MO070: Noncanonical IKKS and the Type 1 Interferon Pathway Activate Inflammation and Cell Death in Tubular Cells and Contribute to Renal Injury

Abstract BACKGROUND AND AIMS Deleterious consequences of type 1 interferons (T1-INFs) in the renal tissue have been envisioned in the context of viral and autoimmune diseases and in clinical therapies dealing with their administration.(1–3) Moreover, a participation of the T1-INF pathway has been suggested in the acutely injured kidney. (4) However, the pathogenic processes triggered by the T1-INFs in the kidneys are still not well defined and hence they need to be better defined. Therefore, we aimed to address whether the T1-INF pathway and molecular routes leading to its activation regulate critical pathogenic mechanisms underlying kidney damage. METHOD The overall activation of the T1-INF pathway, which involves upstream signaling through TBK1/IKKε/IRF3 and downstream engagement of the INFα/β receptor (IFNAR) (5) was studied in models of cultured murine tubular cells (MCT) and mice challenged with the INFs α and β and the proinflammatory inducers TWEAK and LPS. Pharmacological, immune-modulator and genetic approaches were used to inhibit signaling from TBK1/IKKε/IRF3 or IFNAR in tubular cells as well as in murine models of kidney injury induced by LPS or folic acid. RESULTS INFs α and β activated the T1-INF pathway from their interaction with IFNAR thus stimulating intertwined antiviral ISG and inflammatory NF-κB-associated responses in tubular cells and kidney tissue. Both ISGs and NF-κB were also activated by TWEAK and LPS through the TBK1/IKKε/IRF3 signaling pathway, which also mediates cell death programs. Simultaneous pharmacological inhibition of TBK1/IKKε restrained the cytokine production and the ISG response elicited by TWEAK or LPS, and the TWEAK-dependent apoptosis triggered in the presence of proinflammatory cytokines. Moreover, TBK1 silencing also protected from inflammation and prevented the ISG reaction although it promoted cell death. The activity of IKKε accelerated the TBK1-induced NF-κB activation without showing relevant participation in this mechanism by itself, despite it having a contribution to cell death. An improvement of the kidney injury (inflammation and tubular cell death) in murine models of LPS and folic acid nephrotoxicity was observed by restraining the T1-INF pathway through pharmacological inhibition of TBK1/IKKε or IFNAR immune-neutralization. By contrast, fueling the TBK1/IKKε or the IFNAR signaling worsened the renal injury. CONCLUSION T1-INFs and proinflammatory modulators activate related proinflammatory and antiviral signaling pathways in tubular cells that otherwise may favor kidney injury thus offering alternative targets for nephroprotection.