Endothelial STING and STAT1 mediate interferon-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

doi:10.1172/JCI189570

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

Nina Martino,¹ Erin K. Sanders,² Ramon Bossardi Ramos,¹ Iria Di John Portela,¹ Fatma Awadalla,¹ Shuhan Lu,¹ Dareen Chuy,¹ Neil Poddar,¹ Mei Xing G Zuo,¹ Uma Balasubramanian,¹ Peter A. Vincent,¹ Pilar Alcaide,² and Alejandro P. Adam¹

Published September 16, 2025 - More info

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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. This work focuses 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 interferon (IFNI)-like gene signature in response to endotoxemia in mouse kidneys and brains. In cultured primary human endothelial cells, IL-6 induced a transient IFNI-like gene expression in a non-canonical, interferon-independent fashion. We further show that STAT3, which we had previously shown 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 the IRFs 1, 3, and 4. Inhibition of this pathway in endothelial-specific STING knockout mice or global STAT1 knockout mice led to reduced severity of an acute endotoxemic challenge and prevented the 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 new insights into the complex response to acute inflammatory responses, and offer the possibility of potential novel therapeutic strategies for independently controlling the intracellular responses to IL-6 in order to tailor the inflammatory response.

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

Nina Martino,¹ Erin K. Sanders,² Ramon Bossardi Ramos,¹ Iria Di John Portela,¹ Fatma Awadalla,¹ Shuhan Lu,¹ Dareen Chuy,¹ Neil Poddar,¹ Mei Xing G Zuo,¹ Uma Balasubramanian,¹ Peter A. Vincent,¹ Pilar Alcaide,² and Alejandro P. Adam¹

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

Nina Martino,1 Erin K. Sanders,2 Ramon Bossardi Ramos,1 Iria Di John Portela,1 Fatma Awadalla,1 Shuhan Lu,1 Dareen Chuy,1 Neil Poddar,1 Mei Xing G Zuo,1 Uma Balasubramanian,1 Peter A. Vincent,1 Pilar Alcaide,2 and Alejandro P. Adam1

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Nina Martino,¹ Erin K. Sanders,² Ramon Bossardi Ramos,¹ Iria Di John Portela,¹ Fatma Awadalla,¹ Shuhan Lu,¹ Dareen Chuy,¹ Neil Poddar,¹ Mei Xing G Zuo,¹ Uma Balasubramanian,¹ Peter A. Vincent,¹ Pilar Alcaide,² and Alejandro P. Adam¹