Inhibition of the Interaction of TREM-1 and eCIRP Attenuates Inflammation and Improves Survival in Hepatic Ischemia/Reperfusion

Borjas, Timothy; Jacob, Asha; Yen, Hao-Ting; Patel, Vihas; Coppa, Gene F.; Aziz, Monowar; Wang, Ping

doi:10.1097/shk.0000000000001894

Cited by 10 publications

(30 citation statements)

References 44 publications

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“…In lung fibroblasts, eCIRP amplifies pro-inflammatory cytokines in a TLR4-dependent manner, triggering pulmonary fibrosis ( 54 ). As a receptor for eCIRP, TREM-1 plays a vital role in ischemia-reperfusion in the liver, intestine, and other organs ( 60 ), and induces inflammation in macrophages and neutrophils ( 35 ), forming NETs ( 61 ). In hemorrhagic shock and sepsis, TREM-1 can also be a key target of eCIRP ( 16 , 56 , 62 ).…”

Section: Role Of Ecirp In Inflammatory Diseasesmentioning

confidence: 99%

“…During hepatic I/R, the binding of eCIRP to TREM-1 increases the number of inflammatory cells in the liver leading to increased tissue damage therein. 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 ).…”

Section: Inhibitors Of Cirpmentioning

confidence: 99%

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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: Role Of Ecirp In Inflammatory Diseasesmentioning

confidence: 99%

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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“…Extracellular cold-inducible RNA-binding protein levels started to increase by 4 hours after hepatic I/R and significantly increased from baseline at 24 hours later. The protective effects of an anti-CIRP antibody and TREM-1 inhibition via peptide inhibitor have been shown in hepatic I/R 8,11 . Therefore, eCIRP released into circulation as early as 4 hours after hepatic I/R could bind to exogenous PS-OMe miR130 and has the potential to prevent hepatic I/R injury.…”

Section: Discussionmentioning

confidence: 99%

A novel miRNA mimic attenuates organ injury after hepatic ischemia/reperfusion

Borjas

Jacob

Kobritz

et al. 2023

J Trauma Acute Care Surg

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INTRODUCTION: Extracellular cold-inducible RNA-binding protein (eCIRP) is a novel mediator of inflammation and tissue injury. It has been shown that miRNA 130b-3p acts as an endogenous inhibitor of eCIRP. Because RNA mimics are unstable after in vivo administration, we have chemically engineered miRNA 130b-3p mimic (named PS-OMe miR130) to improve its stability by protection from nuclease activity. We hypothesize that PS-OMe miR130 reduces eCIRP-mediated injury and inflammation in a murine model of hepatic ischemia/ reperfusion (I/R), a model of sterile inflammation. METHODS:Adult male mice underwent 70% hepatic ischemia for 60 minutes and 24-hour reperfusion. At the start of reperfusion, mice were treated intravenously with vehicle (phosphate-buffered saline) or PS-OMe miR130. Blood and liver tissue were collected after 24 hours for biochemical analysis. Apoptosis in the liver tissue was determined by transferase dUTP nick-end labeling assay. RESULTS:After hepatic I/R, organ injury markers including aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase significantly decreased after PS-OMe miR130 treatment. Furthermore, histological analysis of liver sections demonstrated significantly less injury in PS-OMe miR130 treatment mice versus vehicle mice. In addition, tumor necrosis factor α mRNA, interleukin-1β mRNA, and neutrophil infiltration (myeloperoxidase activity and granulocyte receptor 1 immunohistochemistry) were significantly attenuated after PS-OMe miR130 treatment. Finally, apoptosis significantly decreased in liver tissue after treatment. CONCLUSION:PS-OMe miR130 decreases eCIRP-mediated injury and inflammation in a murine model of hepatic I/R.

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“…These authors also synthesized a novel peptide inhibitor, M3, that could block the interaction between eCIRP and TREM-1 and inhibit the eCIRP-mediated inflammatory response. Borjas et al [ 67 ]. used M3 to treat hepatic ischemia/reperfusion (I/R) mice and found that M3 attenuated hepatic I/R injury by inhibiting TREM-1.…”

Section: Trem-1 Ligandsmentioning

confidence: 99%

The role of triggering receptor expressed on myeloid cells-1 (TREM-1) in central nervous system diseases

Kan

Zhang

et al. 2022

Mol Brain

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Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily and is mainly expressed on the surface of myeloid cells such as monocytes, macrophages, and neutrophils. It plays an important role in the triggering and amplification of inflammatory responses, and it is involved in the development of various infectious and non-infectious diseases, autoimmune diseases, and cancers. In recent years, TREM-1 has also been found to participate in the pathological processes of several central nervous system (CNS) diseases. Targeting TREM-1 may be a promising strategy for treating these diseases. This paper aims to characterize TREM-1 in terms of its structure, signaling pathway, expression, regulation, ligands and pathophysiological role in CNS diseases.

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Inhibition of the Interaction of TREM-1 and eCIRP Attenuates Inflammation and Improves Survival in Hepatic Ischemia/Reperfusion

Cited by 10 publications

References 44 publications

Exosome-derived CIRP: An amplifier of inflammatory diseases

Exosome-derived CIRP: An amplifier of inflammatory diseases

A novel miRNA mimic attenuates organ injury after hepatic ischemia/reperfusion

The role of triggering receptor expressed on myeloid cells-1 (TREM-1) in central nervous system diseases

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