|
1
|
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.
Collapse
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
| |
Collapse
|
|
2
|
Liu W, Wu DH, Wang T, Wang M, Xu Y, Ren Y, Lyu Y, Wu R. CIRP contributes to multiple organ damage in acute pancreatitis by increasing endothelial permeability. Commun Biol 2025; 8:403. [PMID: 40065057 PMCID: PMC11894170 DOI: 10.1038/s42003-025-07772-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 02/18/2025] [Indexed: 03/14/2025] Open
Abstract
Acute pancreatitis can lead to systemic inflammation and multiple organ damage. Increased endothelial permeability is a hallmark of systemic inflammation. Several studies have demonstrated that cold-inducible RNA-binding protein (CIRP) functions as a proinflammatory factor in various diseases. However, its role in endothelial barrier dysfunction during acute pancreatitis remains unknown. To study this, acute pancreatitis was induced by two hourly intraperitoneal injections of 4.0 g/kg L-arginine in wild-type (WT) or CIRP knockout mice. Our results showed that CIRP levels in the pancreas, small intestine, lung, and liver were upregulated at 72 h after the induction of acute pancreatitis in WT mice. CIRP deficiency significantly attenuated tissue injury, edema, and extravasation of Evans blue in the pancreas, small intestine, lung, and liver at 72 h after L-arginine injection. Administration of C23, a specific antagonist of CIRP, at 2 h after the last injection of L-arginine also produced similar protective effects as CIRP knockout in mice. In vitro studies showed that recombinant CIRP caused a significant reduction in transcellular electric resistance in HUVEC monolayers. Immunocytochemical analysis of endothelial cells exposed to CIRP revealed an increased formation of actin stress fibers. VE-cadherin and β-catenin staining showed intercellular gaps were formed in CIRP-stimulated cells. Western blot analysis showed that CIRP induced SRC phosphorylation at TYR416. Exposure to the SRC inhibitor PP2 reduced CIRP-induced endothelial barrier dysfunction in HUVEC monolayers. In conclusion, blocking CIRP mitigates acute pancreatitis-induced multiple organ damage by alleviating endothelial hyperpermeability. Targeting CIRP may be a potential therapeutic option for acute pancreatitis.
Collapse
Affiliation(s)
- Wuming Liu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Derek H Wu
- Macaulay Honors College, CUNY Brooklyn College, Brooklyn, NY, USA
| | - Tao Wang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Mengzhou Wang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yujia Xu
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yifan Ren
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yi Lyu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Rongqian Wu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| |
Collapse
|
|
3
|
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.
Collapse
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.
| |
Collapse
|
|
4
|
Zhang F, Hu Z, Jacob A, Brenner M, Wang P. An eCIRP inhibitor attenuates fibrosis and ferroptosis in ischemia and reperfusion induced chronic kidney disease. Mol Med 2025; 31:11. [PMID: 39794717 PMCID: PMC11724597 DOI: 10.1186/s10020-025-01071-2] [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: 11/22/2024] [Accepted: 01/07/2025] [Indexed: 01/13/2025] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) is a leading cause of death in the United States, and renal fibrosis represents a pathologic hallmark of CKD. Extracellular cold-inducible RNA-binding protein (eCIRP) is a stress response protein involved in acute inflammation, tissue injury and regulated cell death. However, the role of eCIRP in chronic inflammation and tissue injury has not been elucidated. We hypothesize that eCIRP is involved in renal ischemia/reperfusion (RIR)-induced CKD and that C23, an antagonist to eCIRP, is beneficial in attenuating renal fibrosis and ferroptosis in RIR-induced CKD. METHODS C57BL/6 (WT) or CIRP-/- mice underwent renal injury with total blockage of blood perfusion by clamping bilateral renal pedicles for 28 min. In the WT mice at the time of reperfusion, they were treated with C23 (8 mg/kg) or vehicle. Blood and kidneys were harvested for further analysis at 21 days thereafter. In a separate cohort, mice underwent bilateral RIR and treatment with C23 or vehicle and were then subjected to left nephrectomy 72 h thereafter. Mice were then monitored for additional 19 days, and glomerular filtration rate (GFR) was assessed using a noninvasive transcutaneous method. RESULTS In the RIR-induced CKD, CIRP-/- mice showed decreased collagen deposition, fibronectin staining, and renal injury as compared to the WT mice. Administration of C23 ameliorated renal fibrosis by decreasing the expression of active TGF-β1, α-SMA, collagen deposition, fibronectin and macrophage infiltration to the kidneys. Furthermore, intervention with C23 significantly decreased renal ferroptosis by reducing iron accumulation, increasing the expression of glutathione peroxidase 4 (GPX4) and lipid peroxidation in the kidneys of RIR-induced CKD mice. Treatment with C23 also attenuated BUN and creatinine. Finally, GFR was significantly decreased in RIR mice with left nephrectomy and C23 treatment partially prevented their decrease. CONCLUSION Our data show that eCIRP plays an important role in RIR-induced CKD. Treatment with C23 decreased renal inflammation, alleviated chronic renal injury and fibrosis, and inhibited ferroptosis in the RIR-induced CKD mice.
Collapse
Affiliation(s)
- Fangming Zhang
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- TheraSource LLC, 350 Community Drive, Manhasset, NY, USA
| | - Zhijian Hu
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - Asha Jacob
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine, Manhasset, NY, USA
| | - Max Brenner
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, USA.
- TheraSource LLC, 350 Community Drive, Manhasset, NY, USA.
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine, Manhasset, NY, USA.
| | - Ping Wang
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, USA.
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine, Manhasset, NY, USA.
| |
Collapse
|
|
5
|
Rashid N, Hu Z, Jacob A, Wang P. Extracellular Cold-Inducible RNA-Binding Protein and Hemorrhagic Shock: Mechanisms and Therapeutics. Biomedicines 2024; 13:12. [PMID: 39857596 PMCID: PMC11759867 DOI: 10.3390/biomedicines13010012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/12/2024] [Accepted: 12/19/2024] [Indexed: 01/27/2025] Open
Abstract
Hemorrhagic shock is a type of hypovolemic shock and a significant cause of trauma-related death worldwide. The innate immune system has been implicated as a key mediator in developing severe complications after shock. Inflammation from the innate immune system begins at the time of initial insult; however, its activation is exaggerated, resulting in early and late-stage complications. Hypoxia and hypoperfusion lead to the release of molecules that act as danger signals known as damage-associated molecular patterns (DAMPs). DAMPs continue to circulate after shock, resulting in excess inflammation and tissue damage. We recently discovered that cold-inducible RNA-binding protein released into the extracellular space acts as a DAMP. During hemorrhagic shock, hypoperfusion leads to cell necrosis and the release of CIRP into circulation, triggering both systemic inflammation and local tissue damage. In this review, we discuss extracellular cold-inducible RNA-binding protein (eCIRP)'s role in sterile inflammation, as well as its various mechanisms of action. We also share our more newly developed anti-eCIRP agents with the eventual goal of producing drug therapies to mitigate organ damage, reduce mortality, and improve patient outcomes related to hemorrhagic shock. Finally, we suggest that future preclinical studies are required to develop the listed therapeutics for hemorrhagic shock and related conditions. In addition, we emphasize on the challenges to the translational phase and caution that the therapy should allow the immune system to continue to function well against secondary infections during hospitalization.
Collapse
Affiliation(s)
- Naureen Rashid
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA; (N.R.); (Z.H.)
| | - Zhijian Hu
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA; (N.R.); (Z.H.)
| | - Asha Jacob
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA; (N.R.); (Z.H.)
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 11030, USA
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 11030, USA
| | - Ping Wang
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA; (N.R.); (Z.H.)
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 11030, USA
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 11030, USA
| |
Collapse
|
|
6
|
Chen J, Chen X, Zhang K. RNA-binding protein biomarkers NR4A2 and NR4A3 in renal ischemia-reperfusion injury diagnosis. Medicine (Baltimore) 2024; 103:e40426. [PMID: 39560530 PMCID: PMC11576014 DOI: 10.1097/md.0000000000040426] [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: 09/25/2024] [Accepted: 10/18/2024] [Indexed: 11/20/2024] Open
Abstract
BACKGROUND The diagnosis of renal ischemia and reperfusion injury (RIRI) is crucial for renal transplant recipients. RNA-binding proteins (RBPs) may have an impact on disease development. Therefore, this study explored the biomarkers associated with RBPs in RIRI. METHODS The RIRI related datasets, GSE37838 and GSE43974, and 3964 RBPs were employed in this research. The differential expression analysis was implemented for RIRI and control to gain differentially expressed genes in GSE37838. Then, differentially expressed genes were overlapped with RBPs to acquire intersection genes. Further, the machine learning, diagnostic analysis, and expression validation were executed to filtered biomarkers for RIRI. Additionally, pathway enrichment, molecular networks, and drug prediction were proceed. RESULTS The area under the curve values of NR4A2 and NR4A3 were >0.7, as well as the expression trend was consistent in both datasets, and all of them were remarkably highly expressed in RIRI. Therefore, they were considered as biomarkers of RIRI. Enrichment analyses revealed that they were both associated with neuroactive ligand-receptor interactions, among others. Further, the lncRNA-miRNA-mRNA and transcription factors (TF)-mRNA network was constructed, revealing that they were all regulated by noncoding RNAs and TF, such as SNHG5-hsa-mir-10b-5p-NR4A3, CREB1, TFAP2A, etc. In addition, a large number of biomarker-related drugs were predicted, among which cadmium acetate, potassium chromate (VI), etc were associated with NR4A2 and NR4A3. CONCLUSION In this study, we identified biomarkers associated with RBPs in RIRI, explored their associated pathways and drugs, which provided new insights into the clinical diagnosis and treatment of RIRI.
Collapse
Affiliation(s)
- Junrui Chen
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ximing Chen
- Urinary Nephropathy Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Keqin Zhang
- Urinary Nephropathy Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
7
|
Ma X, Lin Y, Zhang L, Miao S, Zhang H, Li H, Fu X, Han L, Li P. GSDMD in regulated cell death: A novel therapeutic target for sepsis. Int Immunopharmacol 2024; 135:112321. [PMID: 38795599 DOI: 10.1016/j.intimp.2024.112321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 04/30/2024] [Accepted: 05/19/2024] [Indexed: 05/28/2024]
Abstract
Sepsis is a life-threatening multi-organ dysfunction syndrome caused by an abnormal host response to infection. Regulated cell death is essential for maintaining tissue homeostasis and eliminating damaged, infected, or aging cells in multicellular organisms. Gasdermin D, as a member of the gasdermin family, plays a crucial role in the formation of cytoplasmic membrane pores. Research has found that GSDMD plays important roles in various forms of regulated cell death such as pyroptosis, NETosis, and necroptosis. Therefore, through mediating regulated cell death, GSDMD regulates different stages of disease pathophysiology. This article mainly summarizes the concept of GSDMD, its role in regulated cell death, its involvement in organ damage associated with sepsis-related injuries mediated by regulated cell death via GSDMD activation and introduces potential drugs targeting GSDMD that may provide more effective treatment options for sepsis patients through drug modification.
Collapse
Affiliation(s)
- Xiangli Ma
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China.
| | - Yujie Lin
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Ling Zhang
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Shaoyi Miao
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Haidan Zhang
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Hongyao Li
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Xu Fu
- Key Laboratory of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Li Han
- Key Laboratory of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Peiwu Li
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China.
| |
Collapse
|
|
8
|
Zhang Y, Zhang Y, Song J, Cheng X, Zhou C, Huang S, Zhao W, Zong Z, Yang L. Targeting the "tumor microenvironment": RNA-binding proteins in the spotlight in colorectal cancer therapy. Int Immunopharmacol 2024; 131:111876. [PMID: 38493688 DOI: 10.1016/j.intimp.2024.111876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/04/2024] [Accepted: 03/13/2024] [Indexed: 03/19/2024]
Abstract
Colorectal cancer (CRC) is the third most common cancer and has the second highest mortality rate among cancers. The development of CRC involves both genetic and epigenetic abnormalities, and recent research has focused on exploring the ex-transcriptome, particularly post-transcriptional modifications. RNA-binding proteins (RBPs) are emerging epigenetic regulators that play crucial roles in post-transcriptional events. Dysregulation of RBPs can result in aberrant expression of downstream target genes, thereby affecting the progression of colorectal tumors and the prognosis of patients. Recent studies have shown that RBPs can influence CRC pathogenesis and progression by regulating various components of the tumor microenvironment (TME). Although previous research on RBPs has primarily focused on their direct regulation of colorectal tumor development, their involvement in the remodeling of the TME has not been systematically reported. This review aims to highlight the significant role of RBPs in the intricate interactions within the CRC tumor microenvironment, including tumor immune microenvironment, inflammatory microenvironment, extracellular matrix, tumor vasculature, and CRC cancer stem cells. We also highlight several compounds under investigation for RBP-TME-based treatment of CRC, including small molecule inhibitors such as antisense oligonucleotides (ASOs), siRNAs, agonists, gene manipulation, and tumor vaccines. The insights gained from this review may lead to the development of RBP-based targeted novel therapeutic strategies aimed at modulating the TME, potentially inhibiting the progression and metastasis of CRC.
Collapse
Affiliation(s)
- Yiwei Zhang
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Nanchang University, No. 1 MinDe Road, 330006 Nanchang, China; Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Mingde Rd., Nanchang 330006, Jiangxi, China; Queen Mary School, Nanchang University, 330006 Nanchang, China
| | - Yujun Zhang
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Nanchang University, No. 1 MinDe Road, 330006 Nanchang, China; Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Mingde Rd., Nanchang 330006, Jiangxi, China
| | - Jingjing Song
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Nanchang University, No. 1 MinDe Road, 330006 Nanchang, China; Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Mingde Rd., Nanchang 330006, Jiangxi, China; School of Ophthalmology and Optometry of Nanchang University, China
| | - Xifu Cheng
- School of Ophthalmology and Optometry of Nanchang University, China
| | - Chulin Zhou
- The Second Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Shuo Huang
- The Second Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Wentao Zhao
- The 3rd Clinical Department of China Medical University, 10159 Shenyang, China
| | - Zhen Zong
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Nanchang University, No. 1 MinDe Road, 330006 Nanchang, China.
| | - Lingling Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Mingde Rd., Nanchang 330006, Jiangxi, China.
| |
Collapse
|
|
9
|
Yao F, Zhao Y, Yu Q, Hu W, Lin Y, Chen Y, Li L, Sun C, Li S, Wang K, Yang M, Zhou R, Hu W. Extracellular CIRP induces abnormal activation of fibroblast-like synoviocytes from patients with RA via the TLR4-mediated HDAC3 pathways. Int Immunopharmacol 2024; 128:111525. [PMID: 38218010 DOI: 10.1016/j.intimp.2024.111525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/04/2024] [Accepted: 01/07/2024] [Indexed: 01/15/2024]
Abstract
The development of rheumatoid arthritis (RA) is closely related to the excessive activation of fibroblast-like synoviocytes (FLSs), which are regulated by a variety of endogenous proinflammatory molecules. Extracellular cold-inducible RNA-binding protein (CIRP), as a novel endogenous proinflammatory molecule, plays an important role in inflammatory diseases. More importantly, the synovial concentration of CIRP in patients with RA was significantly higher than that in patients with osteoarthritis (OA). Thus, this study aimed to investigate the role of extracellular CIRP in the abnormal activation of RA-FLSs and its related mechanisms. Our study showed that extracellular CIRP induced proliferation, migration and invasion of RA-FLSs, increased the expression of N-cadherin and MMP-3, and promoted the release of IL-1β and IL-33. However, blocking of extracellular CIRP with C23 inhibited CIRP-induced abnormal activation of RA-FLSs and alleviated the arthritis severity in AA rats. Accumulating evidence suggests that the activity and proinflammatory effects of CIRP are mediated through Toll-like receptor 4 (TLR4). Further studies demonstrated that the TLR4 knockdown inhibited CIRP-induced abnormal activation, and histone deacetylase 3 (HDAC3) expression in RA-FLSs. In addition, we found that HDAC3 knockdown and the specific inhibitor RGFP966 significantly suppressed CIRP-induced abnormal activation of RA-FLSs. We further found that treatment with HDAC3 specific inhibitor effectively alleviated the severity of arthritis in AA rats. Taken together, these findings indicate that extracellular CIRP induces abnormal activation of RA-FLSs via the TLR4-mediated HDAC3 pathways.
Collapse
Affiliation(s)
- Feng Yao
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Yingjie Zhao
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Qiuxia Yu
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Weirong Hu
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Yi Lin
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Yong Chen
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Lin Li
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Anhui Medical University, China
| | - Cheng Sun
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Shufang Li
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Ke Wang
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Min Yang
- The 2nd Department of Intensive Care Unit, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
| | - Renpeng Zhou
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
| | - Wei Hu
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
| |
Collapse
|
|
10
|
Yamaga S, Aziz M, Murao A, Brenner M, Wang P. DAMPs and radiation injury. Front Immunol 2024; 15:1353990. [PMID: 38333215 PMCID: PMC10850293 DOI: 10.3389/fimmu.2024.1353990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 01/15/2024] [Indexed: 02/10/2024] Open
Abstract
The heightened risk of ionizing radiation exposure, stemming from radiation accidents and potential acts of terrorism, has spurred growing interests in devising effective countermeasures against radiation injury. High-dose ionizing radiation exposure triggers acute radiation syndrome (ARS), manifesting as hematopoietic, gastrointestinal, and neurovascular ARS. Hematopoietic ARS typically presents with neutropenia and thrombocytopenia, while gastrointestinal ARS results in intestinal mucosal injury, often culminating in lethal sepsis and gastrointestinal bleeding. This deleterious impact can be attributed to radiation-induced DNA damage and oxidative stress, leading to various forms of cell death, such as apoptosis, necrosis and ferroptosis. Damage-associated molecular patterns (DAMPs) are intrinsic molecules released by cells undergoing injury or in the process of dying, either through passive or active pathways. These molecules then interact with pattern recognition receptors, triggering inflammatory responses. Such a cascade of events ultimately results in further tissue and organ damage, contributing to the elevated mortality rate. Notably, infection and sepsis often develop in ARS cases, further increasing the release of DAMPs. Given that lethal sepsis stands as a major contributor to the mortality in ARS, DAMPs hold the potential to function as mediators, exacerbating radiation-induced organ injury and consequently worsening overall survival. This review describes the intricate mechanisms underlying radiation-induced release of DAMPs. Furthermore, it discusses the detrimental effects of DAMPs on the immune system and explores potential DAMP-targeting therapeutic strategies to alleviate radiation-induced injury.
Collapse
Affiliation(s)
- Satoshi Yamaga
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
| | - Atsushi Murao
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Max Brenner
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
| |
Collapse
|
|
11
|
Feng Z, Cao X, Zhao C, Niu J, Yan Y, Shi T, Hao J, Zheng X. Serum CIRP increases the risk of acute kidney injury after cardiac surgery. Front Med (Lausanne) 2024; 10:1258622. [PMID: 38235271 PMCID: PMC10791772 DOI: 10.3389/fmed.2023.1258622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 11/20/2023] [Indexed: 01/19/2024] Open
Abstract
Introduction Acute kidney injury (AKI) is a frequent perioperative complication. The underlying mechanisms of cardiac surgery-associated AKI are still not completely elucidated. Cold-induced RNA-binding protein (CIRP) has been subsequently found to be regulated by various stress conditions. During cardiac surgery and cardiopulmonary bypass (CPB), the host is subjected to hypothermia and inadequate organ perfusion, resulting in an upregulation of CIRP secretion. The aim of this study is to evaluate the role of elevated extracellular CIRP level as a contributing factor in the development of AKI. Methods A total of 292 patients who underwent cardiac surgery were retrospectively enrolled and their serum samples were collected preoperative and postoperative. Demographic data, intraoperative data, in-hospital outcomes, and the occurrence of AKI were also collected for the patients. The correlation between CIRP and intraoperative procedures, as well as its association with postoperative outcomes were analyzed. Results In multivariable analysis, higher ΔCIRP (p = 0.036) and body mass index (p = 0.015) were independent risk factors for postoperative AKI. Meanwhile, patients with postoperative AKI exhibited lower survival rate in 2-year follow-up (p = 0.008). Compared to off-pump coronary artery bypass grafting surgery, patients who underwent on-pump coronary artery bypass grafting, valve surgery, aortic dissection and other surgery showed higher ΔCIRP, measuring 1,093, 666, 914 and 258 pg/mL, respectively (p < 0.001). The levels of ΔCIRP were significantly higher in patients who underwent CPB compared to those who did not (793.0 ± 648.7 vs. 149.5 ± 289.1 pg/mL, p < 0.001). Correlation analysis revealed a positive correlation between ΔCIRP levels and the duration of CPB (r = 0.502, p < 0.001). Patients with higher CIRP levels are at greater risk of postoperative AKI (OR: 1.67, p = 0.032), especially the stage 2-3 AKI (OR: 2.11, p = 0.037). Conclusion CIRP secretion increases with prolonged CPB time after cardiac surgery, and CIRP secretion is positively correlated with the duration of CPB. Cardiac surgeries with CPB exhibited significantly higher levels of CIRP compared to non-CPB surgeries. Elevation of CIRP level is an independent risk factor for the incidence of AKI, especially the severe AKI, and were associated with adverse in-hospital outcomes.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Xinglong Zheng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi'an, Shaanxi, China
| |
Collapse
|
|
12
|
Liu W, Bi J, Ren Y, Chen H, Zhang J, Wang T, Wang M, Zhang L, Zhao J, Wu Z, Lv Y, Liu B, Wu R. Targeting extracellular CIRP with an X-aptamer shows therapeutic potential in acute pancreatitis. iScience 2023; 26:107043. [PMID: 37360693 PMCID: PMC10285643 DOI: 10.1016/j.isci.2023.107043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 03/02/2023] [Accepted: 06/01/2023] [Indexed: 06/28/2023] Open
Abstract
Severe acute pancreatitis (AP) is associated with a high mortality rate. Cold-inducible RNA binding protein (CIRP) can be released from cells in inflammatory conditions and extracellular CIRP acts as a damage-associated molecular pattern. This study aims to explore the role of CIRP in the pathogenesis of AP and evaluate the therapeutic potential of targeting extracellular CIRP with X-aptamers. Our results showed that serum CIRP concentrations were significantly increased in AP mice. Recombinant CIRP triggered mitochondrial injury and ER stress in pancreatic acinar cells. CIRP-/- mice suffered less severe pancreatic injury and inflammatory responses. Using a bead-based X-aptamer library, we identified an X-aptamer that specifically binds to CIRP (XA-CIRP). Structurally, XA-CIRP blocked the interaction between CIRP and TLR4. Functionally, it reduced CIRP-induced pancreatic acinar cell injury in vitro and L-arginine-induced pancreatic injury and inflammation in vivo. Thus, targeting extracellular CIRP with X-aptamers may be a promising strategy to treat AP.
Collapse
Affiliation(s)
- Wuming Liu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Jianbin Bi
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yifan Ren
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of General Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Huan Chen
- BioBank, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Jia Zhang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Gastroenterology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Tao Wang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Mengzhou Wang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Lin Zhang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Junzhou Zhao
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yi Lv
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Bing Liu
- BioBank, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Rongqian Wu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| |
Collapse
|
|
13
|
Hu Z, Zhang F, Brenner M, Jacob A, Wang P. The protective effect of H151, a novel STING inhibitor, in renal ischemia-reperfusion-induced acute kidney injury. Am J Physiol Renal Physiol 2023; 324:F558-F567. [PMID: 37102684 PMCID: PMC10228668 DOI: 10.1152/ajprenal.00004.2023] [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: 01/13/2023] [Revised: 04/12/2023] [Accepted: 04/24/2023] [Indexed: 04/28/2023] Open
Abstract
Renal ischemia-reperfusion (RIR)-induced acute kidney injury (AKI) is a common renal functional disorder with high morbidity and mortality. Stimulator of interferon (IFN) genes (STING) is the cytosolic DNA-activated signaling pathway that mediates inflammation and injury. Our recent study showed that extracellular cold-inducible RNA-binding protein (eCIRP), a newly identified damage-associated molecular pattern, activates STING and exacerbates hemorrhagic shock. H151 is a small molecule that selectively binds to STING and inhibits STING-mediated activity. We hypothesized that H151 attenuates eCIRP-induced STING activation in vitro and inhibits RIR-induced AKI in vivo. In vitro, renal tubular epithelial cells incubated with eCIRP showed increased levels of IFN-β, STING pathway downstream cytokine, IL-6, tumor necrosis factor-α, and neutrophil gelatinase-associated lipocalin, whereas coincubation with eCIRP and H151 diminished those increases in a dose-dependent manner. In vivo, 24 h after bilateral renal ischemia-reperfusion, glomerular filtration rate was decreased in RIR-vehicle-treated mice, whereas glomerular filtration rate was unchanged in RIR-H151-treated mice. In contrast to sham, serum blood urea nitrogen, creatinine, and neutrophil gelatinase-associated lipocalin were increased in RIR-vehicle, but in RIR-H151, these levels were significantly decreased from RIR-vehicle. In contrast to sham, kidney IFN-β mRNA, histological injury score, and TUNEL staining were also increased in RIR-vehicle, but in RIR-H151, these levels were significantly decreased from RIR-vehicle. Importantly, in contrast to sham, in a 10-day survival study, survival decreased to 25% in RIR-vehicle, but RIR-H151 had a survival of 63%. In conclusion, H151 inhibits eCIRP-induced STING activation in renal tubular epithelial cells. Therefore, STING inhibition by H151 can be a promising therapeutic intervention for RIR-induced AKI.NEW & NOTEWORTHY Renal ischemia-reperfusion (RIR)-induced acute kidney injury (AKI) is a common renal functional disorder with a high morbidity and mortality rate. Stimulator of interferon genes (STING) is the cytosolic DNA-activated signaling pathway responsible for mediating inflammation and injury. Extracellular cold-inducible RNA-binding protein (eCIRP) activates STING and exacerbates hemorrhagic shock. H151, a novel STING inhibitor, attenuated eCIRP-induced STING activation in vitro and inhibited RIR-induced AKI. H151 shows promise as a therapeutic intervention for RIR-induced AKI.
Collapse
Affiliation(s)
- Zhijian Hu
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York, United States
| | - Fangming Zhang
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York, United States
| | - Max Brenner
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York, United States
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
| | - Asha Jacob
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York, United States
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
| | - Ping Wang
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York, United States
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
| |
Collapse
|
|
14
|
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.
Collapse
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
| | | |
Collapse
|
|
15
|
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.
Collapse
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
| |
Collapse
|
|
16
|
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.
Collapse
|
|
17
|
Reilly B, Tan C, Murao A, Nofi C, Jha A, Aziz M, Wang P. Necroptosis-Mediated eCIRP Release in Sepsis. J Inflamm Res 2022; 15:4047-4059. [PMID: 35873387 PMCID: PMC9304637 DOI: 10.2147/jir.s370615] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 07/07/2022] [Indexed: 11/25/2022] Open
Abstract
Introduction Extracellular cold-inducible RNA-binding protein (eCIRP) is an endogenous pro-inflammatory mediator that exacerbates injury in inflammation and sepsis. The mechanisms in which eCIRP is released have yet to be fully explored. Necroptosis is a programmed cell death that is dependent on the activation of mixed lineage kinase domain-like pseudo kinase (MLKL) which causes the release of damage-associated molecular patterns. We hypothesize that eCIRP is released through necroptosis and intensifies inflammation in sepsis. Methods RAW264.7 cells were treated with pan-caspase inhibitor z-VAD (15 μM) 1 h before stimulation with LPS (1 μg/mL). Necroptosis inhibitor, Necrostatin-1 (Nec-1) (10 μM) was added to the cells with LPS simultaneously. After 24 h of LPS stimulation, cytotoxicity was determined by LDH assay. eCIRP levels in the culture supernatants and phospho-MLKL (p-MLKL) from cell lysates were assessed by Western blot. p-MLKL interaction with the cell membrane was visualized by immunofluorescence. Sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP). Mice were treated with Nec-1 (1 mg/kg) or DMSO. 20 h post-surgery, serum and peritoneal fluid levels of eCIRP, TNF-α and IL-6 were determined by ELISA. H&E staining of lung tissue sections was performed. Results We found that in RAW264.7 cells, LPS+z-VAD induces necroptosis as evidenced by an increase in p-MLKL levels and causes eCIRP release. Nec-1 reduces both p-MLKL activation and eCIRP release in LPS+z-VAD-treated RAW264.7 cells. Nec-1 also inhibits the release of eCIRP, TNF-α and IL-6 in the serum and peritoneal fluid in CLP-induced septic mice. We predicted a transient interaction between eCIRP and MLKL using a computational model, suggesting that eCIRP may exit the cell via the pores formed by p-MLKL. Conclusion Necroptosis is a novel mechanism of eCIRP release in sepsis. Targeting necroptosis may ameliorate inflammation and injury in sepsis by inhibiting eCIRP release.
Collapse
Affiliation(s)
- Bridgette Reilly
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - Chuyi Tan
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - Atsushi Murao
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - Colleen Nofi
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, USA.,Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA
| | - Alok Jha
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, USA.,Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA.,Department of Molecular Medicine, 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.,Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA.,Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA
| |
Collapse
|
|
18
|
Change in Oxidative Stress and Mitochondrial Dynamics in Response to Elevated Cold-Inducible RNA-Binding Protein in Cardiac Surgery-Associated Acute Kidney Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3576892. [PMID: 35855864 PMCID: PMC9288297 DOI: 10.1155/2022/3576892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 06/04/2022] [Accepted: 06/21/2022] [Indexed: 11/18/2022]
Abstract
Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common yet serious complication that is closely related to cardiopulmonary bypass (CPB). Extracellular cold-inducible RNA-binding protein (eCIRP) can mediate aseptic inflammation and trigger intracellular oxidative stress. In the present study, expression of serum CIRP was significantly elevated post-CPB (
pg/mL vs.
pg/mL,
) and was positively correlated with CPB duration (
,
). Patients with high expression of CIRP had higher risks of postoperative AKI than patients with low CIRP expression (OR: 1.67, 95% CI 1.04-2.68). In a rat CPB model, the serum CIRP concentration increased significantly after CPB. Similarly, the levels of Scr and BUN significantly increased 4 hours after CPB. KIM-1 and NGAL mRNA levels in the CPB group were 8.2 and 4.3 times higher than the sham group, respectively. In addition, the levels of inflammatory cell infiltration, oxidative stress, and apoptosis in the renal tissue of the CPB group were significantly higher compared to the sham group. The expression levels of serum inflammatory factors at 4 hours post-CPB were also increased. Administration of recombinant human CIRP protein promoted the expression of NADPH oxidase via the TLR-4/MyD88 pathway, aggravated intracellular oxidative stress, mediated mitochondrial dynamics disorder, and eventually increased apoptosis in HK-2 cells. However, the CIRP inhibitor C23 improved the CIRP-mediated oxidative stress and mitochondrial dysfunction in both rat and cell models. In summary, elevated CIRP could mediate oxidative stress and mitochondrial dynamics in the kidney to promote CSA-AKI.
Collapse
|
|
19
|
Tan C, Reilly B, Jha A, Murao A, Lee Y, Brenner M, Aziz M, Wang P. Active Release of eCIRP via Gasdermin D Channels to Induce Inflammation in Sepsis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:2184-2195. [PMID: 35418465 PMCID: PMC9050887 DOI: 10.4049/jimmunol.2101004] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 02/23/2022] [Indexed: 12/12/2022]
Abstract
Extracellular cold-inducible RNA binding protein (eCIRP) is an inflammatory mediator that causes inflammation and tissue injury in sepsis. Gasdermin D (GSDMD) is a protein that, when cleaved, forms pores in the cell membrane, releasing intracellular contents into the extracellular milieu to exacerbate inflammation. We hypothesize that eCIRP is released actively from viable macrophages via GSDMD pores. We found that LPS induced eCIRP secretion from macrophages into the extracellular space. LPS significantly increased the expression of caspase-11 and cleavage of the GSDMD, as evidenced by increased N-terminal GSDMD expression in RAW 264.7 cells and mouse primary peritoneal macrophages. GSDMD inhibitor disulfiram decreased eCIRP release in vitro. Treatment with glycine to prevent pyroptosis-induced cell lysis did not significantly decrease eCIRP release from LPS-treated macrophages, indicating that eCIRP was actively released and was independent of pyroptosis. Downregulation of GSDMD gene expression by siRNA transfection suppressed eCIRP release in vitro after LPS stimulation. Moreover, GSDMD-/- peritoneal macrophages and mice had decreased levels of eCIRP in the culture supernatants and in blood treated with LPS in vitro and in vivo, respectively. GSDMD inhibitor disulfiram inhibited serum levels of eCIRP in endotoxemia and cecal ligation and puncture-induced sepsis. We conclude that eCIRP release from living macrophages is mediated through GSDMD pores, suggesting that targeting GSDMD could be a novel and potential therapeutic approach to inhibit eCIRP-mediated inflammation in sepsis.
Collapse
Affiliation(s)
- Chuyi Tan
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY
| | - Bridgette Reilly
- 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
| | - Atsushi Murao
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY
| | - Yongchan Lee
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY
| | - Max Brenner
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY.,Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY; and
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY; .,Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY; and.,Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY; .,Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY; and.,Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY
| |
Collapse
|
|
20
|
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.
Collapse
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
| |
Collapse
|
|
21
|
A novel eCIRP/TREM-1 pathway inhibitor attenuates acute kidney injury. Surgery 2022; 172:639-647. [PMID: 35292178 PMCID: PMC9283225 DOI: 10.1016/j.surg.2022.02.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 02/03/2022] [Accepted: 02/06/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Extracellular cold-inducible RNA-binding protein aggravates acute kidney injury after renal ischemia/reperfusion. Although extracellular cold-inducible RNA-binding protein activates triggering receptor expressed on myeloid cells-1, how this receptor and its antagonism with a novel peptide M3 affects acute kidney injury is poorly understood. We, therefore, hypothesize that inhibiting the extracellular cold-inducible RNA-binding protein/triggering receptor expressed on myeloid cells-1 pathway with M3 attenuates acute kidney injury. METHODS Wild-type and triggering receptor expressed on myeloid cells-1-/- mice were subjected to bilateral 30-minute renal hilum clamping followed by reperfusion or sham. After 4 hours, wild-type mice received M3 (10 mg/kg BW) or normal saline intraperitoneally. After 24 hours, renal tissue and serum were collected for analysis. Additionally, wild-type mice were subjected to bilateral renal ischemia for 34 minutes and treated with M3 at 10 mg/kg BW or vehicle at the time of reperfusion. Survival was monitored for 10 days. RESULTS After renal ischemia/reperfusion, triggering receptor expressed on myeloid cells-1 messenger ribonucleic acid expression increased by 9-fold in wild-type mice compared to sham mice. Wild-type mice also demonstrated significant increases in serum blood urea nitrogen, creatinine, and interleukin-6 and renal tissue levels of interleukin-6 and neutrophil gelatinase-associated lipocalin after renal ischemia/reperfusion compared to sham mice. Triggering receptor expressed on myeloid cells-1-/- mice demonstrated significant reductions in serum blood urea nitrogen, creatinine, and interleukin-6 compared to wild-type mice after renal ischemia/reperfusion. Levels of renal interleukin-6 and neutrophil gelatinase-associated lipocalin were also significantly decreased in the kidneys of triggering receptor expressed on myeloid cells-1-/- mice. Furthermore, treatment with M3 in wild-type mice significantly decreased serum and renal levels of interleukin-6 after renal ischemia/reperfusion. M3 treatment demonstrated significant reductions in renal messenger ribonucleic acid and protein levels of neutrophil gelatinase-associated lipocalin, serum blood urea nitrogen and creatinine, and histologic structural damage as well as apoptosis. Treatment with M3 also increased survival from 35% to 65% in mice with acute kidney injury. CONCLUSION Triggering receptor expressed on myeloid cells-1 mediates the deleterious effects of extracellular cold-inducible RNA-binding protein in acute kidney injury after renal ischemia/reperfusion. The novel extracellular cold-inducible RNA-binding protein/triggering receptor expressed on myeloid cells-1 pathway antagonist, M3, attenuates acute kidney injury and has the potential to be developed as a therapeutic agent for acute kidney injury.
Collapse
|
|
22
|
Abstract
RNA-binding proteins (RBPs) are of fundamental importance for post-transcriptional gene regulation and protein synthesis. They are required for pre-mRNA processing and for RNA transport, degradation and translation into protein, and can regulate every step in the life cycle of their RNA targets. In addition, RBP function can be modulated by RNA binding. RBPs also participate in the formation of ribonucleoprotein complexes that build up macromolecular machineries such as the ribosome and spliceosome. Although most research has focused on mRNA-binding proteins, non-coding RNAs are also regulated and sequestered by RBPs. Functional defects and changes in the expression levels of RBPs have been implicated in numerous diseases, including neurological disorders, muscular atrophy and cancers. RBPs also contribute to a wide spectrum of kidney disorders. For example, human antigen R has been reported to have a renoprotective function in acute kidney injury (AKI) but might also contribute to the development of glomerulosclerosis, tubulointerstitial fibrosis and diabetic kidney disease (DKD), loss of bicaudal C is associated with cystic kidney diseases and Y-box binding protein 1 has been implicated in the pathogenesis of AKI, DKD and glomerular disorders. Increasing data suggest that the modulation of RBPs and their interactions with RNA targets could be promising therapeutic strategies for kidney diseases.
Collapse
|
|
23
|
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.
Collapse
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
| |
Collapse
|
|
24
|
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.
Collapse
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
| |
Collapse
|
|
25
|
Liu W, Yan Y, Han D, Li Y, Wang Q, Li J, Liu F, Zheng X. CIRP Secretion during Cardiopulmonary Bypass Is Associated with Increased Risk of Postoperative Acute Kidney Injury. Thorac Cardiovasc Surg 2021; 69:542-547. [PMID: 34233365 DOI: 10.1055/s-0041-1730450] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
BACKGROUND Systemic inflammation contributes to cardiac surgery-associated acute kidney injury (AKI). Cardiomyocytes and other organs experience hypothermia and hypoxia during cardiopulmonary bypass (CPB), which induces the secretion of cold-inducible RNA-binding protein (CIRP). Extracellular CIRP may induce a proinflammatory response. MATERIALS AND METHODS The serum CIRP levels in 76 patients before and after cardiac surgery were determined to analyze the correlation between CIRP levels and CPB time. The risk factors for AKI after cardiac surgery and the in-hospital outcomes were also analyzed. RESULTS The difference in the levels of CIRP (ΔCIRP) after and before surgery in patients who experienced cardioplegic arrest (CA) was 26-fold higher than those who did not, and 2.7-fold of those who experienced CPB without CA. The ΔCIRP levels were positively correlated with CPB time (r = 0.574, p < 0.001) and cross-clamp time (r = 0.54, p < 0.001). Multivariable analysis indicated that ΔCIRP (odds ratio: 1.003; 95% confidence interval: 1.000-1.006; p = 0.027) was an independent risk factor for postoperative AKI. Patients who underwent aortic dissection surgery had higher levels of CIRP and higher incidence of AKI than other patients. The incidence of AKI and duration of mechanical ventilation in patients whose serum CIRP levels more than 405 pg/mL were significantly higher than those less than 405 pg/mL (65.8 vs. 42.1%, p = 0.038; 23.1 ± 18.2 vs. 13.8 ± 9.2 hours, p = 0.007). CONCLUSION A large amount of CIRP was released during cardiac surgery. The secreted CIRP was associated with the increased risk of AKI after cardiac surgery.
Collapse
Affiliation(s)
- Wenyan Liu
- Department of Blood Purification, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yang Yan
- Department of Cardiovascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Dan Han
- Department of Cardiovascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yongxin Li
- Department of Cardiovascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Qian Wang
- Department of Operation and Anesthesia, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jing Li
- Department of Cardiovascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Fengfeng Liu
- Department of Cardiovascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xinglong Zheng
- Department of Cardiovascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| |
Collapse
|
|
26
|
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.
Collapse
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
| |
Collapse
|
|
27
|
Xu Q, Wang M, Guo H, Liu H, Zhang G, Xu C, Chen H. Emodin Alleviates Severe Acute Pancreatitis-Associated Acute Lung Injury by Inhibiting the Cold-Inducible RNA-Binding Protein (CIRP)-Mediated Activation of the NLRP3/IL-1 β/CXCL1 Signaling. Front Pharmacol 2021; 12:655372. [PMID: 33967799 PMCID: PMC8103163 DOI: 10.3389/fphar.2021.655372] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 02/23/2021] [Indexed: 12/12/2022] Open
Abstract
Objective: Severe acute pancreatitis (SAP) can lead to acute lung injury (ALI). This study investigated the therapeutic effect of emodin and its molecular mechanisms in a rat model of SAP-ALI. Methods: Forty male Sprague-Dawley rats were randomly divided into the groups: Control (CON), SAP (SAP), emodin (EMO), and C23 (C23). The latter three groups of rats were induced for SAP-ALI by retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct and were treated with vehicle, emodin or C23, respectively. One day post induction, their pancreatic and lung injury was assessed by histology and arterial blood gas analysis. In vitro, rat alveolar macrophages (NR8383 cells) were treated with recombinant rat CIRP in the presence or absence of TAK242 (a TLR4 inhibitor), C23 or emodin. The CIRP-mediated activation of the NLRP3/IL-1β/CXCL1 signaling in rat lungs and NR8383 cells was determined. Similarly, the role of IL-1β in the CIRP-induced CXCL1 expression was investigated. Results: Emodin treatment significantly reduced inflammation and tissue damages in the pancreatic and lung tissues in rats with SAP-ALI, accompanied by decreasing serum amylase, CIRP and IL-1β levels and improving lung function. Furthermore, emodin significantly mitigated the SAP-up-regulated CIRP expression in the pancreatic islets and lung tissues, and attenuated the SAP-activated NF-κB signaling, NLRP3 inflammasome formation and CXCL1 expression in lung resident macrophages as well as neutrophil infiltration in the lungs of rats. In addition, treatment with CIRP significantly activated the NF-κB signaling and NLRP3 inflammasome formation and induced IL-1β and CXCL1 expression and pyroptosis in NR8383 cells, which were abrogated by TAK242 and significantly mitigated by C23 or emodin. Moreover, CIRP only induced very lower levels of CXCL1 expression in IL-1β-silencing NR8383 cells and treatment with IL-1β induced CXCL1 expression in NR8383 cells in a dose and time-dependent manner. Conclusion: Emodin may inhibit the CIRP-activated NLRP3/IL-1β/CXCL1signaling to decrease neutrophil infiltration and ameliorate the SAP-ALI in rats.
Collapse
Affiliation(s)
- Qiushi Xu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Mengfei Wang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Haoya Guo
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Huanhuan Liu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Guixin Zhang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Caiming Xu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Hailong Chen
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| |
Collapse
|
|
28
|
Extracellular CIRP Activates the IL-6Rα/STAT3/Cdk5 Pathway in Neurons. Mol Neurobiol 2021; 58:3628-3640. [PMID: 33783711 PMCID: PMC10404139 DOI: 10.1007/s12035-021-02368-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 03/22/2021] [Indexed: 10/21/2022]
Abstract
Extracellular cold-inducible RNA-binding protein (eCIRP) stimulates microglial inflammation causing neuronal damage during ischemic stroke and is a critical mediator of alcohol-induced cognitive impairment. However, the precise role of eCIRP in mediating neuroinflammation remains unknown. In this study, we report that eCIRP activates neurotoxic cyclin-dependent kinase-5 (Cdk5)/p25 through the induction of IL-6Rα/STAT3 pathway in neurons. Amyloid β (Aβ)-mediated neuronal stress, which is associated with Alzheimer's disease, increased the levels of eCIRP released from BV2 microglial cells. The released eCIRP levels from BV2 cells increased 3.2-fold upon stimulation with conditioned medium from Neuro-2a (N2a) cells containing Aβ compared to control N2a supernatant in a time-dependent manner. Stimulation of N2a cells and primary neurons with eCIRP upregulated the neuronal Cdk5 activator p25 expression in a dose- and time-dependent manner. eCIRP directly induced neuronal STAT3 phosphorylation and p25 increase via its novel receptor IL-6Rα. Next, we showed using surface plasmon resonance that eCIRP-derived peptide C23 inhibited the binding of eCIRP to IL-6Rα at 25 μM, with a 40-fold increase in equilibrium dissociation constant (Kd) value (from 8.08 × 10-8 M to 3.43 × 10-6 M), and completely abrogated the binding at 50 μM. Finally, C23 reversed the eCIRP-induced increase in neuronal STAT3 phosphorylation and p25 levels. In conclusion, the current study demonstrates that the upregulation of neuronal IL-6Rα/STAT3/Cdk5 pathway is a key mechanism of eCIRP's role in neuroinflammation and that C23 as a potent inhibitor of this pathway has translational potential in neurodegenerative pathologies controlled by eCIRP.
Collapse
|
|
29
|
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.
Collapse
|
|
30
|
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: 26] [Impact Index Per Article: 5.2] [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.
Collapse
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
| |
Collapse
|
|
31
|
Sharma A, Brenner M, Wang P. Potential Role of Extracellular CIRP in Alcohol-Induced Alzheimer's Disease. Mol Neurobiol 2020; 57:5000-5010. [PMID: 32827106 DOI: 10.1007/s12035-020-02075-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 08/11/2020] [Indexed: 12/15/2022]
Abstract
Alzheimer's disease (AD) is the sixth leading cause of death in the USA and the most common form of neurodegenerative dementia. In AD, microtubule-associated protein tau becomes pathologically phosphorylated and aggregated, leading to neurodegeneration and the cognitive deficits that characterize the disease. Prospective studies have shown that frequent and heavy alcohol drinking is linked to early onset and increased severity of AD. The precise mechanisms of how alcohol leads to AD, however, remain poorly understood. We have shown that extracellular cold-inducible RNA-binding protein (eCIRP) is a critical mediator of memory impairment induced by exposure to binge-drinking levels of alcohol, leading us to reason that eCIRP may be a key player in the relationship between alcohol and AD. In this review, we first discuss the mechanisms by which alcohol promotes AD. We then review eCIRP's role as a critical mediator of acute alcohol intoxication-induced neuroinflammation and cognitive impairment. Next, we explore the potential contribution of eCIRP to the development of alcohol-induced AD by targeting tau phosphorylation. We also consider the effects of eCIRP on neuronal death and neurogenesis linking alcohol with AD. Finally, we highlight the importance of further studying eCIRP as a critical molecular mechanism connecting acute alcohol intoxication, neuroinflammation, and tau phosphorylation in AD along with the potential of therapeutically targeting eCIRP as a new strategy to attenuate alcohol-induced AD.
Collapse
Affiliation(s)
- Archna Sharma
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, 350 Community Dr, Manhasset, NY, 11030, USA
| | - Max Brenner
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, 350 Community Dr, Manhasset, NY, 11030, USA.,Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, 11030, USA
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, 350 Community Dr, Manhasset, NY, 11030, USA. .,Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, 11030, USA. .,Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, 11030, USA.
| |
Collapse
|
|
32
|
Abstract
Extracellular cold-inducible RNA-binding protein (CIRP) exaggerates inflammation in sepsis. Neutrophil reverse transendothelial migration (rTEM) allows neutrophils to migrate from tissues into the circulation. The phenotype of neutrophils after reverse migration is CD54CXCR1. We hypothesize that CIRP induces neutrophil rTEM in sepsis. Sepsis was induced in male C57BL/6 mice by cecal ligation and puncture (CLP), and at 5, 10, or 20 h after CLP the frequencies of reversely migrated (RM) neutrophils were assessed in the blood by flow cytometry. As 20 h of CLP showed highest increase in the frequency of RM neutrophils, we further assessed RM neutrophils in the blood of WT and CIRP mice at this time point. The effect of CIRP on neutrophil rTEM was determined by injecting mice with recombinant mouse CIRP (rmCIRP) intratracheally (i.t.) and assessed the frequencies of RM neutrophils. The expression of neutrophil elastase (NE) and junctional adhesion molecule-C (JAM-C) in the lungs was measured by Western blot. The mean frequency of RM neutrophils in sham mice was 0.4%, whereas the frequencies were significantly increased to 1%, 3%, and 7% at 5, 10, and 20 h of CLP, respectively. The mean frequency of RM neutrophils in the blood of CIRP mice was significantly lower than that of WT mice at 20 h of CLP. The RM neutrophils in the blood was significantly increased after administration of rmCIRP i.t. into mice in a time- and dose-dependent manners. NE expression was upregulated, whereas JAM-C expression was downregulated in the lungs after CLP or rmCIRP administration. For the first time, we have showed that CIRP induces neutrophil rTEM in sepsis by increasing NE and decreasing JAM-C.
Collapse
|
|
33
|
Jacob A, Wang P. Alcohol Intoxication and Cognition: Implications on Mechanisms and Therapeutic Strategies. Front Neurosci 2020; 14:102. [PMID: 32116535 PMCID: PMC7029710 DOI: 10.3389/fnins.2020.00102] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 01/27/2020] [Indexed: 12/23/2022] Open
Abstract
Binge alcohol drinking is highly prevalent in young adults and results in 30% deaths per year in young males. Binge alcohol drinking or acute alcohol intoxication is a risk factor for developing alcohol use disorder (AUD). Three FDA approved drugs are currently in use as therapy for AUD; however, all of them have contra-indications and limitations. Structural brain imaging studies in alcoholics have shown defects in the brain regions involved in memory, cognition and emotional processing. Positron emission tomography (PET) using radiotracers (e.g., 18FDG) and measuring brain glucose metabolism have demonstrated diagnostic and prognostic utility in evaluating patients with cognitive impairment. Using PET imaging, only a few exclusive human studies have addressed the relationship between alcohol intoxication and cognition. Those studies indicate that alcohol intoxication causes reduction in brain activity. Consistent with prior findings, a recent study by us showed that acute alcohol intoxication reduced brain activity in the cortical and subcortical regions including the temporal lobe consisting the hippocampus. Additionally, we have observed a strong correlation between reduction in metabolic activity and spatial cognition impairment in the hippocampus after binge alcohol exposure. We have also demonstrated the involvement of a stress response protein, cold inducible RNA binding protein (CIRP), as a potential mechanistic mediator in acute alcohol intoxication. In this review, we will first discuss in detail prior human PET imaging studies on alcohol intoxication as well as our recent study on acute alcohol intoxication, and review the existing literature on potential mechanisms of acute alcohol intoxication-induced cognitive impairment and therapeutic strategies to mitigate these impairments. Finally, we will highlight the importance of studying brain regions as part of a brain network in delineating the mechanism of acute alcohol intoxication-induced cognitive impairment to aid in the development of therapeutics for such indication.
Collapse
Affiliation(s)
- Asha Jacob
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
- Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| |
Collapse
|
|
34
|
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: 394] [Impact Index Per Article: 65.7] [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.
Collapse
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
| |
Collapse
|
|
35
|
C23, an oligopeptide derived from cold-inducible RNA-binding protein, suppresses inflammation and reduces lung injury in neonatal sepsis. J Pediatr Surg 2019; 54:2053-2060. [PMID: 30691879 PMCID: PMC6609502 DOI: 10.1016/j.jpedsurg.2018.12.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 12/04/2018] [Accepted: 12/23/2018] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Neonatal sepsis remains a leading cause of infant mortality. Cold-inducible RNA binding protein (CIRP) is an inflammatory mediator that induces TNF-α production in macrophages. C23 is a CIRP-derived peptide that blocks CIRP from binding its receptor. We therefore hypothesized that treatment with C23 reduces systemic inflammation and protects the lungs in neonatal sepsis. METHODS Sepsis was induced in C56BL/6 mouse pups (5-7 days) by intraperitoneal injection of adult cecal slurry (0.525 mg/g body weight, LD100). One hour later pups received retroorbital injection of C23 (8 mg/kg) or vehicle (normal saline). Ten hours after sepsis induction, blood and tissues were collected for analysis. RESULTS C23 treatment resulted in a 58% and 69% reduction in serum levels of proinflammatory cytokines IL-6 and IL-1β, respectively, and a 40% and 45% reduction of AST and LDH, as compared to vehicle-treated septic pups. In the lungs, C23 treatment reduced expression of cytokines IL-6 and IL-1β by 78% and 74%. In addition, the mRNA level of neutrophil chemoattractants KC and MIP-2 was reduced by 84% and 74%, respectively. These results corresponded to a reduction in histologic lung injury score. Vehicle-treated pups scored 0.49 ± 0.19, while C23 treatment reduced scores to 0.29 ± 0.12 (p < 0.05; Max = 1). Apoptosis in the lungs, measured by TUNEL assay, was also decreased by 53% with C23 treatment (p < 0.05). CONCLUSIONS Inhibition of CIRP with C23 treatment is protective in septic neonatal mice as demonstrated by reduced inflammatory markers systemically and in the lung. Therefore, C23 has promising therapeutic potential in treatment of neonatal sepsis. LEVEL OF EVIDENCE Level I.
Collapse
|
|
36
|
Liu M, Li Y, Gao S, Yan S, Zhang Q, Liu G, Ji B. A novel target to reduce microglial inflammation and neuronal damage after deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg 2019; 159:2431-2444.e7. [PMID: 31564537 DOI: 10.1016/j.jtcvs.2019.06.115] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 06/11/2019] [Accepted: 06/22/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Neuroinflammation acts as a contributor to neurologic deficits after deep hypothermic circulatory arrest. However, the molecular mechanism remains unclear. This study postulates that cold-inducible RNA-binding protein can promote deep hypothermic circulatory arrest-induced neuroinflammation. METHODS Rats were randomly assigned into 3 groups (n = 5, each group): sham group, deep hypothermic circulatory arrest group, and deep hypothermic circulatory arrest + Cirp-/- group (Cirp-/- group). Murine microglial BV2 cells were administered by adeno-associated viral vectors containing cold-inducible RNA-binding protein small interference RNA or negative control small interference RNA at 2 days before 4-hour oxygen-glucose deprivation at 18°C. Microglial activation, cell death, neuroinflammation, and related protein expression were assessed in tissue samples and cell cultures. RESULTS Cold-inducible RNA-binding protein was elevated along with evident neuroinflammation and neuronal damage in rats exposed to deep hypothermic circulatory arrest. In Cirp-/- rats, histologic injury (3.00 [interquartile range, 2.00-3.00] vs 1.00 [interquartile range, 1.00-1.50] neuropathological score, P < .001) and microglial activation (40 ± 4 vs 13 ± 7 CA1 area, P < .001) were alleviated after deep hypothermic circulatory arrest. With RNA-sequencing analysis, this associated with reduction of key proinflammatory cytokines induced by inhibiting Brd2-NF-κB signals. In BV2 cells treated with small interference RNA-cold-inducible RNA-binding protein, similar protective effects were observed, including decreased proinflammatory cytokines and cytotoxicity. Brd2-NF-κB signals were confirmed by the addition of Brd2 inhibitor JQ1. Notably, the conditioned medium from BV2 cells transfected with small interference RNA cold-inducible RNA-binding protein significantly reduced apoptosis in neural SH-SY5Y cells after oxygen-glucose deprivation, which was similar to that after JQ1 administration. CONCLUSIONS Enhanced cold-inducible RNA-binding protein in microglia aggravates neuronal injury by promoting the release of proinflammatory cytokines, which might be mediated through Brd2-NF-κB signals during deep hypothermic circulatory arrest.
Collapse
Affiliation(s)
- Mingyue Liu
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Yongnan Li
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China; Department of Cardiac Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Sizhe Gao
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Shujie Yan
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Qiaoni Zhang
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Gang Liu
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Bingyang Ji
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
| |
Collapse
|
|
37
|
Bai T, Yang K, Qin C, Xu T, Yu X, Zhang J. Cryptotanshinone ameliorates renal ischaemia–reperfusion injury by inhibiting apoptosis and inflammatory response. Basic Clin Pharmacol Toxicol 2019; 125:420-429. [PMID: 31219678 DOI: 10.1111/bcpt.13275] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 06/06/2019] [Indexed: 12/17/2022]
Affiliation(s)
- Tao Bai
- Department of Urology Renmin Hospital of Wuhan University Wuhan China
| | - Kang Yang
- Department of Urology Renmin Hospital of Wuhan University Wuhan China
| | - Cong Qin
- Department of Urology Renmin Hospital of Wuhan University Wuhan China
| | - Tao Xu
- Department of Urology Renmin Hospital of Wuhan University Wuhan China
| | - Xi Yu
- Department of Urology Renmin Hospital of Wuhan University Wuhan China
| | - Jie Zhang
- Department of Urology Renmin Hospital of Wuhan University Wuhan China
| |
Collapse
|
|
38
|
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: 135] [Impact Index Per Article: 22.5] [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.
Collapse
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
| |
Collapse
|
|
39
|
Chen X, Jiang J, Wu X, Li J, Li S. Plasma Cold-Inducible RNA-Binding Protein Predicts Lung Dysfunction After Cardiovascular Surgery Following Cardiopulmonary Bypass: A Prospective Observational Study. Med Sci Monit 2019; 25:3288-3297. [PMID: 31054221 PMCID: PMC6512755 DOI: 10.12659/msm.914318] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background Cold-inducible RNA-binding protein (CIRP) has been identified as an inflammatory mediator that exerts its function in inflammatory diseases. However, the roles of CIRP in patients who received cardiovascular surgery necessitating cardiopulmonary bypass (CPB) are still unknown. The aim of this study was to examine CIRP levels and attempt to evaluate whether CIRP could serve as a predictor for lung dysfunction after cardiovascular surgery. Material/Methods Plasma CIRP levels were detected by ELISA in 31 patients who received cardiovascular surgery at different time points. Selective inflammatory cytokines (TNF-α, IL-6, IL-10, and TLR4) and mediators (Ang II, PAI-1, and soluble E-selectin) were also detected. Selective laboratory and clinical parameters were recorded at scheduled time points. Results Compared with pre-operation levels, CIRP levels significantly increased 6 h after cardiovascular surgery with CPB. Multiple linear regression analysis showed that the length of CPB time contributed to CIRP production (P=0.013). Furthermore, CIRP was associated with Ang II (r=0.438, P=0.016), PAI-1 (r=0.485, P=0.006), and soluble E-selectin (r=0.470, P=0.008), which partly reflected lung injuries. Multiple linear regression analysis showed that CIRP levels were independently associated with PaO2/FiO2 ratios (P=0.021). Conclusions The length of CPB time contributed to the upregulation of CIRP in patients who received cardiovascular surgery with CPB. CIRP levels could serve as a biomarker to predict the onset of lung injury induced by cardiovascular surgery.
Collapse
Affiliation(s)
- Xia Chen
- Department of Anesthesiology, Shanghai General Hospital of Nanjing Medical University, Shanghai, China (mainland).,Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (mainland)
| | - Jihong Jiang
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (mainland)
| | - Xinwan Wu
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (mainland)
| | - Jinbao Li
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (mainland)
| | - Shitong Li
- Department of Anesthesiology, Shanghai General Hospital of Nanjing Medical University, Shanghai, China (mainland).,Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (mainland)
| |
Collapse
|
|
40
|
McGinn JT, Aziz M, Zhang F, Yang WL, Nicastro JM, Coppa GF, Wang P. Cold-inducible RNA-binding protein-derived peptide C23 attenuates inflammation and tissue injury in a murine model of intestinal ischemia-reperfusion. Surgery 2018; 164:1191-1197. [PMID: 30154017 PMCID: PMC6261788 DOI: 10.1016/j.surg.2018.06.048] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 06/05/2018] [Accepted: 06/22/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Cold-inducible RNA-binding protein is a novel damage-associated molecular pattern that causes inflammation. C23, a short peptide derived from cold-inducible RNA-binding protein, has been found to have efficacy in blocking cold-inducible RNA-binding protein's activity. We hypothesized that C23 reduces inflammation and tissue injury induced by intestinal ischemia-reperfusion. METHODS Male C57BL/6 mice were subjected to 60 minutes of intestinal ischemia by clamping the superior mesenteric artery. Immediately after reperfusion, either normal saline (vehicle) or C23 peptide (8 mg/kg body weight) was injected intraperitoneally. Four hours after reperfusion, blood, intestinal, and lung tissues were collected for analysis of inflammatory and tissue injury parameters. RESULTS Cold-inducible RNA-binding protein levels in the intestinal tissues were significantly increased following intestinal ischemia-reperfusion. Histologic examination of the intestine revealed a significant reduction in injury score in the C23 group by 48% as compared with the vehicles after intestinal ischemia-reperfusion. The serum levels of lactate dehydrogenase and aspartate aminotransferase were increased in animals that underwent vehicle-treated intestinal ischemia-reperfusion, whereas C23-treated animals exhibited significant reductions by 48% and 53%, respectively. The serum and intestinal tissue levels of tumor necrosis factor α were elevated in vehicle-treated intestinal ischemia-reperfusion mice but decreased by 72% and 69%, respectively, in C23-treated mice. Interleukin-6 mRNA levels in the lungs were reduced by 86% in the C23-treated group in comparison to the vehicle-treated group after intestinal ischemia-reperfusion. Expression of macrophage inflammatory protein 2 and level of myeloperoxidase activity in the lungs were dramatically increased after intestinal ischemia-reperfusion and significantly reduced by 91% and 25%, respectively, in the C23-treated group. CONCLUSION C23 has potential to be developed into a possible therapy for reperfusion injury after mesenteric ischemia and reperfusion.
Collapse
Affiliation(s)
- Joseph T McGinn
- Department of Surgery and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York
| | - Fangming Zhang
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York
| | - Weng-Lang Yang
- Department of Surgery and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York; Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York
| | - Jeffrey M Nicastro
- Department of Surgery and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York
| | - Gene F Coppa
- Department of Surgery and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York
| | - Ping Wang
- Department of Surgery and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York; Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York.
| |
Collapse
|
|
41
|
Stanojcic M, Jeschke MG. What's New in Shock, March 2018? Shock 2018; 49:239-242. [PMID: 29432388 DOI: 10.1097/shk.0000000000001081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
| | - Marc G Jeschke
- Sunnybrook Research Institute, Toronto, Ontario, Canada.,Department of Surgery, Division of Plastic Surgery, University of Toronto, Ontario, Canada.,Department of Immunology, University of Toronto, Ontario, Canada.,Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| |
Collapse
|