Mitochondrial protein CMPK2 regulates IFN alpha-enhanced foam cell formation, potentially contributing to premature atherosclerosis in SLE

Arthritis Research & Therapy

Chien-Hsiang Wu¹  De-Wei Wu¹  Jenn-Haung Lai²  Chuan-Yueh Huang³  Ling-Jun Ho³  Li-Feng Hung³ 

[1] Department of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Lin-Kou, Tao-Yuan, Taiwan, Republic of China;Department of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Lin-Kou, Tao-Yuan, Taiwan, Republic of China;Graduate Institute of Clinical Research, National Defense Medical Center, Taipei, Taiwan, Republic of China;Institute of Cellular and System Medicine, National Health Research Institute, Zhunan, Taiwan, Republic of China;

关键词: CMPK2;    Atherosclerosis;    Interferon alpha;    Macrophages;    Foam cell formation;    Mitochondria;   

DOI  :  10.1186/s13075-021-02470-6

来源: Springer

【 摘 要 】

BackgroundPremature atherosclerosis occurs in patients with SLE; however, the mechanisms remain unclear. Both mitochondrial machinery and proinflammatory cytokine interferon alpha (IFN-α) potentially contribute to atherogenic processes in SLE. Here, we explore the roles of the mitochondrial protein cytidine/uridine monophosphate kinase 2 (CMPK2) in IFN-α-mediated pro-atherogenic events.MethodsFoam cell measurements were performed by oil red O staining, Dil-oxLDL uptake and the BODIPY approach. The mRNA and protein levels were measured by qPCR and Western blotting, respectively. Isolation of CD4+ T cells and monocytes was performed with monoclonal antibodies conjugated with microbeads. Manipulation of protein expression was conducted by either small interference RNA (siRNA) knockdown or CRISPR/Cas9 knockout. The expression of mitochondrial reactive oxygen species (mtROS) was determined by flow cytometry and confocal microscopy.ResultsIFN-α enhanced oxLDL-induced foam cell formation and Dil-oxLDL uptake by macrophages. In addition to IFN-α, several triggers of atherosclerosis, including thrombin and IFN-γ, can induce CMPK2 expression, which was elevated in CD4+ T cells and CD14+ monocytes isolated from SLE patients compared to those isolated from controls. The analysis of cellular subfractions revealed that CMPK2 was present in both mitochondrial and cytosolic fractions. IFN-α-induced CMPK2 expression was inhibited by Janus kinase (JAK)1/2 and tyrosine kinase 2 (Tyk2) inhibitors. Both the knockdown and knockout of CMPK2 attenuated IFN-α-mediated foam cell formation, which involved the reduction of scavenger receptor class A (SR-A) expression. CMPK2 also regulated IFN-α-enhanced mtROS production and inflammasome activation.ConclusionsThe study suggests that CMPK2 plays contributing roles in the pro-atherogenic effects of IFN-α.

【 授权许可】

CC BY