved in the structural and functional stabilization of complex I and in the mitochondrial translocation of STAT3 was significantly up-regulated in patients’ cells. Phosphorylation at S727 of STAT3 was increased in patients’cells, which, in addition, unveiled a shift in the relative expression of the STAT3α/β splisoforms. Conclusion: Altogether the results obtained suggest the occurrence in circulating mononucleate cells from psoriatic patients of an altered activity of complex I likely mediated by up-regulation of GRIM19/STAT3β, which might lead to a chronic activation of T-lymphocytes thereby contributing to the development of psoriasis.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11369/304566
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