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Crosstalk between TBK1/IKKε and the type I interferon pathway contributes to tubulointerstitial inflammation and kidney tubular injury

Affiliation
Department of Nephrology and Hypertension ,IIS-Fundación Jiménez Díaz ,Universidad Autónoma de Madrid ,Madrid ,Spain
Córdoba-David, Gina;
Affiliation
Department of Nephrology and Hypertension ,IIS-Fundación Jiménez Díaz ,Universidad Autónoma de Madrid ,Madrid ,Spain
García-Giménez, Jorge;
Affiliation
Department of Nephrology and Hypertension ,IIS-Fundación Jiménez Díaz ,Universidad Autónoma de Madrid ,Madrid ,Spain
Cardoso Castelo-Branco, Regiane;
Affiliation
Department of Nephrology and Hypertension ,IIS-Fundación Jiménez Díaz ,Universidad Autónoma de Madrid ,Madrid ,Spain
Carrasco, Susana;
Affiliation
Department of Pathology ,IIS-Fundación Jiménez Díaz ,Universidad Autónoma de Madrid ,Madrid ,Spain
Cannata, Pablo;
Affiliation
Department of Nephrology and Hypertension ,IIS-Fundación Jiménez Díaz ,Universidad Autónoma de Madrid ,Madrid ,Spain
Ortiz, Alberto;
Affiliation
Department of Nephrology and Hypertension ,IIS-Fundación Jiménez Díaz ,Universidad Autónoma de Madrid ,Madrid ,Spain
Ramos, Adrián M.

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.

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License Holder: Copyright © 2022 Córdoba-David, García-Giménez, Cardoso Castelo-Branco, Carrasco, Cannata, Ortiz and Ramos.

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