Neutrophil elastase triggers the development of autoimmune diabetes by exacerbating innate immune responses in pancreatic islets of non-obese diabetic mice.

Abstract

Type 1 diabetes is an autoimmune disease resulted from self-destruction of insulin-producing pancreatic β cells. However, the pathological pathways that trigger the autoimmune destruction remain poorly understood. Clinical studies have demonstrated close associations of neutrophils and neutrophil elastase (NE) with β-cell autoimmunity in patients with Type 1 diabetes. The present study aims to investigate the impact of NE inhibition on development of autoimmune diabetes in NOD mice. NE pharmacological inhibitor (sivelestat) or biological inhibitor (elafin) was supplemented into NOD mice to evaluate their effects on islet inflammation and diabetogenesis. The impact of NE inhibition on innate and adaptive immune cells was measured with flow cytometry and immunohistochemistry. A significant but transient increase in neutrophil infiltration accompanied with elevated NE activity was observed in the neonatal period of NOD mice. Treatment of NOD mice with sivelestat or elafin at the early age led to a marked reduction in spontaneous development of insulitis and autoimmune diabetes. Mechanistically, inhibition of NE significantly attenuated infiltration of macrophages and islet inflammation, thus ameliorating cytotoxic T cell-mediated autoimmune attack of pancreatic β cells. In vitro studies showed that NE directly induced inflammatory responses in both min6 β cells and RAW264.7 macrophages, and promoted macrophage migration. These findings support an important role of NE in triggering the onset and progression of β-cell autoimmunity, and suggest that pharmacological inhibition of NE may represent a promising therapeutic strategy for treatment of autoimmune diabetes.

• Authors: Lingling Shu, Ling Zhong, Yang Xiao, Xiaoping Wu, Yang Liu, Xue Jiang, Tao Tang, RubyLaiChong Hoo, Zhiguang Zhou, Aimin Xu
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 134 Issue 13 Pg. 1679-1696 (07 17 2020) ISSN: 1470-8736 [Electronic] England
• PMID: 32633320 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• Leukocyte Elastase

Topics

• Animals
• Diabetes Mellitus, Type 1 (enzymology, genetics, immunology)
• Female
• Humans
• Immunity, Innate
• Insulin-Secreting Cells (immunology)
• Islets of Langerhans (enzymology, immunology)
• Leukocyte Elastase (genetics, immunology)
• Mice
• Mice, Inbred NOD
• Neutrophil Infiltration
• Neutrophils (enzymology, immunology)
• T-Lymphocytes, Cytotoxic (immunology)