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Conference Paper: Pharmacological Inhibition of Neutrophil Elastase Attenuates Insulitis &Autoimmune Diabetes in Mice

TitlePharmacological Inhibition of Neutrophil Elastase Attenuates Insulitis &Autoimmune Diabetes in Mice
Authors
Issue Date2018
PublisherAmerican Diabetes Association. The Journal's web site is located at http://diabetes.diabetesjournals.org/
Citation
American Diabetes Association 78th Scientific Sessions, Orlando, Florida, USA, 22-26 June 2018. In Diabetes, 2018, v. 67 n. Suppl. 1 How to Cite?
AbstractBackground: Type 1 diabetes is an autoimmune disease resulted from self-destruction of insulin-producing pancreatic beta-cells. However, the pathological pathways that trigger the autoimmune destruction remain poorly understood. Our previous studies demonstrated that increased circulating neutrophil elastase (NE) is closely associated with beta-cell autoimmunity in patients with T1D. Here we investigate the role and mechanism whereby NE participates in the pathogenesis of T1D, and to explore the therapeutic potential of the pharmacological NE inhibitors for autoimmune diabetes. Method: Biochemical and immunological analysis were adopted to determine the dynamic change in the infiltration and activation of neutrophils in pancreas of NOD mice. NE-specific endogenous (pre-elafin/elafin) or pharmaceutical (sivelestat) inhibitors were supplemented into NOD mice to evaluate their effects on diabetes incidence and insultitis. Flow cytometry was employed to explore the effects of NE in mediating the crosstalk of immune cells. Results: A dynamic change in the infiltration of neutrophils was observed in pancreatic islets of NOD mice, leading to a transient elevation of local NE activity. Supplementation of NE-specific inhibitors rectified the elevated pancreatic NE activity, alleviated insulitis and reduced the development of T1D in NOD mice. Inhibition of NE activity significantly attenuated the infiltration of pro-inflammatory macrophages into pancreas, reduced the production of inflammatory cytokines. In vitro studies showed that NE directly induced inflammatory responses in both min6 beta-cells and RAW264.7 macrophages through the activation of TLR4-IκB-NFκB pathway. Discussion: NE-mediated crosstalk between beta-cell and macrophages forms a vicious feedback loop, resulting in the exaggerated beta-cell damage in NOD mice. Pharmacological inhibition of NE may represent a promising therapeutic strategy for treatment of autoimmune diabetes.
DescriptionGeneral Poster Session
Persistent Identifierhttp://hdl.handle.net/10722/261974
ISSN
2019 Impact Factor: 7.72
2015 SCImago Journal Rankings: 5.185

 

DC FieldValueLanguage
dc.contributor.authorShu, L-
dc.contributor.authorZhong, L-
dc.contributor.authorXiao, Y-
dc.contributor.authorHoo, RLC-
dc.contributor.authorXu, A-
dc.date.accessioned2018-09-28T04:51:12Z-
dc.date.available2018-09-28T04:51:12Z-
dc.date.issued2018-
dc.identifier.citationAmerican Diabetes Association 78th Scientific Sessions, Orlando, Florida, USA, 22-26 June 2018. In Diabetes, 2018, v. 67 n. Suppl. 1-
dc.identifier.issn0012-1797-
dc.identifier.urihttp://hdl.handle.net/10722/261974-
dc.descriptionGeneral Poster Session-
dc.description.abstractBackground: Type 1 diabetes is an autoimmune disease resulted from self-destruction of insulin-producing pancreatic beta-cells. However, the pathological pathways that trigger the autoimmune destruction remain poorly understood. Our previous studies demonstrated that increased circulating neutrophil elastase (NE) is closely associated with beta-cell autoimmunity in patients with T1D. Here we investigate the role and mechanism whereby NE participates in the pathogenesis of T1D, and to explore the therapeutic potential of the pharmacological NE inhibitors for autoimmune diabetes. Method: Biochemical and immunological analysis were adopted to determine the dynamic change in the infiltration and activation of neutrophils in pancreas of NOD mice. NE-specific endogenous (pre-elafin/elafin) or pharmaceutical (sivelestat) inhibitors were supplemented into NOD mice to evaluate their effects on diabetes incidence and insultitis. Flow cytometry was employed to explore the effects of NE in mediating the crosstalk of immune cells. Results: A dynamic change in the infiltration of neutrophils was observed in pancreatic islets of NOD mice, leading to a transient elevation of local NE activity. Supplementation of NE-specific inhibitors rectified the elevated pancreatic NE activity, alleviated insulitis and reduced the development of T1D in NOD mice. Inhibition of NE activity significantly attenuated the infiltration of pro-inflammatory macrophages into pancreas, reduced the production of inflammatory cytokines. In vitro studies showed that NE directly induced inflammatory responses in both min6 beta-cells and RAW264.7 macrophages through the activation of TLR4-IκB-NFκB pathway. Discussion: NE-mediated crosstalk between beta-cell and macrophages forms a vicious feedback loop, resulting in the exaggerated beta-cell damage in NOD mice. Pharmacological inhibition of NE may represent a promising therapeutic strategy for treatment of autoimmune diabetes.-
dc.languageeng-
dc.publisherAmerican Diabetes Association. The Journal's web site is located at http://diabetes.diabetesjournals.org/-
dc.relation.ispartofDiabetes-
dc.relation.ispartofAmerican Diabetes Association 78th Scientific sessions-
dc.titlePharmacological Inhibition of Neutrophil Elastase Attenuates Insulitis &Autoimmune Diabetes in Mice-
dc.typeConference_Paper-
dc.identifier.emailShu, L: shinyshu@hku.hk-
dc.identifier.emailZhong, L: kelsey@hku.hk-
dc.identifier.emailHoo, RLC: rubyhoo@hkucc.hku.hk-
dc.identifier.emailXu, A: amxu@hkucc.hku.hk-
dc.identifier.authorityHoo, RLC=rp01334-
dc.identifier.authorityXu, A=rp00485-
dc.identifier.doi10.2337/db18-1732-P-
dc.identifier.hkuros292563-
dc.identifier.volume67-
dc.identifier.issueSuppl. 1-
dc.publisher.placeUnited States-

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