2. Academic Validation
  3. IAPs antagonist SM164 ameliorates experimental MPO-ANCA-associated vasculitis via enhancing fatty acid oxidation in neutrophils

IAPs antagonist SM164 ameliorates experimental MPO-ANCA-associated vasculitis via enhancing fatty acid oxidation in neutrophils

  • Rheumatology (Oxford). 2022 Oct 29;keac621. doi: 10.1093/rheumatology/keac621.
Luo-Yi Wang 1 2,  Rui-Xue Wang 1,  Chen Wang 1,  Su-Fang Chen 1,  Xiao-Jing Sun 1,  Zhi-Ying Li 1,  Min Chen 1,  Mark A Little 3,  Ming-Hui Zhao 1 4
Affiliations

Affiliations

  • 1 Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.
  • 2 Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Henan, China.
  • 3 Trinity Health Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, St. James' Hospital Campus; Irish Centre for Vascular Biology, Trinity College Dublin, Dublin, Ireland.
  • 4 Peking-Tsinghua Center for Life Sciences, Beijing, China.
PMID: 36308438 DOI: 10.1093/rheumatology/keac621
Abstract

Objectives: Antineutrophil 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 IAPs 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 expressions of three IAPs (cIAP1, cIAP2 and XIAP) were 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.

Keywords

ANCA; IAPs; SM164; glomerulonephritis; immunometabolism.

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