Crosstalk between TBK1/IKKε and the type I interferon pathway contributes to tubulointerstitial inflammation and kidney tubular injury
The type I interferon (TI-IFN) pathway regulates innate immunity, inflammation, and apoptosis during infection. However, the contribution of the TI-IFN pathway or upstream signaling pathways to tubular injury in kidney disease is poorly understood. Upon observing evidence of activation of upstream r...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.987979/full |
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| author | Gina Córdoba-David Jorge García-Giménez Regiane Cardoso Castelo-Branco Susana Carrasco Susana Carrasco Pablo Cannata Alberto Ortiz Alberto Ortiz Alberto Ortiz Adrián M. Ramos Adrián M. Ramos |
| author_facet | Gina Córdoba-David Jorge García-Giménez Regiane Cardoso Castelo-Branco Susana Carrasco Susana Carrasco Pablo Cannata Alberto Ortiz Alberto Ortiz Alberto Ortiz Adrián M. Ramos Adrián M. Ramos |
| author_sort | Gina Córdoba-David |
| collection | DOAJ |
| description | The type I interferon (TI-IFN) pathway regulates innate immunity, inflammation, and apoptosis during infection. However, the contribution of the TI-IFN pathway or upstream signaling pathways to tubular injury in kidney disease is poorly understood. Upon observing evidence of activation of upstream regulators of the TI-IFN pathway in a transcriptomics analysis of murine kidney tubulointerstitial injury, we have now addressed the impact of the TI-IFN and upstream signaling pathways on kidney tubulointerstitial injury. In cultured tubular cells and kidney tissue, IFNα/β binding to IFNAR activated the TI-IFN pathway and recruited antiviral interferon-stimulated genes (ISG) and NF-κB-associated proinflammatory responses. TWEAK and lipopolysaccharide (LPS) signaled through TBK1/IKKε and IRF3 to activate both ISGs and NF-κB. In addition, TWEAK recruited TLR4 to stimulate TBK1/IKKε-dependent ISG and inflammatory responses. Dual pharmacological inhibition of TBK1/IKKε with amlexanox decreased TWEAK- or LPS-induced ISG and cytokine responses, as well as cell death induced by a complex inflammatory milieu that included TWEAK. TBK1 or IRF3 siRNA prevented the TWEAK-induced ISG and inflammatory gene expression while IKKε siRNA did not. In vivo, kidney IFNAR and IFNβ were increased in murine LPS and folic acid nephrotoxicity while IFNAR was increased in human kidney biopsies with tubulointerstitial damage. Inhibition of TBK1/IKKε with amlexanox or IFNAR neutralization decreased TI-IFN pathway activation and protected from kidney injury induced by folic acid or LPS. In conclusion, TI-IFNs, TWEAK, and LPS engage interrelated proinflammatory and antiviral responses in tubular cells. Moreover, inhibition of TBK1/IKKε with amlexanox, and IFNAR targeting, may protect from tubulointerstitial kidney injury. |
| first_indexed | 2024-04-11T06:50:39Z |
| format | Article |
| id | doaj.art-d9d07cab29264c209ddd190484ee81c1 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T06:50:39Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-d9d07cab29264c209ddd190484ee81c12022-12-22T04:39:14ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-09-011310.3389/fphar.2022.987979987979Crosstalk between TBK1/IKKε and the type I interferon pathway contributes to tubulointerstitial inflammation and kidney tubular injuryGina Córdoba-David0Jorge García-Giménez1Regiane Cardoso Castelo-Branco2Susana Carrasco3Susana Carrasco4Pablo Cannata5Alberto Ortiz6Alberto Ortiz7Alberto Ortiz8Adrián M. Ramos9Adrián M. Ramos10Department of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, SpainDepartment of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, SpainDepartment of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, SpainDepartment of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, SpainRICORS 2040, Madrid, SpainDepartment of Pathology, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, SpainDepartment of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, SpainRICORS 2040, Madrid, SpainDepartment of Medicine, Universidad Autónoma de Madrid, Madrid, SpainDepartment of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, SpainRICORS 2040, Madrid, SpainThe type I interferon (TI-IFN) pathway regulates innate immunity, inflammation, and apoptosis during infection. However, the contribution of the TI-IFN pathway or upstream signaling pathways to tubular injury in kidney disease is poorly understood. Upon observing evidence of activation of upstream regulators of the TI-IFN pathway in a transcriptomics analysis of murine kidney tubulointerstitial injury, we have now addressed the impact of the TI-IFN and upstream signaling pathways on kidney tubulointerstitial injury. In cultured tubular cells and kidney tissue, IFNα/β binding to IFNAR activated the TI-IFN pathway and recruited antiviral interferon-stimulated genes (ISG) and NF-κB-associated proinflammatory responses. TWEAK and lipopolysaccharide (LPS) signaled through TBK1/IKKε and IRF3 to activate both ISGs and NF-κB. In addition, TWEAK recruited TLR4 to stimulate TBK1/IKKε-dependent ISG and inflammatory responses. Dual pharmacological inhibition of TBK1/IKKε with amlexanox decreased TWEAK- or LPS-induced ISG and cytokine responses, as well as cell death induced by a complex inflammatory milieu that included TWEAK. TBK1 or IRF3 siRNA prevented the TWEAK-induced ISG and inflammatory gene expression while IKKε siRNA did not. In vivo, kidney IFNAR and IFNβ were increased in murine LPS and folic acid nephrotoxicity while IFNAR was increased in human kidney biopsies with tubulointerstitial damage. Inhibition of TBK1/IKKε with amlexanox or IFNAR neutralization decreased TI-IFN pathway activation and protected from kidney injury induced by folic acid or LPS. In conclusion, TI-IFNs, TWEAK, and LPS engage interrelated proinflammatory and antiviral responses in tubular cells. Moreover, inhibition of TBK1/IKKε with amlexanox, and IFNAR targeting, may protect from tubulointerstitial kidney injury.https://www.frontiersin.org/articles/10.3389/fphar.2022.987979/fullTBK1/IKKεtype I interferonkidney injuryTWEAKLPSinflammation |
| spellingShingle | Gina Córdoba-David Jorge García-Giménez Regiane Cardoso Castelo-Branco Susana Carrasco Susana Carrasco Pablo Cannata Alberto Ortiz Alberto Ortiz Alberto Ortiz Adrián M. Ramos Adrián M. Ramos Crosstalk between TBK1/IKKε and the type I interferon pathway contributes to tubulointerstitial inflammation and kidney tubular injury Frontiers in Pharmacology TBK1/IKKε type I interferon kidney injury TWEAK LPS inflammation |
| title | Crosstalk between TBK1/IKKε and the type I interferon pathway contributes to tubulointerstitial inflammation and kidney tubular injury |
| title_full | Crosstalk between TBK1/IKKε and the type I interferon pathway contributes to tubulointerstitial inflammation and kidney tubular injury |
| title_fullStr | Crosstalk between TBK1/IKKε and the type I interferon pathway contributes to tubulointerstitial inflammation and kidney tubular injury |
| title_full_unstemmed | Crosstalk between TBK1/IKKε and the type I interferon pathway contributes to tubulointerstitial inflammation and kidney tubular injury |
| title_short | Crosstalk between TBK1/IKKε and the type I interferon pathway contributes to tubulointerstitial inflammation and kidney tubular injury |
| title_sort | crosstalk between tbk1 ikkε and the type i interferon pathway contributes to tubulointerstitial inflammation and kidney tubular injury |
| topic | TBK1/IKKε type I interferon kidney injury TWEAK LPS inflammation |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.987979/full |
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