Endothelial STING and STAT1 mediate IFN-independent effects of IL-6 in an endotoxemia-induced model of shock
Nina Martino, Erin K. Sanders, Ramon Bossardi Ramos, Iria Di John Portela, Fatma Awadalla, Shuhan Lu, Dareen Chuy, Neil Poddar, Mei Xing G. Zuo, Uma Balasubramanian, Peter A. Vincent, Pilar Alcaide, Alejandro P. Adam
Nina Martino, Erin K. Sanders, Ramon Bossardi Ramos, Iria Di John Portela, Fatma Awadalla, Shuhan Lu, Dareen Chuy, Neil Poddar, Mei Xing G. Zuo, Uma Balasubramanian, Peter A. Vincent, Pilar Alcaide, Alejandro P. Adam
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Research Article Inflammation Vascular biology

Endothelial STING and STAT1 mediate IFN-independent effects of IL-6 in an endotoxemia-induced model of shock

Abstract

Severe systemic inflammatory reactions, including sepsis, often lead to shock, organ failure, and death, in part through an acute release of cytokines that promote vascular dysfunction. However, little is known about the vascular endothelial signaling pathways regulating the transcriptional profile in failing organs. Our work focused on signaling downstream of IL-6, due to its clinical importance as a biomarker for disease severity and predictor of mortality. Here, we show that loss of endothelial expression of the IL-6 pathway inhibitor SOCS3 promoted a type I IFN–like (IFNI-like) gene signature in response to endotoxemia in mouse kidneys and brains. In cultured primary human endothelial cells, IL-6 induced transient IFNI-like gene expression in a noncanonical, IFN-independent fashion. We further show that STAT3, which we had previously demonstrated to control IL-6–driven endothelial barrier function, was dispensable for this activity. Instead, IL-6 promoted a transient increase in cytosolic mitochondrial DNA and required STAT1, cGAS, STING, and IRF1, -3, and -4. Inhibition of this pathway in endothelial cell–specific STING-KO mice or global STAT1-KO mice led to reduced the severity of the response to acute endotoxemic challenge and prevented expression of an endotoxin-induced IFNI-like gene signature. These results suggest that permeability and DNA-sensing responses are driven by parallel pathways downstream of this cytokine, provide potential insights into the complex response to acute inflammatory responses, and offer the possibility of novel therapeutic strategies for independently controlling the intracellular responses to IL-6 in order to tailor the inflammatory response.

Authors

Nina Martino, Erin K. Sanders, Ramon Bossardi Ramos, Iria Di John Portela, Fatma Awadalla, Shuhan Lu, Dareen Chuy, Neil Poddar, Mei Xing G. Zuo, Uma Balasubramanian, Peter A. Vincent, Pilar Alcaide, Alejandro P. Adam

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Figure 1

Endothelial transcriptional response in the kidney endothelium.

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Endothelial transcriptional response in the kidney endothelium. (A) LPS ...
(A) LPS induces physiological changes associated with a strong inflammatory reaction: increased severity, hypothermia, and an acute loss of body weight. *P < 0.05 (severity: Mann-Whitney U test; temperature: Welch’s t test; weight: unpaired t test). (B) Schematic of TRAP approach. EC, endothelial cell. (C) Ratio of normalized counts (TRAP-Seq over whole kidney RNA-Seq) obtained from the same organs. (D) Heatmap of the top 100 most significant changes in kidney expression for bulk RNA-Seq (left) and TRAP-Seq (right). Lookup table (LUT) corresponds to z-score. (E) Strong correlation between whole kidney and endothelial gene expression in response to LPS. (F) Endothelial expression of multiple IFN-regulated genes significantly correlates with disease severity (P < 0.05).