학술논문
Inhibitor of apoptosis proteins antagonist SM164 ameliorates experimental MPO-ANCA-associated vasculitis via enhancing fatty acid oxidation in neutrophils.
Document Type
Article
Author
Source
Subject
*RNA analysis
*PROTEIN metabolism
*PROTEINS
*ENDOTHELIAL cells
*IN vivo studies
*SEQUENCE analysis
*IMMUNOGLOBULINS
*IMMUNOHISTOCHEMISTRY
*WESTERN immunoblotting
*ANTINEUTROPHIL cytoplasmic antibodies
*APOPTOSIS
*HEALTH outcome assessment
*MANN Whitney U Test
*NEUTROPHILS
*RATS
*GENE expression
*T-test (Statistics)
*GENE expression profiling
*FLUORESCENT antibody technique
*DESCRIPTIVE statistics
*RESEARCH funding
*POLYMERASE chain reaction
*DATA analysis software
*VASCULITIS
*FATTY acids
*OXIDATION-reduction reaction
*CHEMICAL inhibitors
*DISEASE risk factors
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Language
ISSN
1462-0324
Abstract
Objectives Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of life-threatening autoimmune diseases. Inhibitors of apoptosis proteins (IAPs) are a class of molecules engaged in cell death and inflammation, interventions of which are proven effective in a number of inflammatory diseases. Here we tested whether targeting IAPs could ameliorate AAV and explored the potential mechanism. Methods We collected 19 kidney specimens from patients with myeloperoxidase (MPO)-AAV to investigate the expression of IAPs. The IAP pan-inhibitor SM164 was used to treat the experimental autoimmune vasculitis (EAV) rat model of AAV. RNA sequencing of renal cortex and enrichment analysis were developed to interpret gene expression. Functional experiments were performed to investigate the role of SM164 on neutrophils and endothelial cells. Results The expression of three IAPs (cIAP1, cIAP2 and XIAP) was upregulated in kidneys of AAV patients compared with normal controls. SM164 dramatically reduced renal injury in EAV rats. Transcriptomic analysis revealed prominent alterations in fatty acid oxidation and respiratory burst following SM164 treatment. Functional studies demonstrated that SM164 inhibited neutrophil activation induced by MPO-ANCA positive IgG or serum from MPO-AAV patients, and such inhibitory effect was abolished by gene silencing or pharmacological inhibition of fatty acid oxidation. SM164 also inhibited the adhesion of neutrophils to endothelial cells with little effect on the endothelial injury induced by serum from MPO-AAV patients. Conclusion Inhibition of IAPs with SM164 played a protective role in AAV through enhancing intracellular fatty acid oxidation in neutrophils. [ABSTRACT FROM AUTHOR]