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Shantha Kumara HMC, Addison P, Yan XH, Sharma AR, Mitra N, Angammana HN, Hedjar Y, Chen YR, Cekic V, Richard WL. Plasma extracellular cold inducible RNA-binding protein levels are elevated for 1 month post-colectomy which may promote metastases. World J Gastrointest Oncol 2025; 17:100678. [DOI: 10.4251/wjgo.v17.i4.100678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 01/10/2025] [Accepted: 02/19/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Cold-inducible RNA-binding protein (CIRP) is related to a family of stress-induced RNA-binding proteins. It is primarily found in the nucleus, where it regulates transcription. Under stress, CIRP translocates to the cytoplasm where it modulates translation; a subset is secreted as extracellular CIRP (eCIRP) which is a damage-associated molecular pattern (DAMP) molecule that stimulates the production of inflammatory mediators. Elevated blood eCIRP levels may foster immune tolerance and facilitate tumor growth. Increased CIRP levels have been noted in various malignancies including colorectal cancer (CRC). This study’s objective was to determine plasma eCIRP levels before and after minimally invasive colorectal resection (MICR) for CRC.
AIM To assess plasma eCIRP levels prior to and following minimally invasive colorectal resection in the context of cancer pathology.
METHODS MICR patients from an IRB-approved data/tissue bank for whom plasma samples were available were eligible. Plasma specimens were obtained preoperatively (preop) and at least 3 time’s postop [between postoperative day (POD) 1-41]; late samples were grouped into 7-day blocks and were considered separate time points. eCIRP levels were assessed via enzyme-linked immunosorbent assay (pg/mL) and results presented as mean ± SD, analysis with Wilcoxon paired t-test).
RESULTS A total of 83 CRC patients who underwent MICR [colon 66%, rectal 34%; laparoscopic-assisted (LA), 70%; hand-assisted laparoscopic (HAL), 30%] were studied. The mean preop eCIRP level was 896.8 ± 757.0 pg/mL. Elevations in mean plasma levels (P = < 0.001) were noted on POD1 (2549 ± 2632 pg/mL, n = 83), POD3 (1871 ± 1362 pg/mL, n = 77), POD7-13 (1788 ± 1403 pg/mL, n = 57), POD14-20 (1473 ± 738.8 pg/mL, n = 30), and POD21-27 (1681 ± 1375 pg/mL, n = 21). No significant differences were noted at POD 28-41. Higher values were noted in the HAL’s (vs LA) group, however, there were more rectal cancers in the former.
CONCLUSION Elevated plasma eCIRP levels persist for a month post MICR for CRC (change from baseline, 77%-184%); highest values seen on POD1. The initial surge may be due to the acute inflammatory response while later elevations may be related to wound healing and remodeling. The higher levels noted in the HAL’s group (with greater IL and more rectal cases) suggest the extent of surgical trauma impacts eCIRP levels. Further investigations are needed.
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Affiliation(s)
- H M C Shantha Kumara
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Poppy Addison
- Division of Colon and Rectal Surgery, Department of Surgery, Staten Island University Hospital, Northwell Health, Staten Island, NY 10305, United States
| | - Xiao-Hong Yan
- Department of Pathology and Cell Biology, Columbia University Medical Center, Vanderbilt Clinic, New York, NY 10032, United States
| | - Anuj Raj Sharma
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Neil Mitra
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Hansani N Angammana
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Yanni Hedjar
- Department of Surgery, Brookdale Hospital and Medical Center, Brooklyn, NY 11212, United States
| | - Yi-Ru Chen
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Vesna Cekic
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Whelan L Richard
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
- Donald and Barbara Zucker School of Medicine, Hofstra/Northwell 500 Hofstra Blvd, Hempstead, NY 11549, United States
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Turan I, Ozacmak HS, Ozacmak VH, Barut F. Modulation of the Oxidative Stress and ICAM-1/TLR4/NF-Κβ Levels by Metformin in Intestinal Ischemia/Reperfusion Injury in Rats. Cell Biochem Biophys 2025:10.1007/s12013-025-01687-5. [PMID: 40009289 DOI: 10.1007/s12013-025-01687-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/27/2025] [Indexed: 02/27/2025]
Abstract
Metformin, a biguanide drug, is used for its antihyperglycemic effects. The purpose of the present study was to investigate the effects of metformin on the experimental model of intestinal ischemia-reperfusion (I/R) injury. Ischemia was induced by superior mesenteric artery occlusion followed by reperfusion. Metformin was administered orally by gavage at doses of 50, 100 or 200 mg/kg for one week before the surgery. Rats were divided to five groups (n = 8 for each): Sham control group; I/R control group; Metformin50 treated I/R group; Metformin100 treated I/R group; and Metformin200 treated I/R group. Tissue levels of malondialdehyde (MDA), glutathione (GSH), myeloperoxidase (MPO) activity, intercellular adhesion molecule-1 (ICAM-1), toll-like receptor 4 (TLR4), and nuclear factor-κB (NF-κB) as well as histological analysis were evaluated. Metformin treatment decreased the levels of MDA in 100 and 200 mg/kg doses besides lowering the MPO activity and ICAM-1 levels in all doses. Metformin also reduced NF-κB levels at dose of 200 mg/kg and improved histopathological scores at doses of 100 and 200 mg/kg. The treatment with metformin can prevent I/R-induced intestinal injury through down-regulating ICAM-1 and NF-κB levels, reducing oxidative stress, and lowering neutrophil accumulation. We propose that metformin could be a therapeutic agent in intestinal I/R.
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Affiliation(s)
- Inci Turan
- Zonguldak Bulent Ecevit University Faculty of Medicine, Department of Physiology, Zonguldak, Turkey.
| | - Hale Sayan Ozacmak
- Zonguldak Bulent Ecevit University Faculty of Medicine, Department of Physiology, Zonguldak, Turkey
| | - Veysel Haktan Ozacmak
- Zonguldak Bulent Ecevit University Faculty of Medicine, Department of Physiology, Zonguldak, Turkey
| | - Figen Barut
- Zonguldak Bulent Ecevit University Faculty of Medicine, Department of Pathology, Zonguldak, Turkey
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Lapin D, Sharma A, Wang P. Extracellular cold-inducible RNA-binding protein in CNS injury: molecular insights and therapeutic approaches. J Neuroinflammation 2025; 22:12. [PMID: 39838468 PMCID: PMC11752631 DOI: 10.1186/s12974-025-03340-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 01/07/2025] [Indexed: 01/23/2025] Open
Abstract
Central nervous system (CNS) injuries, such as ischemic stroke (IS), intracerebral hemorrhage (ICH) and traumatic brain injury (TBI), are a significant global burden. The complex pathophysiology of CNS injury is comprised of primary and secondary injury. Inflammatory secondary injury is incited by damage-associated molecular patterns (DAMPs) which signal a variety of resident CNS cells and infiltrating immune cells. Extracellular cold-inducible RNA-binding protein (eCIRP) is a DAMP which acts through multiple immune and non-immune cells to promote inflammation. Despite the well-established role of eCIRP in systemic and sterile inflammation, its role in CNS injury is less elucidated. Recent literature suggests that eCIRP is a pleiotropic inflammatory mediator in CNS injury. eCIRP is also being evaluated as a clinical biomarker to indicate prognosis in CNS injuries. This review provides a broad overview of CNS injury, with a focus on immune-mediated secondary injury and neuroinflammation. We then review what is known about eCIRP in CNS injury, and its known mechanisms in both CNS and non-CNS cells, identifying opportunities for further study. We also explore eCIRP's potential as a prognostic marker of CNS injury severity and outcome. Next, we provide an overview of eCIRP-targeting therapeutics and suggest strategies to develop these agents to ameliorate CNS injury. Finally, we emphasize exploring novel molecular mechanisms, aside from neuroinflammation, by which eCIRP acts as a critical mediator with significant potential as a therapeutic target and prognostic biomarker in CNS injury.
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Affiliation(s)
- Dmitriy Lapin
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, 11030, USA
- Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, 11030, USA
| | - Archna Sharma
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, 11030, USA.
- Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, 11030, USA.
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, 11030, USA.
- Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, 11030, USA.
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Hollis R, Li J, Lee Y, Jin H, Zhou M, Nofi CP, Sfakianos M, Coppa G, Aziz M, Wang P. A NOVEL OPSONIC EXTRACELLULAR CIRP INHIBITOR MOP3 ALLEVIATES GUT ISCHEMIA/REPERFUSION INJURY. Shock 2025; 63:101-109. [PMID: 39178245 DOI: 10.1097/shk.0000000000002467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/25/2024]
Abstract
ABSTRACT Introduction: Gut ischemia and reperfusion (I/R) injury promotes the release of damage-associated molecular patterns (DAMPs) such as extracellular cold-inducible RNA-binding protein (eCIRP). Gut I/R often leads to acute lung injury (ALI), a major contributor to mortality. Milk fat globule-epidermal growth factor-factor VIII-derived oligopeptide-3 (MOP3) is a novel peptide that attenuates sepsis by opsonizing eCIRP and facilitating its phagocytic clearance. We hypothesized that MOP3 reduces inflammation, mitigates gut and lung injury, and improves survival in gut I/R injury. Methods: Phagocytosis of FITC-labeled eCIRP by intestinal epithelial cells was determined by confocal microscopy, and the cell supernatant was evaluated for cytokine expression by ELISA. Adult C57BL/6 mice underwent 60 min of gut ischemia via superior mesenteric artery occlusion followed by reperfusion. Mice were treated with MOP3 or vehicle via retro-orbital injection at the time of reperfusion. At 4 h post-I/R, blood, gut, and lungs were harvested for further assay. In additional mice, 36-h survival was assessed. Plasma levels of injury and inflammatory markers were measured with colorimetry and ELISA, respectively. Tissue mRNA expression was measured with qPCR. Myeloperoxidase (MPO), TUNEL, histologic injury, and ZO-1 immunohistochemistry assessments were performed. Results: MOP3 significantly increased eCIRP phagocytosis by intestinal epithelial cells ( P < 0.01) and decreased IL-6 release ( P < 0.001). Gut I/R caused elevated plasma eCIRP levels. MOP3 treatment significantly reduced plasma levels of IL-1β ( P < 0.01), IL-6 ( P < 0.05), and lactate dehydrogenase ( P < 0.05) along with a significant decrease in gut ( P < 0.05) and lung ( P < 0.001) injury scores as well as gut cell death ( P < 0.05). Moreover, MOP3 reduced pulmonary levels of chemokines and the granulocyte activation marker MPO after gut I/R. Mechanistically, ZO-1 expression in the gut was decreased following gut I/R injury, whereas MOP3 significantly reversed the decrease in ZO-1 mRNA expression ( P < 0.001). Finally, mice treated with MOP3 exhibited a significant decrease in mortality ( P < 0.05). Conclusions: Treatment with MOP3 effectively mitigates organ injury induced by gut I/R. This beneficial effect is attributed to the facilitation of eCIRP clearance, directing the potential of MOP3 as an innovative therapeutic approach for this critical and often fatal condition.
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Affiliation(s)
| | - Jingsong Li
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York
| | - Yongchan Lee
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York
| | - Hui Jin
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York
| | - Mian Zhou
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York
| | | | - Maria Sfakianos
- Department of Surgery, Zucker School of Medicine, Manhasset, New York
| | - Gene Coppa
- Department of Surgery, Zucker School of Medicine, Manhasset, New York
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Gong T, Wang QD, Loughran PA, Li YH, Scott MJ, Billiar TR, Liu YT, Fan J. Mechanism of lactic acidemia-promoted pulmonary endothelial cells death in sepsis: role for CIRP-ZBP1-PANoptosis pathway. Mil Med Res 2024; 11:71. [PMID: 39465383 PMCID: PMC11514876 DOI: 10.1186/s40779-024-00574-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Accepted: 09/30/2024] [Indexed: 10/29/2024] Open
Abstract
BACKGROUND Sepsis is often accompanied by lactic acidemia and acute lung injury (ALI). Clinical studies have established that high serum lactate levels are associated with increased mortality rates in septic patients. We further observed a significant correlation between the levels of cold-inducible RNA-binding protein (CIRP) in plasma and bronchoalveolar lavage fluid (BALF), as well as lactate levels, and the severity of post-sepsis ALI. The underlying mechanism, however, remains elusive. METHODS C57BL/6 wild type (WT), Casp8-/-, Ripk3-/-, and Zbp1-/- mice were subjected to the cecal ligation and puncture (CLP) sepsis model. In this model, we measured intra-macrophage CIRP lactylation and the subsequent release of CIRP. We also tracked the internalization of extracellular CIRP (eCIRP) in pulmonary vascular endothelial cells (PVECs) and its interaction with Z-DNA binding protein 1 (ZBP1). Furthermore, we monitored changes in ZBP1 levels in PVECs and the consequent activation of cell death pathways. RESULTS In the current study, we demonstrate that lactate, accumulating during sepsis, promotes the lactylation of CIRP in macrophages, leading to the release of CIRP. Once eCIRP is internalized by PVEC through a Toll-like receptor 4 (TLR4)-mediated endocytosis pathway, it competitively binds to ZBP1 and effectively blocks the interaction between ZBP1 and tripartite motif containing 32 (TRIM32), an E3 ubiquitin ligase targeting ZBP1 for proteasomal degradation. This interference mechanism stabilizes ZBP1, thereby enhancing ZBP1-receptor-interacting protein kinase 3 (RIPK3)-dependent PVEC PANoptosis, a form of cell death involving the simultaneous activation of multiple cell death pathways, thereby exacerbating ALI. CONCLUSIONS These findings unveil a novel pathway by which lactic acidemia promotes macrophage-derived eCIRP release, which, in turn, mediates ZBP1-dependent PVEC PANoptosis in sepsis-induced ALI. This finding offers new insights into the molecular mechanisms driving sepsis-related pulmonary complications and provides potential new therapeutic strategies.
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Affiliation(s)
- Ting Gong
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
- Department of Anesthesiology, Shenzhen Hospital of Southern Medical University, Shenzhen, 518110, Guangdong, China.
| | - Qing-De Wang
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Patricia A Loughran
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Yue-Hua Li
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Melanie J Scott
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, 15219, USA
| | - You-Tan Liu
- Department of Anesthesiology, Shenzhen Hospital of Southern Medical University, Shenzhen, 518110, Guangdong, China.
| | - Jie Fan
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
- Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, 15240, USA.
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Yao Z, Liang Y, Pan C, Zeng K, Qu Z. Lonicerin alleviates intestinal myenteric neuron injury induced by hypoxia/reoxygenation treated macrophages by downregulating EZH2. J Biochem Mol Toxicol 2024; 38:e23810. [PMID: 39163614 DOI: 10.1002/jbt.23810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 03/01/2024] [Accepted: 08/02/2024] [Indexed: 08/22/2024]
Abstract
Intestinal ischemia-reperfusion (IR) injury is a common gastrointestinal disease that induces severe intestinal dysfunction. Intestinal myenteric neurons participate in maintaining the intestinal function, which will be severely injured by IR. Macrophages are widely reported to be involved in the pathogenesis of organ IR injury, including intestine, which is activated by NLRP3 signaling. Lonicerin (LCR) is a natural extracted monomer with inhibitory efficacy against the NLRP3 pathway in macrophages. The present study aims to explore the potential protective function of LCR in intestinal IR injury. Myenteric neurons were extracted from mice. RAW 264.7 cells were stimulated by H/R with or without 10 μM and 30 μM LCR. Remarkable increased release of IL-6, MCP-1, and TNF-α were observed in H/R treated RAW 264.7 cells, along with an upregulation of NLRP3, cleaved-caspase-1, IL-1β, and EZH2, which were sharply repressed by LCR. Myenteric neurons were cultured with the supernatant collected from each group. Markedly decreased neuron number and shortened length of neuron axon were observed in the H/R group, which were signally reversed by LCR. RAW 264.7 cells were stimulated by H/R, followed by incubated with 30 μM LCR with or without pcDNA3.1-EZH2. The inhibition of LCR on NLRP3 signaling in H/R treated RAW 264.7 cells was abolished by EZH2 overexpression. Furthermore, the impact of LCR on neuron number and neuron axon length in myenteric neurons in the H/R group was abated by EZH2 overexpression. Collectively, LCR alleviated intestinal myenteric neuron injury induced by H/R treated macrophages via downregulating EZH2.
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Affiliation(s)
- Zhiguang Yao
- Department of Surgical District 2, Eighth People's Hospital of Dongguan City, Dongguan, China
| | - Yuan Liang
- Department of Pediatrics, Eighth People's Hospital of Dongguan City, Dongguan, China
| | - Chunyan Pan
- Department of Health Management, Eighth People's Hospital of Dongguan City, Dongguan, China
| | - Kun Zeng
- Department of Science and Education, Eighth People's Hospital of Dongguan City, Dongguan, China
| | - Zhibo Qu
- Department of Surgical District 2, Eighth People's Hospital of Dongguan City, Dongguan, China
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Nofi CP, Prince JM, Aziz M, Wang P. The Novel MFG-E8-derived Oligopeptide, MOP3, Improves Outcomes in a Preclinical Murine Model of Neonatal Sepsis. J Pediatr Surg 2024; 59:1282-1290. [PMID: 38582704 DOI: 10.1016/j.jpedsurg.2024.03.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 03/04/2024] [Indexed: 04/08/2024]
Abstract
INTRODUCTION Neonatal sepsis is a devastating inflammatory condition that remains a leading cause of morbidity and mortality. Milk fat globule-EGF-factor VIII (MFG-E8) is a glycoprotein that reduces inflammation, whereas extracellular cold-inducible RNA binding protein (eCIRP) worsens inflammation. This study aimed to determine the therapeutic potential of a novel MFG-E8-derived oligopeptide 3 (MOP3) designed to clear eCIRP and protect against inflammation, organ injury, and mortality in neonatal sepsis. METHODS C57BL6 mouse pups were injected intraperitoneally with cecal slurry (CS) and treated with MOP3 (20 μg/g) or vehicle. 10 h after injection, blood, lungs, and intestines were collected for analyses, and in a 7-day experiment, pups were monitored for differences in mortality. RESULTS MOP3 treatment protected septic pups from inflammation by reducing eCIRP, IL-6, TNFα, and LDH. MOP3 reduced lung and intestinal inflammation and injury as assessed by reductions in tissue mRNA levels of inflammatory markers, histopathologic injury, and apoptosis in lung and intestines. MOP3 also significantly improved 7-day overall survival for CS-septic mouse pups compared to vehicle (75% vs. 46%, respectively). CONCLUSION Deriving from MFG-E8 and designed to clear eCIRP, MOP3 protects against sepsis-induced inflammation, organ injury, and mortality in a preclinical model of neonatal sepsis, implicating it as an exciting potential new therapeutic. LEVEL OF EVIDENCE Level 1.
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Affiliation(s)
- Colleen P Nofi
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, USA; Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, USA; Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA.
| | - Jose M Prince
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, USA; Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, USA; Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, USA; Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA; Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, USA; Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, USA; Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA; Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA
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Murao A, Jha A, Aziz M, Wang P. An engineered poly(A) tail attenuates gut ischemia/reperfusion-induced acute lung injury. Surgery 2024; 175:1346-1351. [PMID: 38342730 PMCID: PMC11001521 DOI: 10.1016/j.surg.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 12/28/2023] [Accepted: 01/02/2024] [Indexed: 02/13/2024]
Abstract
BACKGROUND Gut ischemia/reperfusion causes the release of damage-associated molecular patterns, leading to acute lung injury and high mortality. Cold-inducible ribonucleic acid-binding protein is a ribonucleic acid chaperon that binds the polyadenylation tail of messenger ribonucleic acid intracellularly. Upon cell stress, cold-inducible ribonucleic acid-binding protein is released, and extracellular cold-inducible ribonucleic acid-binding protein acts as a damage-associated molecular pattern, worsening inflammation. To inhibit extracellular cold-inducible ribonucleic acid-binding protein, we have recently developed an engineered polyadenylation tail named A12. Here, we sought to investigate the therapeutic potential of A12 in gut ischemia/reperfusion-induced acute lung injury. METHODS Male C57BL6/J mice underwent superior mesenteric artery occlusion and were treated with intraperitoneal A12 (0.5 nmol/g body weight) or vehicle at the time of reperfusion. Blood and lungs were collected 4 hours after gut ischemia/reperfusion. Systemic levels of extracellular cold-inducible ribonucleic acid-binding protein, interleukin-6, aspartate transaminase, alanine transaminase, and lactate dehydrogenase were determined. The pulmonary gene expression of cytokines (interleukin-6, interleukin-1β) and chemokines (macrophage-inflammatory protein-2, keratinocyte-derived chemokine) was also assessed. In addition, lung myeloperoxidase, injury score, and cell death were determined. Mice were monitored for 48 hours after gut ischemia/reperfusion for survival assessment. RESULTS Gut ischemia/reperfusion significantly increased the serum extracellular cold-inducible ribonucleic acid-binding protein levels. A12 treatment markedly reduced the elevated serum interleukin-6, alanine transaminase, aspartate transaminase, and lactate dehydrogenase by 53%, 23%, 23%, and 24%, respectively, in gut ischemia/reperfusion mice. A12 also significantly decreased cytokine and chemokine messenger ribonucleic acids and myeloperoxidase activity in the lungs of gut ischemia/reperfusion mice. Histological analysis revealed that A12 attenuated tissue injury and cell death in the lungs of gut ischemia/reperfusion mice. Finally, administration of A12 markedly improved the survival of gut ischemia/reperfusion mice. CONCLUSION A12, a novel extracellular cold-inducible ribonucleic acid-binding protein inhibitor, diminishes inflammation and mitigates acute lung injury when employed as a treatment during gut ischemia/reperfusion. Hence, the targeted approach toward extracellular cold-inducible ribonucleic acid-binding protein emerges as a promising therapeutic strategy for alleviating gut ischemia/reperfusion-induced acute lung injury.
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Affiliation(s)
- Atsushi Murao
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY
| | - Alok Jha
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY; Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY; Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY.
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Li Z, Sun S, Xiao Q, Tan S, Jin H, Hu B. Neuron Derived Cold-Inducible RNA-Binding Protein Promotes NETs Formation to Exacerbate Brain Endothelial Barrier Disruption after Ischemic Stroke. Aging Dis 2024; 16:AD.2024.0204-1. [PMID: 38377019 PMCID: PMC11745456 DOI: 10.14336/ad.2024.0204-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 02/04/2024] [Indexed: 02/22/2024] Open
Abstract
In ischemic stroke, neutrophils are the first-line peripheral immune cells infiltrating the brain tissue to form neutrophil extracellular traps (NETs). The present study aimed to investigate the role of neuronal cold-inducible RNA-binding protein (CIRP) in promoting NETs-induced brain endothelial barrier destruction and cerebral edema after ischemic stroke. We found that the expression of NETs and neuronal CIRP in the penumbra increased at 6 hours after transient middle cerebral artery occlusion (tMCAO) and increased significantly at 24 hours, reaching a peak at 3 days. NETs degradation or CIRP inhibition can alleviate the leakage of brain endothelial barrier and reverse the decreased expression of tight junction proteins (zonula occludens-1, claudin-5 and occludin) in tMCAO mice. Oxygen-glucose deprivation/reperfusion treated primary neurons or recombinant CIRP could induce NETs formation via TLR4/p38 signaling pathway in vitro. Transcription factor specificity protein 1 (sp1) was responsible for the increased neuronal CIRP expression and the inhibition of sp1 could suppress the increased CIRP expression, reduce NETs formation, and diminish brain endothelial barrier leakage in tMCAO mice. We also found the upregulated CIRP level was associated with severe cerebral edema in patients with acute ischemic stroke. In conclusion, the increased expression of transcription factor sp1 after ischemic stroke can lead to elevated CIRP expression and release from the neurons, which subsequently interacts with neutrophils and promotes NETs formation, resulting in brain endothelial barrier destruction and cerebral edema.
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Affiliation(s)
- Zhifang Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shuai Sun
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qinghui Xiao
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Senwei Tan
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Huijuan Jin
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Bo Hu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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10
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Gao Y, Liu H, Zhou J, Guo M, Sun J, Duan M. THE PROTECTIVE EFFECT OF C23 IN A RAT MODEL OF CARDIAC ARREST AND RESUSCITATION. Shock 2023; 59:892-901. [PMID: 36930651 DOI: 10.1097/shk.0000000000002113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/18/2023]
Abstract
ABSTRACT Background : Systemic inflammation acts as a contributor to neurologic deficits after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Extracellular cold-inducible RNA-binding, protein (CIRP) has been demonstrated to be responsible in part for the inflammation through binding to toll-like receptor 4 (TLR4) after cerebral ischemia. The short peptide C23 derived from CIRP has a high affinity for TLR4, we hypothesize that C23 reduces systemic inflammation after CA/CPR by blocking the binding of CIRP to TLR4. Methods : Adult male SD rats in experimental groups were subjected to 5 min of CA followed by resuscitation. C23 peptide (8 mg/kg) or normal saline was injected intraperitoneally at the beginning of the return of spontaneous circulation (ROSC). Results : The expressions of CIRP, TNF-α, IL-6, and IL-1β in serum and brain tissues were significantly increased at 24 h after ROSC ( P < 0.05). C23 treatment could markedly decrease the expressions of TNF-α, IL-6, and IL-1β in serum ( P < 0.05). Besides, it can decrease the expressions of TLR4, TNF-α, IL-6, and IL-1β in the cortex and hippocampus and inhibit the colocalization of CIRP and TLR4 ( P < 0.05). In addition, C23 treatment can reduce the apoptosis of hippocampus neurons ( P < 0.05). Finally, the rats in the C23 group have improved survival rate and neurological prognosis ( P < 0.05). Conclusions: These findings suggest that C23 can reduce systemic inflammation and it has the potential to be developed into a possible therapy for post-CA syndrome.
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Affiliation(s)
- Yu Gao
- Department of anesthesiology, Zhongda Hospital Southeast University, Nanjing 210000, Jiangsu, China
| | - Haoxin Liu
- Department of anesthesiology, Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu, China
| | - Jiejie Zhou
- Department of Anesthesiology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210000, Jiangsu, China
| | - Min Guo
- Department of anesthesiology, Changzhi People's Hospital Affiliated to Changzhi Medical College, Changzhi 046000, Shanxi, China
| | - Jie Sun
- Department of anesthesiology, Zhongda Hospital Southeast University, Nanjing 210000, Jiangsu, China
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11
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Zhang P, Bai L, Tong Y, Guo S, Lu W, Yuan Y, Wang W, Jin Y, Gao P, Liu J. CIRP attenuates acute kidney injury after hypothermic cardiovascular surgery by inhibiting PHD3/HIF-1α-mediated ROS-TGF-β1/p38 MAPK activation and mitochondrial apoptotic pathways. Mol Med 2023; 29:61. [PMID: 37127576 PMCID: PMC10152741 DOI: 10.1186/s10020-023-00655-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 04/18/2023] [Indexed: 05/03/2023] Open
Abstract
BACKGROUND The ischemia-reperfusion (IR) environment during deep hypothermic circulatory arrest (DHCA) cardiovascular surgery is a major cause of acute kidney injury (AKI), which lacks preventive measure and treatment. It was reported that cold inducible RNA-binding protein (CIRP) can be induced under hypoxic and hypothermic stress and may have a protective effect on multiple organs. The purpose of this study was to investigate whether CIRP could exert renoprotective effect during hypothermic IR and the potential mechanisms. METHODS Utilizing RNA-sequencing, we compared the differences in gene expression between Cirp knockout rats and wild-type rats after DHCA and screened the possible mechanisms. Then, we established the hypothermic oxygen-glucose deprivation (OGD) model using HK-2 cells transfected with siRNA to verify the downstream pathways and explore potential pharmacological approach. The effects of CIRP and enarodustat (JTZ-951) on renal IR injury (IRI) were investigated in vivo and in vitro using multiple levels of pathological and molecular biological experiments. RESULTS We discovered that Cirp knockout significantly upregulated rat Phd3 expression, which is the key regulator of HIF-1α, thereby inhibiting HIF-1α after DHCA. In addition, deletion of Cirp in rat model promoted apoptosis and aggravated renal injury by reactive oxygen species (ROS) accumulation and significant activation of the TGF-β1/p38 MAPK inflammatory pathway. Then, based on the HK-2 cell model of hypothermic OGD, we found that CIRP silencing significantly stimulated the expression of the TGF-β1/p38 MAPK inflammatory pathway by activating the PHD3/HIF-1α axis, and induced more severe apoptosis through the mitochondrial cytochrome c-Apaf-1-caspase 9 and FADD-caspase 8 death receptor pathways compared with untransfected cells. However, silencing PHD3 remarkably activated the expression of HIF-1α and alleviated the apoptosis of HK-2 cells in hypothermic OGD. On this basis, by pretreating HK-2 and rats with enarodustat, a novel HIF-1α stabilizer, we found that enarodustat significantly mitigated renal cellular apoptosis under hypothermic IR and reversed the aggravated IRI induced by CIRP defect, both in vitro and in vivo. CONCLUSION Our findings indicated that CIRP may confer renoprotection against hypothermic IRI by suppressing PHD3/HIF-1α-mediated apoptosis. PHD3 inhibitors and HIF-1α stabilizers may have clinical value in renal IRI.
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Affiliation(s)
- Peiyao Zhang
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 102308, China
- Department of Cardiopulmonary Bypass, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Liting Bai
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Yuanyuan Tong
- Department of Anesthesiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
| | - Shengwen Guo
- Department of Anesthesiology, Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, Fujian, 361000, China
| | - Wenlong Lu
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 102308, China
| | - Yue Yuan
- Department of Endocrinology, Drum Tower Hospital affiliated to Nanjing University Medical School, Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, 210008, China
| | - Wenting Wang
- Department of Cardiopulmonary Bypass, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Yu Jin
- Department of Cardiopulmonary Bypass, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Peng Gao
- Department of Cardiopulmonary Bypass, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Jinping Liu
- Department of Cardiopulmonary Bypass, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167, North Lishi Road, Xicheng District, Beijing, 100037, China.
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12
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Han J, Zhang Y, Ge P, Dakal TC, Wen H, Tang S, Luo Y, Yang Q, Hua B, Zhang G, Chen H, Xu C. Exosome-derived CIRP: An amplifier of inflammatory diseases. Front Immunol 2023; 14:1066721. [PMID: 36865547 PMCID: PMC9971932 DOI: 10.3389/fimmu.2023.1066721] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 01/26/2023] [Indexed: 02/16/2023] Open
Abstract
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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Affiliation(s)
- Jingrun Han
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Yibo Zhang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China.,Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Peng Ge
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China.,Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Tikam Chand Dakal
- Genome and Computational Biology Lab, Mohanlal Sukhadia University, Udaipur, Rajasthan, India
| | - Haiyun Wen
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China.,Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Shuangfeng Tang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Yalan Luo
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China.,Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Qi Yang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China.,Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Bianca Hua
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Comprehensive Cancer Center, Monrovia, CA, United States
| | - Guixin Zhang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Hailong Chen
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China.,Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Caiming Xu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.,Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Comprehensive Cancer Center, Monrovia, CA, United States
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13
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Extracellular CIRP Upregulates Proinflammatory Cytokine Expression via the NF-kappaB and ERK1/2 Signaling Pathways in Psoriatic Keratinocytes. Mediators Inflamm 2022; 2022:5978271. [PMID: 36110097 PMCID: PMC9470347 DOI: 10.1155/2022/5978271] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 07/22/2022] [Accepted: 08/24/2022] [Indexed: 11/29/2022] Open
Abstract
Psoriasis is a chronic inflammatory skin disease, and elevation of proinflammatory cytokine levels is a critical driver of the pathogenesis of psoriasis. Extracellular cold-inducible RNA-binding protein (eCIRP) has been shown to play a role in various acute and chronic inflammatory diseases. C23, a short peptide derived from CIRP, competitively binds CIRP receptors and reduces damage in inflammatory diseases. However, the effect of eCIRP in psoriasis has not been studied. In the present study, we investigated the role of eCIRP in the expression of proinflammatory cytokines in keratinocytes. Our data show that eCIRP expression was increased in the sera of psoriasis patients and imiquimod- (IMQ-) induced psoriatic mice and cells stimulated with proinflammatory cytokines (IL-1α, IL-17A, IL-22, oncostatin M, and TNF-α; mix M5). Recombinant human CIRP (rhCIRP) promoted the expression of the proinflammatory cytokines TNF-α, IL-6, and IL-8 and the activation of NF-kappaB (NF-κB) and ERK1/2 in cultured keratinocytes. We then found that the above effects of eCIRP could be blocked by C23 in both normal keratinocytes and M5-stimulated psoriatic keratinocytes. In addition, in vivo experiments revealed that C23 could effectively ameliorate IMQ-induced psoriatic dermatitis. TNF-α and IL-6 mRNA expressions were reduced in the skin lesions of mice with C23-treated IMQ-induced psoriasis, and this effect was accompanied by inhibition of the NF-κB and ERK1/2 signaling pathways. In summary, eCIRP plays an important role in the pathogenesis of psoriasis and may become a new target for psoriasis treatment.
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14
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Kobritz M, Borjas T, Patel V, Coppa G, Aziz M, Wang P. H151, A SMALL MOLECULE INHIBITOR OF STING AS A NOVEL THERAPEUTIC IN INTESTINAL ISCHEMIA-REPERFUSION INJURY. Shock 2022; 58:241-250. [PMID: 35959789 PMCID: PMC9489661 DOI: 10.1097/shk.0000000000001968] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Intestinal 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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Affiliation(s)
- Molly Kobritz
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York, USA
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Timothy Borjas
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York, USA
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Vihas Patel
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York, USA
| | - Gene Coppa
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York, USA
| | - Monowar Aziz
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York, USA
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Ping Wang
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York, USA
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA
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15
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Nofi CP, Wang P, Aziz M. Chromatin-Associated Molecular Patterns (CAMPs) in sepsis. Cell Death Dis 2022; 13:700. [PMID: 35961978 PMCID: PMC9372964 DOI: 10.1038/s41419-022-05155-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 07/28/2022] [Accepted: 08/01/2022] [Indexed: 01/21/2023]
Abstract
Several molecular patterns have been identified that recognize pattern recognition receptors. Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) are commonly used terminologies to classify molecules originating from pathogen and endogenous molecules, respectively, to heighten the immune response in sepsis. Herein, we focus on a subgroup of endogenous molecules that may be detected as foreign and similarly trigger immune signaling pathways. These chromatin-associated molecules, i.e., chromatin containing nuclear DNA and histones, extracellular RNA, mitochondrial DNA, telomeric repeat-containing RNA, DNA- or RNA-binding proteins, and extracellular traps, may be newly classified as chromatin-associated molecular patterns (CAMPs). Herein, we review the release of CAMPs from cells, their mechanism of action and downstream immune signaling pathways, and targeted therapeutic approaches to mitigate inflammation and tissue injury in inflammation and sepsis.
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Affiliation(s)
- Colleen P. Nofi
- grid.250903.d0000 0000 9566 0634Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY USA ,Elmezi Graduate School of Molecular Medicine, Manhasset, NY USA ,grid.512756.20000 0004 0370 4759Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY USA
| | - Ping Wang
- grid.250903.d0000 0000 9566 0634Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY USA ,Elmezi Graduate School of Molecular Medicine, Manhasset, NY USA ,grid.512756.20000 0004 0370 4759Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY USA ,grid.512756.20000 0004 0370 4759Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY USA
| | - Monowar Aziz
- grid.250903.d0000 0000 9566 0634Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY USA ,Elmezi Graduate School of Molecular Medicine, Manhasset, NY USA ,grid.512756.20000 0004 0370 4759Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY USA ,grid.512756.20000 0004 0370 4759Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY USA
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16
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Bolourani S, Sari E, Brenner M, Wang P. The role of eCIRP in bleomycin-induced pulmonary fibrosis in mice. PLoS One 2022; 17:e0266163. [PMID: 35377906 PMCID: PMC8979429 DOI: 10.1371/journal.pone.0266163] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 03/15/2022] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE AND DESIGN We examined the role of eCIRP in the pathogenesis of bleomycin-induced pulmonary fibrosis (PF). MATERIAL AND METHODS Publicly available gene expression omnibus datasets were analyzed for the expression of CIRP in lung samples from patients with PF. Wild type (WT) or CIRP-/- mice received daily injections of 10 μg/g bleomycin for 10 days. A subset of bleomycin-injected WT mice was treated with the eCIRP antagonist C23 (8 μg/g/day) from day 10 to day 19. At three weeks, transthoracic echocardiography was performed to measure the degree of pulmonary hypertension, and lung tissues were collected and analyzed for markers of fibrosis. RESULTS Analysis of the mRNA data of human lung samples showed a significant positive correlation between CIRP and α-smooth muscle actin (α-SMA), an important marker of fibrosis. Moreover, the expression of CIRP was higher in patients with acute exacerbation of PF than in patients with stable PF. CIRP-/- mice showed attenuated induction of α-SMA and collagens (Col1a1, Col3a1), reduced hydroxyproline content, decreased histological fibrosis scores, and improved pulmonary hypertension as compared to WT mice. WT mice treated with C23 also had significant attenuation of the above endpoint measure. CONCLUSIONS Our study demonstrates that eCIRP plays a key role in promoting the development of PF, and blocking eCIRP with C23 can significantly attenuate this process.
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Affiliation(s)
- Siavash Bolourani
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, United States of America
- Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, United States of America
- Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States of America
| | - Ezgi Sari
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, United States of America
| | - Max Brenner
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, United States of America
- Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States of America
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States of America
| | - Ping Wang
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, United States of America
- Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, United States of America
- Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States of America
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States of America
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17
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Bazid H, Shoeib M, Elsayed A, Mostafa M, Shoeib M, El Gayed EMA, Abdallah R. Expression of cold-inducible RNA binding protein in psoriasis. J Immunoassay Immunochem 2022; 43:384-402. [DOI: 10.1080/15321819.2022.2039183] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- Heba Bazid
- Dermatology and Andrology Department, Faculty of Medicine, Menoufia University
| | - Mohamed Shoeib
- Clinical Pathology Department, National Research Center, Cairo, Egypt
| | - Asmaa Elsayed
- Dermatology and Andrology Department, National Research Center, Cairo, Egypt
| | - Mohammed Mostafa
- Medical Biochemistry Depaetment, Faculty of Medicine, Menoufia University
| | - May Shoeib
- Pathology Department, Faculty of Medicine, Menoufia University
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18
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Zhong P, Zhou M, Zhang J, Peng J, Zeng G, Huang H. The role of Cold-Inducible RNA-binding protein in respiratory diseases. J Cell Mol Med 2021; 26:957-965. [PMID: 34953031 PMCID: PMC8831972 DOI: 10.1111/jcmm.17142] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/25/2021] [Accepted: 12/09/2021] [Indexed: 12/28/2022] Open
Abstract
Cold‐inducible RNA‐binding protein (CIRP) is a stress‐response protein that is expressed in various types of cells and acts as an RNA chaperone, modifying the stability of its targeted mRNA. Intracellular CIRP could also be released into extracellular space and once released, extracellular CIRP (eCIRP) acts as a damage‐associated molecular pattern (DAMP) to induce and amplify inflammation. Recent studies have found that eCIRP could promote acute lung injury (ALI) via activation of macrophages, neutrophils, pneumocytes and lung vascular endothelial cells in context of sepsis, haemorrhagic shock, intestinal ischemia/reperfusion injury and severe acute pancreatitis. In addition, CIRP is also highly expressed in the bronchial epithelial cells and its expression is upregulated in the bronchial epithelial cells of patients with chronic obstructive pulmonary diseases (COPD) and rat models with chronic bronchitis. CIRP is a key contributing factor in the cold‐induced exacerbation of COPD by promoting the expression of inflammatory genes and hypersecretion of airway mucus in the bronchial epithelial cells. Besides, CIRP is also involved in regulating pulmonary fibrosis, as eCIRP could directly activate and induce an inflammatory phenotype in pulmonary fibroblast. This review summarizes the findings of CIRP investigation in respiratory diseases and the underlying molecular mechanisms.
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Affiliation(s)
- Peng Zhong
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei, China.,Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Miao Zhou
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jingjing Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei, China.,Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Jianye Peng
- The Second Affiliated Hospital, Department of Cardiovascular Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, Hengyang, Hunan, China.,Clinical Medicine Research Center of Arteriosclerotic Disease of Hunan Province, Hengyang, Hunan, China
| | - Gaofeng Zeng
- The Second Affiliated Hospital, Department of Cardiovascular Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, Hengyang, Hunan, China.,Clinical Medicine Research Center of Arteriosclerotic Disease of Hunan Province, Hengyang, Hunan, China
| | - He Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei, China.,Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
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19
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Abstract
Significance: Sepsis is defined as a life-threatening organ dysfunction caused by dysregulated host response to infection. This leads to an uncontrolled inflammatory response at the onset of infection, followed by immunosuppression. The development of a specific treatment modality for sepsis is still challenging, reflecting our inadequate understanding of its pathophysiology. Understanding the mechanism and transition of the early hyperinflammation to late stage of immunosuppression in sepsis is critical for developing sepsis therapeutics. Recent Advances: Damage-associated molecular patterns (DAMPs) are intracellular molecules and released upon tissue injury and cell death in sepsis. DAMPs are recognized by pattern recognition receptors to initiate inflammatory cascades. DAMPs not only elicit an inflammatory response but also they subsequently induce immunosuppression, both are equally important for exacerbating sepsis. Recent advances on a new DAMP, extracellular cold-inducible RNA-binding protein for fueling inflammation and immunosuppression in sepsis, have added a new avenue into the dual functions of DAMPs in sepsis. Critical Issues: The molecular modification of DAMPs and their binding to pattern recognition receptors transit dynamically by the cellular environment in pathophysiologic conditions. Correlation between the dynamic changes of the impacts of DAMPs and the clinical outcomes in sepsis still lacks adequate understanding. Here, we focus on the impacts of DAMPs that cause inflammation as well as induce immunosuppression in sepsis. We further discuss the therapeutic potential by targeting DAMPs to attenuate inflammation and immunosuppression for mitigating sepsis. Future Directions: Uncovering pathways of the transition from inflammation to immunosuppression of DAMPs is a potential therapeutic avenue for mitigating sepsis.
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Affiliation(s)
- Mian Zhou
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA.,Departments of Surgery and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York, USA
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20
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Kübler M, Beck S, Peffenköver LL, Götz P, Ishikawa-Ankerhold H, Preissner KT, Fischer S, Lasch M, Deindl E. The Absence of Extracellular Cold-Inducible RNA-Binding Protein (eCIRP) Promotes Pro-Angiogenic Microenvironmental Conditions and Angiogenesis in Muscle Tissue Ischemia. Int J Mol Sci 2021; 22:ijms22179484. [PMID: 34502391 PMCID: PMC8431021 DOI: 10.3390/ijms22179484] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/27/2021] [Accepted: 08/30/2021] [Indexed: 12/11/2022] Open
Abstract
Extracellular Cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, is released from cells upon hypoxia and cold-stress. The overall absence of extra- and intracellular CIRP is associated with increased angiogenesis, most likely induced through influencing leukocyte accumulation. The aim of the present study was to specifically characterize the role of eCIRP in ischemia-induced angiogenesis together with the associated leukocyte recruitment. For analyzing eCIRPs impact, we induced muscle ischemia via femoral artery ligation (FAL) in mice in the presence or absence of an anti-CIRP antibody and isolated the gastrocnemius muscle for immunohistological analyses. Upon eCIRP-depletion, mice showed increased capillary/muscle fiber ratio and numbers of proliferating endothelial cells (CD31+/CD45−/BrdU+). This was accompanied by a reduction of total leukocyte count (CD45+), neutrophils (MPO+), neutrophil extracellular traps (NETs) (MPO+CitH3+), apoptotic area (ascertained via TUNEL assay), and pro-inflammatory M1-like polarized macrophages (CD68+/MRC1−) in ischemic muscle tissue. Conversely, the number of regenerative M2-like polarized macrophages (CD68+/MRC1+) was elevated. Altogether, we observed that eCIRP depletion similarly affected angiogenesis and leukocyte recruitment as described for the overall absence of CIRP. Thus, we propose that eCIRP is mainly responsible for modulating angiogenesis via promoting pro-angiogenic microenvironmental conditions in muscle ischemia.
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Affiliation(s)
- Matthias Kübler
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig- Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Sebastian Beck
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig- Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Lisa Lilian Peffenköver
- Department of Biochemistry, Faculty of Medicine, Justus Liebig University, 35392 Giessen, Germany; (L.L.P.); (K.T.P.); (S.F.)
| | - Philipp Götz
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig- Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Hellen Ishikawa-Ankerhold
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Department of Internal Medicine I, Faculty of Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Klaus T. Preissner
- Department of Biochemistry, Faculty of Medicine, Justus Liebig University, 35392 Giessen, Germany; (L.L.P.); (K.T.P.); (S.F.)
| | - Silvia Fischer
- Department of Biochemistry, Faculty of Medicine, Justus Liebig University, 35392 Giessen, Germany; (L.L.P.); (K.T.P.); (S.F.)
| | - Manuel Lasch
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig- Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Elisabeth Deindl
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig- Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
- Correspondence: ; Tel.: +49-(0)-89-2180-76504
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21
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Bolourani S, Sari E, Brenner M, Wang P. Extracellular CIRP Induces an Inflammatory Phenotype in Pulmonary Fibroblasts via TLR4. Front Immunol 2021; 12:721970. [PMID: 34367191 PMCID: PMC8342891 DOI: 10.3389/fimmu.2021.721970] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 07/09/2021] [Indexed: 12/24/2022] Open
Abstract
Extracellular cold-inducible RNA-binding protein (eCIRP), a new damage-associated molecular pattern (DAMP), has been recently shown to play a critical role in promoting the development of bleomycin-induced pulmonary fibrosis. Although fibroblast activation is a critical component of the fibrotic process, the direct effects of eCIRP on fibroblasts have never been examined. We studied eCIRP’s role in the induction of inflammatory phenotype in pulmonary fibroblasts and its connection to bleomycin-induced pulmonary fibrosis in mice. We found that eCIRP causes the induction of proinflammatory cytokines and differentially expression-related pathways in a TLR4-dependent manner in pulmonary fibroblasts. Our analysis further showed that the accessory pathways MD2 and Myd88 are involved in the induction of inflammatory phenotype. In order to study the connection of the enrichment of these pathways in priming the microenvironment for pulmonary fibrosis, we investigated the gene expression profile of lung tissues from mice subjected to bleomycin-induced pulmonary fibrosis collected at various time points. We found that at day 14, which corresponds to the inflammatory-to-fibrotic transition phase after bleomycin injection, TLR4, MD2, and Myd88 were induced, and the transcriptome was differentially enriched for genes in those pathways. Furthermore, we also found that inflammatory cytokines gene expressions were induced, and the cellular responses to these inflammatory cytokines were differentially enriched on day 14. Overall, our results show that eCIRP induces inflammatory phenotype in pulmonary fibroblasts in a TLR4 dependent manner. This study sheds light on the mechanism by which eCIRP induced inflammatory fibroblasts, contributing to pulmonary fibrosis.
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Affiliation(s)
- Siavash Bolourani
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, United States.,Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, United States.,Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
| | - Ezgi Sari
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Max Brenner
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, United States.,Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, United States.,Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States.,Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
| | - Ping Wang
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, United States.,Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, United States.,Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States.,Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
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22
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Sui M, Xu D, Zhao W, Lu H, Chen R, Duan Y, Li Y, Zhu Y, Zhang L, Zeng L. CIRBP promotes ferroptosis by interacting with ELAVL1 and activating ferritinophagy during renal ischaemia-reperfusion injury. J Cell Mol Med 2021; 25:6203-6216. [PMID: 34114349 PMCID: PMC8256344 DOI: 10.1111/jcmm.16567] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 03/29/2021] [Accepted: 04/05/2021] [Indexed: 12/21/2022] Open
Abstract
Renal ischaemia-reperfusion (IR) is a major cause of acute kidney injury (AKI). Cold-inducible RNA-binding protein (CIRBP) may contribute to AKI because its deficiency protects against renal IR injury in a mechanism believed to involve ferroptosis. We aimed to investigate whether ferroptosis is associated with CIRBP-mediated renal damage. The differential expression of CIRBP was examined in tubular epithelial (HK2) cells during hypoxia-reoxygenation (HR) or in response to erastin, an inducer of ferroptosis. CIRBP expression was increased in response to HR or erastin in HK2 cells but the silencing of CIRBP inhibited HR and erastin-induced ferroptosis together with ferritinophagy. We discovered an interaction between CIRBP and ELAVL1 using STRING software, which was verified through co-immunoprecipitation and fluorescence colocalization assays. We found that ELAVL1 is a critical regulator in the activation of ferritinophagy and the promotion of ferroptosis. HR or erastin also induced the expression of ELAVL1. An autophagy inhibitor (hydroxychloroquine) or si-ELAVL1 transfection reversed CIRBP-enhanced ferritinophagy activation and ferroptosis in HK2 cells under HR. Injection of anti-CIRBP antibody into a mouse model of IR inhibited ferroptosis and decreased renal IR injury in vivo. In summary, our results provide evidence that ferritinophagy-mediated ferroptosis could be responsible for CIRBP-enhanced renal IR injury.
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Affiliation(s)
- Mingxing Sui
- Department of Organ TransplantationShanghai Changhai HospitalShanghaiChina
| | - Da Xu
- Department of UrologyThe Third Affiliated Hospital of Naval Medical UniversityShanghaiChina
| | - Wenyu Zhao
- Department of Organ TransplantationShanghai Changhai HospitalShanghaiChina
| | - Hanlan Lu
- Department of Organ TransplantationShanghai Changhai HospitalShanghaiChina
| | - Rui Chen
- Department of Organ TransplantationShanghai Changhai HospitalShanghaiChina
| | - Yazhe Duan
- Department of Organ TransplantationShanghai Changhai HospitalShanghaiChina
| | - Yanhua Li
- Department of Organ TransplantationShanghai Changhai HospitalShanghaiChina
| | - Youhua Zhu
- Department of Organ TransplantationShanghai Changhai HospitalShanghaiChina
- The Committee of Experts of China Organ DonationBeijingChina
| | - Lei Zhang
- Department of Organ TransplantationShanghai Changhai HospitalShanghaiChina
| | - Li Zeng
- Department of Organ TransplantationShanghai Changhai HospitalShanghaiChina
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23
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Wang L, Li RF, Guan XL, Liang SS, Gong P. The Value of Extracellular Cold-Inducible RNA-Binding Protein (eCIRP) in Predicting the Severity and Prognosis of Patients After Cardiac Arrest: A Preliminary Observational Study. Shock 2020; 56:229-236. [PMID: 34276038 DOI: 10.1097/shk.0000000000001702] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Extracellular cold-inducible RNA-binding protein (eCIRP) acting as a novel damage-associated molecular pattern molecule promotes systemic inflammatory responses, including neuroinflammation in cerebral ischemia. We aimed to observe the changes of serum eCIRP and evaluate whether the increased serum eCIRP was associated with the severity and prognosis in patients with restoration of spontaneous circulation (ROSC). METHODS A total of 73 patients after ROSC were divided into non-survivor (n = 48) and survivor (n = 25) groups based on 28-day survival. Healthy volunteers (n = 25) were enrolled as controls. Serum eCIRP, procalcitonin (PCT), the pro-inflammatory mediators tumor necrosis factor (TNF)-α, interleukin-6 (IL)-6 and high mobility group protein (HMGB1), the neurological damage biomarkers neuron-specific enolase (NSE), and soluble protein 100β (S100β) were measured on days 1, 3, and 7 after ROSC. Clinical data and laboratory findings were collected, and the Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE II) were calculated concurrently. Cerebral performance category scores on day 28 after ROSC were recorded. RESULTS Serum eCIRP, IL-6, TNF-α, PCT, and HMGB1, NSE and S100β were significantly increased within the first week after ROSC. The increased levels of eCIRP were positively correlated with IL-6, TNF-α, lactate, NSE, S100β, CPR time, SOFA score, APACHE II score, and HMGB1 after ROSC. Serum eCIRP on days 1, 3, and 7 after ROSC could predict 28-day mortality and neurological prognosis. Serum eCIRP on day 3 after ROSC had a biggest AUC [0.862 (95% CI: 0.741-0.941)] for 28-day mortality and a biggest AUC [0.807 (95% CI: 0.630-0.981)] for neurological prognosis. CONCLUSIONS Systemic inflammatory response with increased serum eCIRP occurred in patients after ROSC. Increased eCIRP level was positively correlated with the aggravation of systemic inflammatory response and the severity after ROSC. Serum eCIRP serves as a potential predictor for 28-day mortality and poor neurological prognosis after ROSC.
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Affiliation(s)
- Ling Wang
- Department of Emergency, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
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24
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Extracellular cold-inducible RNA-binding protein regulates neutrophil extracellular trap formation and tissue damage in acute pancreatitis. J Transl Med 2020; 100:1618-1630. [PMID: 32709888 DOI: 10.1038/s41374-020-0469-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 07/13/2020] [Accepted: 07/14/2020] [Indexed: 02/07/2023] Open
Abstract
Neutrophil extracellular traps (NETs) play a key role in the development of acute pancreatitis (AP). In the present study, we studied the role of extracellular cold-inducible RNA-binding protein (eCIRP), a novel damage-associated-molecular-pattern molecule, in severe AP. C57BL/6 mice underwent retrograde infusion of taurocholate into the pancreatic duct. C23, an eCIRP inhibitor, was given 1 h prior to induction of AP. Pancreatic, lung, and blood samples were collected and levels of citrullinated histone 3, DNA-histone complexes, eCIRP, myeloperoxidase (MPO), amylase, cytokines, matrix metalloproteinase-9 (MMP-9), and CXC chemokines were quantified after 24 h. NETs were detected by electron microscopy in the pancreas and bone marrow-derived neutrophils. Amylase secretion was analyzed in isolated acinar cells. Plasma was obtained from healthy individuals and patients with mild and moderate severe or severe AP. Taurocholate infusion induced NET formation, inflammation, and tissue injury in the pancreas. Pretreatment with C23 decreased taurocholate-induced pancreatic and plasma levels of eCIRP and tissue damage in the pancreas. Blocking eCIRP reduced levels of citrullinated histone 3 and NET formation in the pancreas as well as DNA-histone complexes in the plasma. In addition, administration of C23 attenuated MPO levels in the pancreas and lung of mice exposed to taurocholate. Inhibition of eCIRP reduced pancreatic levels of CXC chemokines and plasma levels of IL-6, HMGB-1, and MMP-9 in mice with severe AP. Moreover, eCIRP was found to be bound to NETs. Coincubation with C23 reduced NET-induced amylase secretion in isolated acinar cells. Patients with severe AP had elevated plasma levels of eCIRP compared with controls. Our novel findings suggest that eCIRP is a potent regulator of NET formation in the inflamed pancreas. Moreover, these results show that targeting eCIRP with C23 inhibits inflammation and tissue damage in AP. Thus, eCIRP could serve as an effective target to attenuate pancreatic damage in patients with AP.
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25
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Zhong P, Peng J, Yuan M, Kong B, Huang H. Cold-inducible RNA-binding protein (CIRP) in inflammatory diseases: Molecular insights of its associated signalling pathways. Scand J Immunol 2020; 93:e12949. [PMID: 32738154 DOI: 10.1111/sji.12949] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 07/16/2020] [Accepted: 07/21/2020] [Indexed: 02/05/2023]
Abstract
Cold-inducible RNA-binding protein (CIRP) was previously identified as an intracellular stress-response protein, which can respond to a variety of stress conditions by changing its expression and regulating mRNA stability through its binding site on the 3'-UTR of its targeted mRNAs. Recently, extracellular CIRP (eCIRP) was discovered to be present in various inflammatory conditions and could act as a pro-inflammatory factor. Genetic studies have demonstrated a key role for eCIRP in inflammatory conditions that led to the importance of targeting eCIRP in these diseases. Currently, the underlying mechanism of eCIRP-induced inflammation is under intensive investigation and several signalling pathways are being explored. Here, we epitomized various signalling pathways that mediate the pro-inflammatory effects of CIRP and also recapitulated all the CIRP-derived peptides that can block the interaction between CIRP and its receptors in inflammatory setting.
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Affiliation(s)
- Peng Zhong
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Jianye Peng
- Department of Cardiovascular Medicine, The second Affiliated Hospital of University of South China, Hengyang, China
| | - Mingjie Yuan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Bin Kong
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - He Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
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26
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Denning NL, Aziz M, Ochani M, Prince JM, Wang P. Inhibition of a triggering receptor expressed on myeloid cells-1 (TREM-1) with an extracellular cold-inducible RNA-binding protein (eCIRP)-derived peptide protects mice from intestinal ischemia-reperfusion injury. Surgery 2020; 168:478-485. [PMID: 32439208 DOI: 10.1016/j.surg.2020.04.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 03/31/2020] [Accepted: 04/02/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Intestinal ischemia-reperfusion injury results in morbidity and mortality from both local injury and systemic inflammation and acute lung injury. Extracellular cold-inducible RNA-binding protein is a damage associated molecular pattern that fuels systemic inflammation and potentiates acute lung injury. We recently discovered a triggering receptor expressed on myeloid cells-1 serves as a novel receptor for extracellular cold-inducible RNA-binding protein. We developed a 7-aa peptide, named M3, derived from the cold-inducible RNA-binding protein, which interferes with cold-inducible RNA-binding protein's binding to a triggering receptor expressed on myeloid cells-1. Here, we hypothesized that M3 protects mice against intestinal ischemia-reperfusion injury. METHODS Intestinal ischemia was induced in C57BL/6 mice via clamping of the superior mesenteric artery for 60 minutes. At reperfusion, mice were treated intraperitoneally with M3 (10 mg/kg body weight) or normal saline vehicle. Mice were killed 4 hours after reperfusion and blood and lungs were collected for various analysis. A 24-hours survival after intestinal ischemia-reperfusion was assessed. RESULTS Serum levels of organ injury markers aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and lactate were increased with intestinal ischemia-reperfusion, while treatment with M3 significantly decreased their levels. Serum, intestinal, and lung levels of proinflammatory cytokines and chemokines were also increased by intestinal ischemia-reperfusion, and treatment with M3 significantly reduced these values. Intestinal ischemia-reperfusion caused significant histological intestinal and lung injuries, which were mitigated by M3. Treatment with M3 improved the survival from 40% to 80% after intestinal ischemia-reperfusion. CONCLUSION Inhibition of triggering receptor expressed on myeloid cells-1 by an extracellular cold-inducible RNA-binding protein-derived small peptide (M3) decreased inflammation, reduced lung injury, and improved survival in intestinal ischemia-reperfusion injury. Thus, blocking the extracellular cold-inducible RNA-binding protein-triggering receptor expressed on myeloid cells-1 interaction is a promising therapeutic avenue for mitigating intestinal ischemia-reperfusion injury.
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Affiliation(s)
- Naomi-Liza Denning
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY; Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY; Elmezzi Graduate School of Molecular Medicine, Manhasset, NY
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY; Elmezzi Graduate School of Molecular Medicine, Manhasset, NY
| | - Mahendar Ochani
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY
| | - Jose M Prince
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY; Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY; Cohen Children's Medical Center at Hofstra/Northwell Health, New Hyde Park, NY
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY; Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY; Elmezzi Graduate School of Molecular Medicine, Manhasset, NY.
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27
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Denning NL, Aziz M, Gurien SD, Wang P. DAMPs and NETs in Sepsis. Front Immunol 2019; 10:2536. [PMID: 31736963 PMCID: PMC6831555 DOI: 10.3389/fimmu.2019.02536] [Citation(s) in RCA: 395] [Impact Index Per Article: 65.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 10/11/2019] [Indexed: 12/21/2022] Open
Abstract
Sepsis is a deadly inflammatory syndrome caused by an exaggerated immune response to infection. Much has been focused on host response to pathogens mediated through the interaction of pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs). PRRs are also activated by host nuclear, mitochondrial, and cytosolic proteins, known as damage-associated molecular patterns (DAMPs) that are released from cells during sepsis. Some well described members of the DAMP family are extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1), histones, and adenosine triphosphate (ATP). DAMPs are released from the cell through inflammasome activation or passively following cell death. Similarly, neutrophil extracellular traps (NETs) are released from neutrophils during inflammation. NETs are webs of extracellular DNA decorated with histones, myeloperoxidase, and elastase. Although NETs contribute to pathogen clearance, excessive NET formation promotes inflammation and tissue damage in sepsis. Here, we review DAMPs and NETs and their crosstalk in sepsis with respect to their sources, activation, release, and function. A clear grasp of DAMPs, NETs and their interaction is crucial for the understanding of the pathophysiology of sepsis and for the development of novel sepsis therapeutics.
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Affiliation(s)
- Naomi-Liza Denning
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, United States.,Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, United States.,Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
| | - Monowar Aziz
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, United States.,Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, United States
| | - Steven D Gurien
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, United States.,Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
| | - Ping Wang
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, United States.,Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, United States.,Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States.,Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
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28
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Liu J, Chen T, Lei P, Tang X, Huang P. Exosomes Released by Bone Marrow Mesenchymal Stem Cells Attenuate Lung Injury Induced by Intestinal Ischemia Reperfusion via the TLR4/NF-κB Pathway. Int J Med Sci 2019; 16:1238-1244. [PMID: 31588189 PMCID: PMC6775266 DOI: 10.7150/ijms.35369] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Accepted: 07/09/2019] [Indexed: 12/13/2022] Open
Abstract
Purpose: Acute lung injury (ALI) is a primary component of multiple organ dysfunction syndromes triggered by intestinal ischemia-reperfusion (IIR) which results in high mortality. Existing treatment options remain unsatisfactory. Mesenchymal stem cells (MSCs) have shown considerable promise as a biological therapy for ALI in preclinical studies. However, there are many limitations to stem cell treatment. This study aimed to investigate whether MSC-derived exosomes, a non-cellular alternative, are able to act in a protective capacity similar to that of MSCs for ALI triggered by IIR in a rat model and to explore the underlying mechanisms. Methods: The IIR model involved occlusion of the superior mesenteric artery of a rat for 75 min then reperfusion for 20 h. Rats then received an intravenous injection of either bone marrow-derived MSCs or MSC-derived exosomes. Pathologic alteration of lung tissue, levels of pro-inflammatory cytokines, apoptotic proteins and TLR4/NF-κB signaling were measured to evaluate the therapeutic effect of treatment with either MSCs or exosomes. Results: Manifestations of acute lung injury after IIR were observed as edema and hemorrhage of alveoli and mesenchyme, and inflammatory cell infiltration. MSCs and MSC-derived exosomes both attenuated IIR-induced lung damage by decreased apoptosis and inflammation accompanied by down-regulation of TLR4 and NF-κB expression. Conclusions: MSC-derived exosomes provide protection similar to that of MSCs against IIR-induced ALI via inhibition of TLR4/NF-κB signaling, suggesting that a potential strategy against IIR-mediated acute lung injury could be therapy with exosomes as a non-cellular alternative to MSC transplantation.
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Affiliation(s)
- Jianpei Liu
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, 510630
| | - Tufeng Chen
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, 510630
| | - Purun Lei
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, 510630
| | - Xiao Tang
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, 510630
| | - Pinjie Huang
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, 510630
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Aziz M, Brenner M, Wang P. Extracellular CIRP (eCIRP) and inflammation. J Leukoc Biol 2019; 106:133-146. [PMID: 30645013 PMCID: PMC6597266 DOI: 10.1002/jlb.3mir1118-443r] [Citation(s) in RCA: 149] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 12/27/2018] [Accepted: 12/30/2018] [Indexed: 12/22/2022] Open
Abstract
Cold-inducible RNA-binding protein (CIRP) was discovered 2 decades ago while studying the mechanism of cold stress adaptation in mammals. Since then, the role of intracellular CIRP (iCIRP) as a stress-response protein has been extensively studied. Recently, extracellular CIRP (eCIRP) was discovered to also have an important role, acting as a damage-associated molecular pattern, raising critical implications for the pathobiology of inflammatory diseases. During hemorrhagic shock and sepsis, inflammation triggers the translocation of CIRP from the nucleus to the cytosol and its release to the extracellular space. eCIRP then induces inflammatory responses in macrophages, neutrophils, lymphocytes, and dendritic cells. eCIRP also induces endoplasmic reticulum stress and pyroptosis in endothelial cells by activating the NF-κB and inflammasome pathways, and necroptosis in macrophages via mitochondrial DNA damage. eCIRP works through the TLR4-MD2 receptors. Studies with CIRP-/- mice reveal protection against inflammation, implicating eCIRP to be a novel drug target. Anti-CIRP Ab or CIRP-derived small peptide may have effective therapeutic potentials in sepsis, acute lung injury, and organ ischemia/reperfusion injuries. The current review focuses on the pathobiology of eCIRP by emphasizing on signal transduction machineries, leading to discovering novel therapeutic interventions targeting eCIRP in various inflammatory diseases.
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Affiliation(s)
- Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY
| | - Max Brenner
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY
- Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset,
NY
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