A novel eCIRP/TREM-1 pathway inhibitor attenuates acute kidney injury

Siskind, Sara; Royster, William; Wang, Haichao

doi:10.1016/j.surg.2022.02.003

Cited by 8 publications

(15 citation statements)

References 37 publications

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“…M3 treatment, on the other hand, had an increased effect on the survival rate of mice after hepatic I/R ( 60 ). When M3 competes with TREM-1, it also blocks the eCIRP signaling pathway in the heart ( 80 ) and kidney ( 81 ). M3 exerts protective effects against sepsis-induced myocardial injury and acute kidney injury after renal I/R by inhibiting the eCIRP/TREM-1 interaction ( 81 ).…”

Section: Inhibitors Of Cirpmentioning

confidence: 99%

Exosome-derived CIRP: An amplifier of inflammatory diseases

Han

Zhang

et al. 2023

Front. Immunol.

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Cold-inducible RNA-binding protein (CIRP) is an intracellular stress-response protein and a type of damage-associated molecular pattern (DAMP) that responds to various stress stimulus by altering its expression and mRNA stability. Upon exposure to ultraviolet (UV) light or low temperature, CIRP get translocated from the nucleus to the cytoplasm through methylation modification and stored in stress granules (SG). During exosome biogenesis, which involves formation of endosomes from the cell membrane through endocytosis, CIRP also gets packaged within the endosomes along with DNA, and RNA and other proteins. Subsequently, intraluminal vesicles (ILVs) are formed following the inward budding of the endosomal membrane, turning the endosomes into multi-vesicle bodies (MVBs). Finally, the MVBs fuse with the cell membrane to form exosomes. As a result, CIRP can also be secreted out of cells through the lysosomal pathway as Extracellular CIRP (eCIRP). Extracellular CIRP (eCIRP) is implicated in various conditions, including sepsis, ischemia-reperfusion damage, lung injury, and neuroinflammation, through the release of exosomes. In addition, CIRP interacts with TLR4, TREM-1, and IL-6R, and therefore are involved in triggering immune and inflammatory responses. Accordingly, eCIRP has been studied as potential novel targets for disease therapy. C23 and M3, polypeptides that oppose eCIRP binding to its receptors, are beneficial in numerous inflammatory illnesses. Some natural molecules such as Luteolin and Emodin can also antagonize CIRP, which play roles similar to C23 in inflammatory responses and inhibit macrophage-mediated inflammation. This review aims to provide a better understanding on CIRP translocation and secretion from the nucleus to the extracellular space and the mechanisms and inhibitory roles of eCIRP in diverse inflammatory illnesses.

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Section: Inhibitors Of Cirpmentioning

confidence: 99%

Exosome-derived CIRP: An amplifier of inflammatory diseases

Han

Zhang

et al. 2023

Front. Immunol.

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“…Renal I/R procedure was performed as previously described (14,35). Before the surgery, the mice were randomly selected as the sham (n = 10), vehicle (n = 14), and treatment (n = 14) groups.…”

Section: Renal I/r Modelmentioning

confidence: 99%

Novel Ps-Ome Mirna130b-3p Reduces Inflammation and Injury and Improves Survival After Renal Ischemia-Reperfusion Injury

Vazquez,

Sfakianos,

Coppa

et al. 2023

Shock

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Introduction Acute kidney injury (AKI) is a prevalent medical disorder characterized by a sudden decline in kidney function, often because of ischemia-reperfusion events. It is associated with significant chronic complications, and currently available therapies are limited to supportive measures. Extracellular cold-inducible RNA-binding protein (eCIRP) has been identified as a mediator that potentiates inflammation following ischemia-reperfusion injury. However, it has been discovered that miRNA 130b-3p acts as an endogenous inhibitor of eCIRP. To address the inherent instability of miRNA in vivo, a chemically modified miRNA mimic called PS-OME miR130 was developed. We hypothesize that administration of PS-OME miR130 following renal ischemia/reperfusion (I/R) can lead to reduced inflammation and injury in a murine model of AKI. Methods C57BL/6 male mice underwent renal I/R by clamping of bilateral renal hilum for 30 min or sham operation. Immediately following closure, mice were intravenously administered vehicle (PBS) or PS-OME miR130 at a dose of 12.5 nmol/mouse. Blood and kidneys were collected after 24 h for further analysis. Separately, mice underwent renal I/R and administered vehicle or treatment and, survival was monitored for 10 days. Results Following renal I/R, mice receiving vehicle showed a significant increase in serum markers of kidney injury and inflammation including BUN, NGAL, KIM-1 and IL-6. Following treatment with PS-OME miR130, these markers were significantly decreased. Kidney tissue mRNA expression for injury and inflammation markers including NGAL, KIM-1, KC, and MIP-2 were increased after renal I/R, however, these markers showed a significant reduction with PS-OME miR130 treatment. Histologically, treatment with PS-OME miR130 showed a significant decrease in neutrophil infiltration and injury severity score, and decreased apoptosis. In the 10-day survival study, mice in the treatment group showed a significant reduction in mortality as compared to vehicle group. Conclusion In a murine renal I/R model, the administration of PS-OME miR130, a direct eCIRP antagonistic miRNA mimic, resulted in the reduction of kidney inflammation and injury, and improved survival. PS-OME miR130 holds promise to be developed as novel therapeutic for AKI as an adjunct to the standard of care.

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“…During sepsis and hemorrhagic shock, CIRP is released into the extracellular space, acting as a DAMP and aggravating the inflammatory response ( Qiang et al, 2013 ; Aziz et al, 2019 ). Extracellular CIRP (eCIRP) release has also been implicated in the progression of AKI following RIR injury through activation of triggering receptor expressed on myeloid cells-1 (TREM-1), a pattern recognition receptor (PRR) involved in the innate immune response ( Gibot et al, 2004 ; Cen et al, 2016 ; Siskind et al, 2022 ). Both mice genetically deficient in TREM-1 and treated with M3, a novel peptide designed to inhibit the interaction of eCIRP with TREM-1, had attenuated renal injury after RIR ( Denning et al, 2020a ; Siskind et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…Extracellular CIRP (eCIRP) release has also been implicated in the progression of AKI following RIR injury through activation of triggering receptor expressed on myeloid cells-1 (TREM-1), a pattern recognition receptor (PRR) involved in the innate immune response ( Gibot et al, 2004 ; Cen et al, 2016 ; Siskind et al, 2022 ). Both mice genetically deficient in TREM-1 and treated with M3, a novel peptide designed to inhibit the interaction of eCIRP with TREM-1, had attenuated renal injury after RIR ( Denning et al, 2020a ; Siskind et al, 2022 ). Recently, we found that eCIRP can independently induce a systemic inflammatory response akin to sepsis through activation of TREM-1, however, the resultant effects on kidney function have not been thoroughly explored ( Denning et al, 2020a ).…”

Section: Introductionmentioning

confidence: 99%

“…Both eCIRP and TREM-1 are upregulated in AKI, and blockade of TREM-1 attenuates AKI severity ( Campanholle et al, 2013 ; Lo et al, 2014 ; Cen et al, 2016 ; Tammaro et al, 2016 ; Tammaro et al, 2017 ; Siskind et al, 2022 ), giving rise to the hypothesis that eCIRP directly induces renal inflammation via activation of TREM-1. In this study, we have demonstrated that circulating eCIRP can independently induce AKI through interaction with TREM-1.…”

Section: Introductionmentioning

confidence: 99%

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Extracellular CIRP induces acute kidney injury via endothelial TREM-1

Siskind

Zhang²,

Wang³

2022

Front. Physiol.

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Introduction: Acute kidney injury is associated with elevated serum levels of extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern released during ischemia/reperfusion injury, hemorrhagic shock, and sepsis. It is unknown if circulating eCIRP and eCIRP-induced activation of receptor triggering receptor expressed on myeloid cells-1 (TREM-1), expressed on endothelial cells, play an important role in the pathogenesis of AKI.Methods: Male B6 wild-type (WT) and TREM-1−/− mice were subjected to intravenous injection of recombinant murine (rm) CIRP. Serum, urine, and renal tissue were collected 6 h later for analysis. Additionally, primary human renal glomerular endothelial cells (HRGEC) were stimulated in vitro with rmCIRP after pretreatment with M3, a novel inhibitory peptide of TREM-1, or vehicle. Supernatants and cells were collected 20 h after stimulation.Results: After injection with rmCIRP, WT mice had a significant increase in serum levels of BUN, creatinine, and NGAL compared to control. Additionally, NGAL was significantly increased in the urine of rmCIRP-injected mice, suggesting that circulating eCIRP can directly induce AKI. The levels of TREM-1 mRNA in the kidneys, as well as soluble (s) TREM-1 released into the serum and urine, were significantly increased in rmCIRP-injected mice. TREM-1−/− mice injected with rmCIRP had attenuated AKI, indicated by significantly decreased serum BUN, creatinine, and NGAL, and renal mRNA expression of NGAL and KIM-1 compared to WT mice. TREM-1−/− mice also had attenuated endothelial activation, with decreased mRNA and protein expression of ICAM-1 in renal tissue. HRGEC stimulated with rmCIRP in vitro had significant increases in cytokine production and sTREM-1 release, which was attenuated in cells treated with M3.Conclusion: Activation of renal TREM-1 with circulating eCIRP is sufficient to cause AKI. Elevated levels of eCIRP may be critical for the development of AKI under conditions such as ischemia/reperfusion injury, hemorrhagic shock, and sepsis. Mice deficient in the TREM-1 receptor have attenuated AKI and reduced endothelial cell activation after injection of rmCIRP. TREM-1 inhibition with M3 attenuates HRGEC activation after eCIRP stimulation. Targeting eCIRP activation of TREM-1 may provide a novel and effective treatment for AKI.

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A novel eCIRP/TREM-1 pathway inhibitor attenuates acute kidney injury

Cited by 8 publications

References 37 publications

Exosome-derived CIRP: An amplifier of inflammatory diseases

Exosome-derived CIRP: An amplifier of inflammatory diseases

Novel Ps-Ome Mirna130b-3p Reduces Inflammation and Injury and Improves Survival After Renal Ischemia-Reperfusion Injury

Extracellular CIRP induces acute kidney injury via endothelial TREM-1

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