Extracellular CIRP activates STING to exacerbate hemorrhagic shock

Chen, Kehong; Cagliani, Joaquín; Aziz, Monowar; Tan, Chuyi; Wang, Haichao

doi:10.1172/jci.insight.143715

Cited by 22 publications

(19 citation statements)

References 38 publications

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“…The role of STING in acute inflammation and critical illness is less known and is a highly active area of ongoing research. Recently, our laboratory demonstrated that STING exacerbates the effects of eCIRP, a DAMP known to amplify inflammation in critical illnesses including sepsis, I/R injury, and hemorrhagic shock (14). Stimulator of interferon gene activation has also been found to play a critical role in the development of sepsis-associated acute lung injury and, recently, in I/R injury (33,34).…”

Section: Discussionmentioning

confidence: 99%

H151, a Small Molecule Inhibitor of Sting as a Novel Therapeutic in Intestinal Ischemia–reperfusion Injury

Kobritz

Borjas

Patel

et al. 2022

Shock

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BackgroundIntestinal ischemia–reperfusion (I/R) injury is a severe disease associated with high mortality. Stimulator of interferon genes (STING) is an intracellular protein that is activated by cytosolic DNA and is implicated in I/R injury, resulting in transcription of type I interferons (IFN-α and IFN-β) and other proinflammatory molecules. Extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, induces STING activation. H151 is a small molecule inhibitor of STING that has not yet been studied as a potential therapeutic. We hypothesize that H151 reduces inflammation, tissue injury, and mortality after intestinal I/R. Methods: In vitro, RAW264.7 cells were pretreated with H151 then stimulated with recombinant murine (rm) CIRP, and IFN-β levels in the culture supernatant were measured at 24 hours after stimulation. In vivo, male C57BL/6 mice were subjected to 60-minute intestinal ischemia via superior mesenteric artery occlusion. At the time of reperfusion, mice were intraperitoneally instilled with H151 (10 mg/kg BW) or 10% Tween-80 in PBS (vehicle). Four hours after reperfusion, the small intestines, lungs, and serum were collected for analysis. Mice were monitored for 24 hours after intestinal I/R to assess survival. Results: In vitro, H151 reduced rmCIRP-induced IFN-β levels in a dose-dependent manner. In vivo, intestinal levels of pIRF3 were increased after intestinal I/R and decreased after H151 treatment. There was an increase in serum levels of tissue injury markers (lactate dehydrogenase, aspartate aminotransferase) and cytokine levels (interleukin 1β, interleukin 6) after intestinal I/R, and these levels were decreased after H151 treatment. Ischemia-reperfusion–induced intestinal and lung injury and inflammation were significantly reduced after H151 treatment, as evaluated by histopathologic assessment, measurement of cell death, chemokine expression, neutrophil infiltration, and myeloperoxidase activity. Finally, H151 improved the survival rate from 41% to 81% after intestinal I/R. Conclusions: H151, a novel STING inhibitor, attenuates the inflammatory response and reduces tissue injury and mortality in a murine model of intestinal I/R. H151 shows promise as a potential therapeutic in the treatment of this disease.

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Section: Discussionmentioning

confidence: 99%

H151, a Small Molecule Inhibitor of Sting as a Novel Therapeutic in Intestinal Ischemia–reperfusion Injury

Kobritz

Borjas

Patel

et al. 2022

Shock

Self Cite

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“…Previously, Yamamoto, Sato and Hemmi [ 37 ] demonstrated a prominent feature of TRIF-dependent IRF signaling in the production of type I IFN. More recently, a hemorrhagic shock model confirmed that the deficiency of the TLR4 and its intracellular adaptor TRIF results in decreased activation of STING’s downstream mediators, TBK1 and IRF3, and the expression of type I IFNs [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Natterin-Induced Neutrophilia Is Dependent on cGAS/STING Activation via Type I IFN Signaling Pathway

Lima

Andrade‐Barros

Bernardo

et al. 2022

IJMS

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Natterin is a potent pro-inflammatory fish molecule, inducing local and systemic IL-1β/IL-1R1-dependent neutrophilia mediated by non-canonical NLRP6 and NLRC4 inflammasome activation in mice, independent of NLRP3. In this work, we investigated whether Natterin activates mitochondrial damage, resulting in self-DNA leaks into the cytosol, and whether the DNA sensor cGAS and STING pathway participate in triggering the innate immune response. Employing a peritonitis mouse model, we found that the deficiency of the tlr2/tlr4, myd88 and trif results in decreased neutrophil influx to peritoneal cavities of mice, indicative that in addition to MyD88, TRIF contributes to neutrophilia triggered by TLR4 engagement by Natterin. Next, we demonstrated that gpcr91 deficiency in mice abolished the neutrophil recruitment after Natterin injection, but mice pre-treated with 2-deoxy-d-glucose that blocks glycolysis presented similar infiltration than WT Natterin-injected mice. In addition, we observed that, compared with the WT Natterin-injected mice, DPI and cyclosporin A treated mice had a lower number of neutrophils in the peritoneal exudate. The levels of dsDNA in the supernatant of the peritoneal exudate and processed IL-33 in the supernatant of the peritoneal exudate or cytoplasmic supernatant of the peritoneal cell lysate of WT Natterin-injected mice were several folds higher than those of the control mice. The recruitment of neutrophils to peritoneal cavity 2 h post-Natterin injection was intensely impaired in ifnar KO mice and partially in il-28r KO mice, but not in ifnγr KO mice. Finally, using cgas KO, sting KO, or irf3 KO mice we found that recruitment of neutrophils to peritoneal cavities was virtually abolished in response to Natterin. These findings reveal cytosolic DNA sensors as critical regulators for Natterin-induced neutrophilia.

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“…Extracellular CIRP was reported to be a danger-associated molecular pattern (DAMP) with pro-inflammatory activity [ 33 ]. The concentration of CIRP in the blood increased in patients with hemorrhagic shock and was associated with a poor prognosis for sepsis [ 34 , 35 ]. Recombinant CIRP has been shown to stimulate the secretion of tumor necrosis factor-α (TNF-α) and high-mobility group protein B1 from macrophages [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Decreased Expression of CIRP Induced by Therapeutic Hypothermia Correlates with Reduced Early Brain Injury after Subarachnoid Hemorrhage

Dai

Zhou

et al. 2022

JCM

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Early brain injury is considered to be a primary reason for the poor prognosis of patients suffering from subarachnoid hemorrhage (SAH). Due to its pro-inflammatory activity, cold-inducible RNA-binding protein (CIRP) has been implicated in the ischemic brain insult, but its possible interplay with hypothermia in SAH treatment remains to be evaluated. One-hundred and thirty-eight Sprague-Dawley rats (300–350 g males) were randomly allocated into the following groups: sham-operated (Sham); SAH; and SAH + hypothermia (SAH + H), each comprised of 46 animals. After treatments, the brain tissues of the three groups were randomly collected after 12 h, 1 d, 3 d, and 7 d, and the expression levels of the CIRP and mitochondrial apoptosis pathway-related proteins Bax, Bcl-2, caspase-9, caspase-3, and cytochrome c measured using Western blotting and real-time PCR. Brain damage was assessed by TUNEL and Nissl staining, the electron microscopy of brain tissue slices as well as functional rotarod tests. Expression of CIRP, Bax, caspase-9, caspase-3, and cytochrome c as well as reduced motor function incidence were higher in the SAH group, particularly during the first 3 d after SAH induction. Hypothermia blunted these SAH responses and apoptosis, thereby indicating reduced inflammatory signaling and less brain cell injury in the early period after SAH. Hypothermia treatment was found to effectively protect the brain tissue from early SAH injury in a rat model and its further evaluation as a therapeutic modality in SAH patients requires further study.

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Extracellular CIRP activates STING to exacerbate hemorrhagic shock

Cited by 22 publications

References 38 publications

H151, a Small Molecule Inhibitor of Sting as a Novel Therapeutic in Intestinal Ischemia–reperfusion Injury

H151, a Small Molecule Inhibitor of Sting as a Novel Therapeutic in Intestinal Ischemia–reperfusion Injury

Natterin-Induced Neutrophilia Is Dependent on cGAS/STING Activation via Type I IFN Signaling Pathway

Decreased Expression of CIRP Induced by Therapeutic Hypothermia Correlates with Reduced Early Brain Injury after Subarachnoid Hemorrhage

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