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α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses

INTRODUCTION: Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE), which is a chronic autoimmune disease. However, the detailed mechanisms underlying this disorder have remained unclear. Alpha2‐antiplasmin (α2AP) is known to perform various functions, such as plasmin...

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Autores principales: Kanno, Yosuke, Miyashita, Mei, Seishima, Mariko, Matsuo, Osamu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416015/
https://www.ncbi.nlm.nih.gov/pubmed/32237065
http://dx.doi.org/10.1002/iid3.302
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author Kanno, Yosuke
Miyashita, Mei
Seishima, Mariko
Matsuo, Osamu
author_facet Kanno, Yosuke
Miyashita, Mei
Seishima, Mariko
Matsuo, Osamu
author_sort Kanno, Yosuke
collection PubMed
description INTRODUCTION: Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE), which is a chronic autoimmune disease. However, the detailed mechanisms underlying this disorder have remained unclear. Alpha2‐antiplasmin (α2AP) is known to perform various functions, such as plasmin inhibition and cytokine production, and to be associated with immune and inflammatory responses. METHODS: We investigated the roles of α2AP in the pathogenesis of LN using a pristane‐induced lupus mouse model. RESULTS: The levels of plasmin‐α2AP complex and α2AP were elevated in the lupus model mice. In addition, α2AP deficiency attenuated the pristane‐induced glomerular cell proliferation, mesangial matrix expansion, collagen production, fibrin deposition, immunoglobulin G deposition, and proinflammatory cytokine production in the model mice. We also showed that interferon‐γ (IFN‐γ), which is an essential inducer of LN, induced α2AP production through the c‐Jun N‐terminal kinase (JNK) pathway in fibroblasts. In addition, plasmin attenuated the IFN‐γ‐induced proinflammatory cytokine production through the AMPK pathway in macrophages, and α2AP eliminated these effects. Furthermore, we showed that α2AP induced proinflammatory cytokine production through the ERK1/2 and JNK pathways in macrophages. CONCLUSION: α2AP regulates the inflammatory responses through plasmin inhibition and proinflammatory cytokine production and is associated with the development of LN. Our findings may be used to develop a novel therapeutic approach for SLE.
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spelling pubmed-74160152020-08-10 α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses Kanno, Yosuke Miyashita, Mei Seishima, Mariko Matsuo, Osamu Immun Inflamm Dis Original Research INTRODUCTION: Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE), which is a chronic autoimmune disease. However, the detailed mechanisms underlying this disorder have remained unclear. Alpha2‐antiplasmin (α2AP) is known to perform various functions, such as plasmin inhibition and cytokine production, and to be associated with immune and inflammatory responses. METHODS: We investigated the roles of α2AP in the pathogenesis of LN using a pristane‐induced lupus mouse model. RESULTS: The levels of plasmin‐α2AP complex and α2AP were elevated in the lupus model mice. In addition, α2AP deficiency attenuated the pristane‐induced glomerular cell proliferation, mesangial matrix expansion, collagen production, fibrin deposition, immunoglobulin G deposition, and proinflammatory cytokine production in the model mice. We also showed that interferon‐γ (IFN‐γ), which is an essential inducer of LN, induced α2AP production through the c‐Jun N‐terminal kinase (JNK) pathway in fibroblasts. In addition, plasmin attenuated the IFN‐γ‐induced proinflammatory cytokine production through the AMPK pathway in macrophages, and α2AP eliminated these effects. Furthermore, we showed that α2AP induced proinflammatory cytokine production through the ERK1/2 and JNK pathways in macrophages. CONCLUSION: α2AP regulates the inflammatory responses through plasmin inhibition and proinflammatory cytokine production and is associated with the development of LN. Our findings may be used to develop a novel therapeutic approach for SLE. John Wiley and Sons Inc. 2020-03-31 /pmc/articles/PMC7416015/ /pubmed/32237065 http://dx.doi.org/10.1002/iid3.302 Text en © 2020 The Authors. Immunity, Inflammation and Disease Published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Kanno, Yosuke
Miyashita, Mei
Seishima, Mariko
Matsuo, Osamu
α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses
title α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses
title_full α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses
title_fullStr α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses
title_full_unstemmed α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses
title_short α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses
title_sort α2ap is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416015/
https://www.ncbi.nlm.nih.gov/pubmed/32237065
http://dx.doi.org/10.1002/iid3.302
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