Cargando…

Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway

Dimethyl itaconate (DI) is a membrane‐permeable itaconate derivative with anti‐inflammatory functions. However, the anti‐inflammatory effect of DI has never been studied in fungal keratitis. In this study, we tested the protective effect of DI against fungal keratitis and assessed the role of NF‐E2‐...

Descripción completa

Detalles Bibliográficos
Autores principales: Gu, Lingwen, Lin, Jing, Wang, Qian, Li, Cui, Peng, Xudong, Fan, Yiqun, Lu, Chunli, Lin, Hao, Niu, Yawen, Zhu, Guoqiang, Zhao, Guiqiu
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/PMC7065235/
https://www.ncbi.nlm.nih.gov/pubmed/31943336
http://dx.doi.org/10.1111/imcb.12316
_version_ 1783505027689611264
author Gu, Lingwen
Lin, Jing
Wang, Qian
Li, Cui
Peng, Xudong
Fan, Yiqun
Lu, Chunli
Lin, Hao
Niu, Yawen
Zhu, Guoqiang
Zhao, Guiqiu
author_facet Gu, Lingwen
Lin, Jing
Wang, Qian
Li, Cui
Peng, Xudong
Fan, Yiqun
Lu, Chunli
Lin, Hao
Niu, Yawen
Zhu, Guoqiang
Zhao, Guiqiu
author_sort Gu, Lingwen
collection PubMed
description Dimethyl itaconate (DI) is a membrane‐permeable itaconate derivative with anti‐inflammatory functions. However, the anti‐inflammatory effect of DI has never been studied in fungal keratitis. In this study, we tested the protective effect of DI against fungal keratitis and assessed the role of NF‐E2‐related factor‐2 (Nrf2)/heme oxygenase‐1 (HO‐1) signaling in this process. Eyes of C57BL/6 (B6) mice were treated with 2 mm DI after infection with Aspergillus fumigatus. Human corneal epithelial cells (HCECs) were pretreated with 0.25 mm DI and then incubated with A. fumigatus. Clinical scoring, slit‐lamp photography, myeloperoxidase determination, flow cytometry and immunostaining were used to assess the disease response and treatment efficacy. PCR, Western blot and ELISA were used to assess the expression of interleukin‐1β (IL‐1β), chemokine (C–X–C motif) ligand 1, IL‐6, IL‐8, Nrf2 and HO‐1. In addition, quantification of viable fungi, absorbance assays and fluorimetry were used to measure DI fungistatic activity. We observed that DI‐treated eyes showed decreased clinical scores, fungal loads, polymorphonuclear neutrophil (PMN) infiltration and cytokine expression, compared with phosphate‐buffered saline‐treated infected eyes. DI treatment decreased the cytokine levels in infected corneas and in HCECs stimulated with A. fumigatus. Moreover, DI treatment increased Nrf2 and HO‐1 expression in corneas and nuclear Nrf2 accumulation in HCECs. DI‐induced cytokine downregulation was inhibited by pretreatment with an Nrf2 or HO‐1 inhibitor. Finally, DI treatment reduced the A. fumigatus absorbance and fungal mass. These data indicate that DI protects against fungal keratitis by limiting inflammation via the Nrf2/HO‐1 signaling pathway and that DI inhibits the growth of A. fumigatus.
format Online
Article
Text
id pubmed-7065235
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-70652352020-03-16 Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway Gu, Lingwen Lin, Jing Wang, Qian Li, Cui Peng, Xudong Fan, Yiqun Lu, Chunli Lin, Hao Niu, Yawen Zhu, Guoqiang Zhao, Guiqiu Immunol Cell Biol Original Articles Dimethyl itaconate (DI) is a membrane‐permeable itaconate derivative with anti‐inflammatory functions. However, the anti‐inflammatory effect of DI has never been studied in fungal keratitis. In this study, we tested the protective effect of DI against fungal keratitis and assessed the role of NF‐E2‐related factor‐2 (Nrf2)/heme oxygenase‐1 (HO‐1) signaling in this process. Eyes of C57BL/6 (B6) mice were treated with 2 mm DI after infection with Aspergillus fumigatus. Human corneal epithelial cells (HCECs) were pretreated with 0.25 mm DI and then incubated with A. fumigatus. Clinical scoring, slit‐lamp photography, myeloperoxidase determination, flow cytometry and immunostaining were used to assess the disease response and treatment efficacy. PCR, Western blot and ELISA were used to assess the expression of interleukin‐1β (IL‐1β), chemokine (C–X–C motif) ligand 1, IL‐6, IL‐8, Nrf2 and HO‐1. In addition, quantification of viable fungi, absorbance assays and fluorimetry were used to measure DI fungistatic activity. We observed that DI‐treated eyes showed decreased clinical scores, fungal loads, polymorphonuclear neutrophil (PMN) infiltration and cytokine expression, compared with phosphate‐buffered saline‐treated infected eyes. DI treatment decreased the cytokine levels in infected corneas and in HCECs stimulated with A. fumigatus. Moreover, DI treatment increased Nrf2 and HO‐1 expression in corneas and nuclear Nrf2 accumulation in HCECs. DI‐induced cytokine downregulation was inhibited by pretreatment with an Nrf2 or HO‐1 inhibitor. Finally, DI treatment reduced the A. fumigatus absorbance and fungal mass. These data indicate that DI protects against fungal keratitis by limiting inflammation via the Nrf2/HO‐1 signaling pathway and that DI inhibits the growth of A. fumigatus. John Wiley and Sons Inc. 2020-02-11 2020-03 /pmc/articles/PMC7065235/ /pubmed/31943336 http://dx.doi.org/10.1111/imcb.12316 Text en © 2020 Australian and New Zealand Society for Immunology Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Gu, Lingwen
Lin, Jing
Wang, Qian
Li, Cui
Peng, Xudong
Fan, Yiqun
Lu, Chunli
Lin, Hao
Niu, Yawen
Zhu, Guoqiang
Zhao, Guiqiu
Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway
title Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway
title_full Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway
title_fullStr Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway
title_full_unstemmed Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway
title_short Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway
title_sort dimethyl itaconate protects against fungal keratitis by activating the nrf2/ho‐1 signaling pathway
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065235/
https://www.ncbi.nlm.nih.gov/pubmed/31943336
http://dx.doi.org/10.1111/imcb.12316
work_keys_str_mv AT gulingwen dimethylitaconateprotectsagainstfungalkeratitisbyactivatingthenrf2ho1signalingpathway
AT linjing dimethylitaconateprotectsagainstfungalkeratitisbyactivatingthenrf2ho1signalingpathway
AT wangqian dimethylitaconateprotectsagainstfungalkeratitisbyactivatingthenrf2ho1signalingpathway
AT licui dimethylitaconateprotectsagainstfungalkeratitisbyactivatingthenrf2ho1signalingpathway
AT pengxudong dimethylitaconateprotectsagainstfungalkeratitisbyactivatingthenrf2ho1signalingpathway
AT fanyiqun dimethylitaconateprotectsagainstfungalkeratitisbyactivatingthenrf2ho1signalingpathway
AT luchunli dimethylitaconateprotectsagainstfungalkeratitisbyactivatingthenrf2ho1signalingpathway
AT linhao dimethylitaconateprotectsagainstfungalkeratitisbyactivatingthenrf2ho1signalingpathway
AT niuyawen dimethylitaconateprotectsagainstfungalkeratitisbyactivatingthenrf2ho1signalingpathway
AT zhuguoqiang dimethylitaconateprotectsagainstfungalkeratitisbyactivatingthenrf2ho1signalingpathway
AT zhaoguiqiu dimethylitaconateprotectsagainstfungalkeratitisbyactivatingthenrf2ho1signalingpathway