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A Splice Switch in SIGIRR Causes a Defect of IL-37-Dependent Anti-Inflammatory Activity in Cystic Fibrosis Airway Epithelial Cells

Cystic fibrosis (CF) is a hereditary disease typically characterized by infection-associated chronic lung inflammation. The persistent activation of toll-like receptor (TLR) signals is considered one of the mechanisms for the CF hyperinflammatory phenotype; however, how negative regulatory signals o...

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Autores principales: Ueno-Shuto, Keiko, Kamei, Shunsuke, Hayashi, Megumi, Fukuyama, Ayami, Uchida, Yuji, Tokutomi, Naofumi, Suico, Mary Ann, Kai, Hirofumi, Shuto, Tsuyoshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9318995/
https://www.ncbi.nlm.nih.gov/pubmed/35887095
http://dx.doi.org/10.3390/ijms23147748
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author Ueno-Shuto, Keiko
Kamei, Shunsuke
Hayashi, Megumi
Fukuyama, Ayami
Uchida, Yuji
Tokutomi, Naofumi
Suico, Mary Ann
Kai, Hirofumi
Shuto, Tsuyoshi
author_facet Ueno-Shuto, Keiko
Kamei, Shunsuke
Hayashi, Megumi
Fukuyama, Ayami
Uchida, Yuji
Tokutomi, Naofumi
Suico, Mary Ann
Kai, Hirofumi
Shuto, Tsuyoshi
author_sort Ueno-Shuto, Keiko
collection PubMed
description Cystic fibrosis (CF) is a hereditary disease typically characterized by infection-associated chronic lung inflammation. The persistent activation of toll-like receptor (TLR) signals is considered one of the mechanisms for the CF hyperinflammatory phenotype; however, how negative regulatory signals of TLRs associate with CF inflammation is still elusive. Here, we showed that the cell surface expression of a single immunoglobulin interleukin-1 receptor (IL-1R)-related molecule (SIGIRR), a membrane protein essential for suppressing TLRs- and IL-1R-dependent signals, was remarkably decreased in CF airway epithelial cells compared to non-CF cells. Notably, CF airway epithelial cells specifically and highly expressed a unique, alternative splice isoform of the SIGIRR that lacks exon 8 (Δ8-SIGIRR), which results in the production of a C-terminal truncated form of the SIGIRR. Δ8-SIGIRR was expressed intracellularly, and its over-expression abolished the cell surface expression and function of the full-length SIGIRR (WT-SIGIRR), indicating its dominant-negative effect leading to the deficiency of anti-inflammatory activity in CF cells. Consistently, IL-37, a ligand for the SIGIRR, failed to suppress viral dsRNA analogue poly(I:C)-dependent JNK activation and IL-8 production, confirming the reduction in the functional WT-SIGIRR expression in the CF cells. Together, our studies reveal that SIGIRR-dependent anti-inflammatory activity is defective in CF airway epithelial cells due to the unique splicing switch of the SIGIRR gene and provides the first evidence of IL-37-SIGIRR signaling as a target of CF airway inflammation.
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spelling pubmed-93189952022-07-27 A Splice Switch in SIGIRR Causes a Defect of IL-37-Dependent Anti-Inflammatory Activity in Cystic Fibrosis Airway Epithelial Cells Ueno-Shuto, Keiko Kamei, Shunsuke Hayashi, Megumi Fukuyama, Ayami Uchida, Yuji Tokutomi, Naofumi Suico, Mary Ann Kai, Hirofumi Shuto, Tsuyoshi Int J Mol Sci Article Cystic fibrosis (CF) is a hereditary disease typically characterized by infection-associated chronic lung inflammation. The persistent activation of toll-like receptor (TLR) signals is considered one of the mechanisms for the CF hyperinflammatory phenotype; however, how negative regulatory signals of TLRs associate with CF inflammation is still elusive. Here, we showed that the cell surface expression of a single immunoglobulin interleukin-1 receptor (IL-1R)-related molecule (SIGIRR), a membrane protein essential for suppressing TLRs- and IL-1R-dependent signals, was remarkably decreased in CF airway epithelial cells compared to non-CF cells. Notably, CF airway epithelial cells specifically and highly expressed a unique, alternative splice isoform of the SIGIRR that lacks exon 8 (Δ8-SIGIRR), which results in the production of a C-terminal truncated form of the SIGIRR. Δ8-SIGIRR was expressed intracellularly, and its over-expression abolished the cell surface expression and function of the full-length SIGIRR (WT-SIGIRR), indicating its dominant-negative effect leading to the deficiency of anti-inflammatory activity in CF cells. Consistently, IL-37, a ligand for the SIGIRR, failed to suppress viral dsRNA analogue poly(I:C)-dependent JNK activation and IL-8 production, confirming the reduction in the functional WT-SIGIRR expression in the CF cells. Together, our studies reveal that SIGIRR-dependent anti-inflammatory activity is defective in CF airway epithelial cells due to the unique splicing switch of the SIGIRR gene and provides the first evidence of IL-37-SIGIRR signaling as a target of CF airway inflammation. MDPI 2022-07-13 /pmc/articles/PMC9318995/ /pubmed/35887095 http://dx.doi.org/10.3390/ijms23147748 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ueno-Shuto, Keiko
Kamei, Shunsuke
Hayashi, Megumi
Fukuyama, Ayami
Uchida, Yuji
Tokutomi, Naofumi
Suico, Mary Ann
Kai, Hirofumi
Shuto, Tsuyoshi
A Splice Switch in SIGIRR Causes a Defect of IL-37-Dependent Anti-Inflammatory Activity in Cystic Fibrosis Airway Epithelial Cells
title A Splice Switch in SIGIRR Causes a Defect of IL-37-Dependent Anti-Inflammatory Activity in Cystic Fibrosis Airway Epithelial Cells
title_full A Splice Switch in SIGIRR Causes a Defect of IL-37-Dependent Anti-Inflammatory Activity in Cystic Fibrosis Airway Epithelial Cells
title_fullStr A Splice Switch in SIGIRR Causes a Defect of IL-37-Dependent Anti-Inflammatory Activity in Cystic Fibrosis Airway Epithelial Cells
title_full_unstemmed A Splice Switch in SIGIRR Causes a Defect of IL-37-Dependent Anti-Inflammatory Activity in Cystic Fibrosis Airway Epithelial Cells
title_short A Splice Switch in SIGIRR Causes a Defect of IL-37-Dependent Anti-Inflammatory Activity in Cystic Fibrosis Airway Epithelial Cells
title_sort splice switch in sigirr causes a defect of il-37-dependent anti-inflammatory activity in cystic fibrosis airway epithelial cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9318995/
https://www.ncbi.nlm.nih.gov/pubmed/35887095
http://dx.doi.org/10.3390/ijms23147748
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