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Lian YQ, Li PF, Guo Y, Tao YL, Liu YN, Liang ZY, Zhu SF. Interaction between ischemia-reperfusion injury and intestinal microecology in organ transplantation and its therapeutic prospects. Front Immunol 2024; 15:1495394. [PMID: 39712022 PMCID: PMC11659223 DOI: 10.3389/fimmu.2024.1495394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 11/15/2024] [Indexed: 12/24/2024] Open
Abstract
Organ transplantation is a vital intervention for end-stage organ failure; however, ischemia-reperfusion injury is a complication of transplantation, affecting the prognosis and survival of transplant recipients. As a complex ecosystem, recent research has highlighted the role of the intestinal microecology in transplantation, revealing its significant interplay with ischemia-reperfusion injury. This review explores the interaction between ischemia-reperfusion injury and intestinal microecology, with a special focus on how ischemia-reperfusion injury affects intestinal microecology and how these microecological changes contribute to complications after organ transplantation, such as infection and rejection. Based on a comprehensive analysis of current research advances, this study proposes potential strategies to improve transplant outcomes, offering guidance for future research and clinical practice.
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Affiliation(s)
- Yong-qi Lian
- Department of Critical Care Medicine, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Peng-fei Li
- Department of Orthopaedics, Inner Mongolia Autonomous Region People’s Hospital, Hohhot, Inner Mongolia Autonomous Region, China
| | - Yan Guo
- Pathology Department, Inner Mongolia Autonomous Region People’s Hospital, Hohhot, Inner Mongolia Autonomous Region, China
| | - Yan-lin Tao
- Department of Surgery ICU, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Ya-nan Liu
- Department of Surgery ICU, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Zhao-yu Liang
- Department of Critical Care Medicine, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Shu-fen Zhu
- Physical Examination Center, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
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2
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Pan LL, Sun Y, Dong X, Ren Z, Li B, Yang P, Zhang L, Sun J. Infant feces-derived Lactobacillus gasseri FWJL-4 mitigates experimental necrotizing enterocolitis via acetate production. Gut Microbes 2024; 16:2430541. [PMID: 39648298 PMCID: PMC11633162 DOI: 10.1080/19490976.2024.2430541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 09/02/2024] [Accepted: 11/11/2024] [Indexed: 12/10/2024] Open
Abstract
Necrotizing enterocolitis (NEC) is a life-threatening disease in premature infants, characterized by high mortality. Recent studies increasingly highlight the role of gut dysbiosis in NEC pathogenesis. Although probiotics have shown some efficacy in preventing NEC, further research is needed to determine potential strains and approaches. In this study, we demonstrated that the novel probiotic strain Lactobacillus gasseri (L. gasseri) FWJL-4, isolated from the feces of healthy infants, significantly enhanced intestinal barrier function, providing substantial protection against NEC. This protective effect was attributed to elevated intestinal acetate levels. Notably, acetate supplementation alone was sufficient to mitigate NEC, mimicking the protective effects of L. gasseri FWJL-4. Mechanistically, we revealed that L. gasseri FWJL-4 inhibited necroptosis and preserved the number of the goblet cells and enterocytes through the production of the short-chain fatty acid acetate, via activation of the acetate receptors G protein-coupled receptor (GPR) 41 and GPR43. Our findings suggest that L. gasseri FWJL-4 enhances intestinal barrier function to protect against NEC, underscoring the potential of probiotic manipulation as a promising strategy for NEC prevention.
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Affiliation(s)
- Li-Long Pan
- Department of Neonatology, Affiliated Children’s Hospital of Jiangnan University (Wuxi Children’s Hospital), Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Yudong Sun
- Department of Neonatology, Affiliated Children’s Hospital of Jiangnan University (Wuxi Children’s Hospital), Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Xiaoliang Dong
- Department of Neonatology, Affiliated Children’s Hospital of Jiangnan University (Wuxi Children’s Hospital), Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Zhengnan Ren
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Binbin Li
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Ping Yang
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Le Zhang
- Department of Neonatology, Affiliated Children’s Hospital of Jiangnan University (Wuxi Children’s Hospital), Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Jia Sun
- Department of Neonatology, Affiliated Children’s Hospital of Jiangnan University (Wuxi Children’s Hospital), Wuxi School of Medicine, Jiangnan University, Wuxi, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
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3
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Yan Q, Jia S, Li D, Yang J. The role and mechanism of action of microbiota-derived short-chain fatty acids in neutrophils: From the activation to becoming potential biomarkers. Biomed Pharmacother 2023; 169:115821. [PMID: 37952355 DOI: 10.1016/j.biopha.2023.115821] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/27/2023] [Accepted: 10/31/2023] [Indexed: 11/14/2023] Open
Abstract
Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, have emerged as critical mediators in the communication between the human microbiota and its host. As the first responder to the inflammatory site, neutrophils play an important role in protecting the host against bacterial infections. Recent investigations revealed that SCFAs generated from microbiota influence various neutrophil activities, including activation, migration, and generation of mediators of inflammatory processes. SCFAs have also been demonstrated to exhibit potential therapeutic benefits in a variety of disorders related to neutrophil dysfunction, including inflammatory bowel disease, viral infectious disorders, and cancer. This study aims to examine the molecular processes behind the complicated link between SCFAs and neutrophils, as well as their influence on neutrophil-driven inflammatory disorders. In addition, we will also provide an in-depth review of current research on the diagnostic and therapeutic value of SCFAs as possible biomarkers for neutrophil-related diseases.
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Affiliation(s)
- Qingzhu Yan
- Department of Ultrasound Medicine, the Second Hospital of Jilin University, Changchun 130000, China
| | - Shengnan Jia
- Digestive Diseases Center, Department of Hepatopancreatobiliary Medicine, the Second Hospital of Jilin University, Changchun 130000, China
| | - Dongfu Li
- Digestive Diseases Center, Department of Hepatopancreatobiliary Medicine, the Second Hospital of Jilin University, Changchun 130000, China.
| | - Junling Yang
- Department of Respiratory Medicine, the Second Hospital of Jilin University, Changchun 130000, China.
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4
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Zhang W, Zhao Y, He Q, Lang R. Therapeutically targeting essential metabolites to improve immunometabolism manipulation after liver transplantation for hepatocellular carcinoma. Front Immunol 2023; 14:1211126. [PMID: 37492564 PMCID: PMC10363744 DOI: 10.3389/fimmu.2023.1211126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 06/26/2023] [Indexed: 07/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent primary liver malignancy worldwide and is associated with a poor prognosis. Sophisticated molecular mechanisms and biological characteristics need to be explored to gain a better understanding of HCC. The role of metabolites in cancer immunometabolism has been widely recognized as a hallmark of cancer in the tumor microenvironment (TME). Recent studies have focused on metabolites that are derived from carbohydrate, lipid, and protein metabolism, because alterations in these may contribute to HCC progression, ischemia-reperfusion (IR) injury during liver transplantation (LT), and post-LT rejection. Immune cells play a central role in the HCC microenvironment and the duration of IR or rejection. They shape immune responses through metabolite modifications and by engaging in complex crosstalk with tumor cells. A growing number of publications suggest that immune cell functions in the TME are closely linked to metabolic changes. In this review, we summarize recent findings on the primary metabolites in the TME and post-LT metabolism and relate these studies to HCC development, IR injury, and post-LT rejection. Our understanding of aberrant metabolism and metabolite targeting based on regulatory metabolic pathways may provide a novel strategy to enhance immunometabolism manipulation by reprogramming cell metabolism.
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Affiliation(s)
- Wenhui Zhang
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, China
| | - Yu Zhao
- Department of Urology Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, China
| | - Qiang He
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, China
| | - Ren Lang
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, China
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Fan S, Feng X, Li K, Li B, Diao Y. Protective Mechanism of Ethyl Gallate against Intestinal Ischemia-Reperfusion Injury in Mice by in Vivo and in Vitro Studies Based on Transcriptomics. Chem Biodivers 2023; 20:e202200643. [PMID: 36513607 DOI: 10.1002/cbdv.202200643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 11/30/2022] [Accepted: 12/13/2022] [Indexed: 12/15/2022]
Abstract
Intestinal ischemia-reperfusion injury (IIRI) is a common clinical disease that can be life-threatening in severe cases. This study aimed to investigate the effects of ethyl gallate (EG) on IIRI and its underlying mechanisms. A mouse model was established to mimic human IIRI by clamping the superior mesenteric artery. Transcriptomics techniques were used in conjunction with experiments to explore the potential mechanisms of EG action. Intestinal histomorphological damage, including intestinal villi damage and mucosal hemorrhage, was significantly reversed by EG. EG also alleviated the oxidative stress, inflammation, and intestinal epithelial apoptosis caused by IIRI. 2592 up-regulated genes and 2754 down-regulated genes were identified after EG treatment, and these differential genes were enriched in signaling pathways, including fat digestion and absorption, and extracellular matrix (ECM) receptor interactions. In IIRI mouse intestinal tissue, expression of the differential protein matrix metalloproteinase 9 (MMP9), as well as its co-protein NF-κB-p65, was significantly increased, while EG inhibited the expression of MMP9 and NF-κB-p65. In Caco-2 cells in an established oxygen-glucose deprivation/reperfusion model (OGD/R), EG significantly reversed the decrease in intestinal barrier trans-epithelial electrical resistance (TEER). However, in the presence of MMP9 inhibitors, EG did not reverse the decreasing trend in TEER. This study illustrates the protective effect and mechanism of action of EG on IIRI and, combined with in vivo and in vitro experiments, it reveals that MMP9 may be the main target of EG action. This study provides new scientific information on the therapeutic effects of EG on IIRI.
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Affiliation(s)
- Shuyuan Fan
- College of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, China
| | - Xiaoyan Feng
- College of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, China
| | - Kun Li
- College of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, China
| | - Bin Li
- College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Yunpeng Diao
- College of Pharmacy, Dalian Medical University, Dalian, 116044, China.,Dalian Anti-Infective Traditional Chinese Medicine, Development Engineering Technology Research Center, China
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Munley JA, Nagpal R, Hanson NC, Mirzaie A, Laquian L, Mohr AM, Efron PA, Arnaoutakis DJ, Cooper MA. Chronic Mesenteric Ischemia Intestinal Dysbiosis Resolves after Revascularization. J Vasc Surg Cases Innov Tech 2022; 9:101084. [PMID: 36970136 PMCID: PMC10033993 DOI: 10.1016/j.jvscit.2022.101084] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 11/11/2022] [Indexed: 12/24/2022] Open
Abstract
Objective Chronic mesenteric ischemia (CMI) is a debilitating condition arising from intestinal malperfusion from mesenteric artery stenosis or occlusion. Mesenteric revascularization has been the standard of care but can result in substantial morbidity and mortality. Most of the perioperative morbidity has been secondary to postoperative multiple organ dysfunction, potentially from ischemia-reperfusion injury. The intestinal microbiome is a dense community of microorganisms in the gastrointestinal tract that help regulate pathways ranging from nutritional metabolism to the immune response. We hypothesized that patients with CMI will have microbiome perturbations that contribute to this inflammatory response and could potentially normalize in the postoperative period. Methods We performed a prospective study of patients with CMI who had undergone mesenteric bypass and/or stenting from 2019 to 2020. Stool samples were collected at three time points: preoperatively at the clinic, perioperatively within 14 days after surgery, and postoperatively at the clinic at >30 days after revascularization. Stool samples from healthy controls were used for comparison. The microbiome was measured using 16S rRNA sequencing on an Illumina-MiSeq sequence platform and analyzed using the QIIME2 (quantitative insights into microbial ecology 2)-DADA2 bioinformatics pipeline with the Silva database. Beta-diversity was analyzed using a principal coordinates analysis and permutational analysis of variance. Alpha-diversity (microbial richness and evenness) was compared using the nonparametric Mann-Whitney U test. Microbial taxa unique to CMI patients vs controls were identified using linear discriminatory analysis effect size analysis. P < .05 was considered statistically significant. Results Eight patients with CMI had undergone mesenteric revascularization (25% men; average age, 71 years). Nine healthy controls were also analyzed (78% men; average age, 55 years). Bacterial alpha-diversity (number of operational taxonomic units) was dramatically reduced preoperatively compared with that of the controls (P = .03). However, revascularization partially restored the species richness and evenness in the perioperative and postoperative phases. Beta-diversity was only different between the perioperative and postoperative groups (P = .03). Further analyses revealed increased abundance of Bacteroidetes and Clostridia taxa preoperatively and perioperatively compared with the controls, which was reduced during the postoperative period. Conclusions The results from the present study have shown that patients with CMI have intestinal dysbiosis that resolves after revascularization. The intestinal dysbiosis is characterized by the loss of alpha-diversity, which is restored perioperatively and maintained postoperatively. This microbiome restoration demonstrates the importance of intestinal perfusion to sustain gut homeostasis and suggests that microbiome modulation could be a possible intervention to ameliorate acute and subacute postoperative outcomes in these patients.
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Acetate, a gut bacterial product, ameliorates ischemia-reperfusion induced acute lung injury in rats. Int Immunopharmacol 2022; 111:109136. [PMID: 35964409 DOI: 10.1016/j.intimp.2022.109136] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/27/2022] [Accepted: 08/05/2022] [Indexed: 11/21/2022]
Abstract
Recent data suggest that short-chain fatty acids (SCFAs), the major fermentation product from gut microbial degradation of dietary fiber, have protective effects against renal ischemia-reperfusion (IR) injury, colitis, and allergic asthma. However, the effect of SCFAs on acute lung injury (ALI) caused by IR is still unclear. In this study, we examine whether SCFAs have protective effects against IR-induced ALI and explore possible protective mechanisms. IR-induced ALI was established by 40 min ischemia followed by 60 min reperfusion in isolated perfused rat lungs. Rats were randomly assigned to one of six groups: control, control + acetate (400 mg/kg), IR, and IR + acetate at one of three dosages (100, 200, 400 mg/kg). Bronchoalveolar lavage fluids (BALF) and lung tissues were obtained and analyzed at the end of the experiment. In vitro, mouse lung epithelial cells (MLE-12) subjected to hypoxia-reoxygenation (HR) were pretreated with acetate (25 mmol/L) and GPR41 or GPR43 siRNA. Acetate decreased lung weight gain, lung weight/body weight ratios, wet/dry weight ratios, pulmonary artery pressure, and protein concentration of the BALF in a dose-dependent manner for IR-induced ALI. Acetate also significantly inhibited the production of TNF-α, IL-6 and CINC-1 in the BALF. Moreover, acetate treatment restored suppressed IκB-α levels and reduced nuclear NF-κB p65 levels in lung tissues. In addition, acetate mitigated IR-induced apoptosis and tight junction disruption in injured lung tissue. In vitro analyses showed that acetate attenuated NF-κB activation and KC/CXCL-1 levels in MLE-12 cells exposed to HR. The protective effects of acetate in vitro were significantly abrogated by GPR41 or GPR43 siRNA. Acetate ameliorates IR-induced acute lung inflammation and its protective mechanism appears to be via the GPR41/43 signaling pathway. Based on our findings, acetate may provide a novel adjuvant therapeutic approach for IR-induced lung injury.
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Dong ZW, Liu H, Su FF, Fan XZ, Zhang Y, Liu P. Cystic fibrosis transmembrane conductance regulator prevents ischemia/reperfusion induced intestinal apoptosis via inhibiting PI3K/AKT/NF-κB pathway. World J Gastroenterol 2022; 28:918-932. [PMID: 35317058 PMCID: PMC8908288 DOI: 10.3748/wjg.v28.i9.918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/14/2021] [Accepted: 01/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Intestinal ischemia/reperfusion (I/R) injury is a fatal syndrome that occurs under many clinical scenarios. The apoptosis of intestinal cells caused by ischemia can cause cell damage and provoke systemic dysfunction during reperfusion. However, the mechanism of I/R-induced apoptosis remains unclear. Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated chloride channel. Few researchers have paid attention to its role in intestinal I/R injury, or the relationship between CFTR and intestinal apoptosis induced by hypoxia/reoxygenation (H/R).
AIM To investigate the effects of CFTR on I/R-induced intestinal apoptosis and its underlying molecular mechanisms.
METHODS An intestinal I/R injury model was established in mice with superior mesenteric artery occlusion, and Caco2 cells were subjected to H/R for the simulation of I/R in vivo.
RESULTS The results suggested that CFTR overexpression significantly increased the Caco2 cell viability and decreased cell apoptosis induced by the H/R. Interestingly, we found that the translocation of p65, an NF-κB member, from the cytoplasm to the nucleus after H/R treatment can be reversed by the overexpression of CFTR, the NF-κB P65 would return from the nucleus to the cytoplasm as determined by immunostaining. We also discovered that CFTR inhibited cell apoptosis in the H/R-treated cells, and this effect was significantly curbed by the NF-κB activator BA, AKT inhibitor GSK690693 and the PI3K inhibitor LY294002. Moreover, we demonstrated that CFTR overexpression could reverse the decreased PI3K/AKT expression induced by the I/R treatment in vivo or H/R treatment in vitro.
CONCLUSION The results of the present study indicate that the overexpression of CFTR protects Caco2 cells from H/R-induced apoptosis; furthermore, it also inhibits H/R-induced apoptosis through the PI3K/AKT/NF-κB signaling pathway in H/R-treated Caco2 cells and intestinal tissues.
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Affiliation(s)
- Zhi-Wei Dong
- Department of General Surgery, Air Force Medical Center, Beijing 100000, China
| | - Hui Liu
- Department of Gastroenterology, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Fei-Fei Su
- Department of Cardiology, Air Force Medical Center, Beijing 100000, China
| | - Xiao-Zhou Fan
- Department of Ultrasound, Air Force Medical Center, Beijing 100000, China
| | - Yong Zhang
- School of Chemistry and Biological Engineering, University of Science and Technology, Beijing 100000, China
| | - Peng Liu
- Research Laboratory of Aero-Medical Support, Air Force Medical Center, Beijing 100000, China
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The Interplay between Autophagy and NLRP3 Inflammasome in Ischemia/Reperfusion Injury. Int J Mol Sci 2021; 22:ijms22168773. [PMID: 34445481 PMCID: PMC8395601 DOI: 10.3390/ijms22168773] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 07/29/2021] [Accepted: 08/12/2021] [Indexed: 12/13/2022] Open
Abstract
Ischemia/reperfusion (I/R) injury is characterized by a limited blood supply to organs, followed by the restoration of blood flow and reoxygenation. In addition to ischemia, blood flow recovery can also lead to very harmful injury, especially inflammatory injury. Autophagy refers to the transport of cellular materials to the lysosomes for degradation, leading to the conversion of cellular components and offering energy and macromolecular precursors. It can maintain the balance of synthesis, decomposition and reuse of the intracellular components, and participate in many physiological processes and diseases. Inflammasomes are a kind of protein complex. Under physiological and pathological conditions, as the cellular innate immune signal receptors, inflammasomes sense pathogens to trigger an inflammatory response. TheNLRP3 inflammasome is the most deeply studied inflammasome and is composed of NLRP3, the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and pro-caspase-1. Its activation triggers the cleavage of pro-interleukin (IL)-1β and pro-IL-18 mediated by caspase-1 and promotes a further inflammatory process. Studies have shown that autophagy and the NLRP3 inflammasome play an important role in the process of I/R injury, but the relevant mechanisms have not been fully explained, especially how the interaction between autophagy and the NLRP3 inflammasome participates in I/R injury, which remains to be further studied. Therefore, we reviewed the recent studies about the interplay between autophagy and the NLRP3 inflammasome in I/R injury and analyzed the mechanisms to provide the theoretical references for further research in the future.
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Liu Y, Wang M, Wang D, Fay WP, Korthuis RJ, Sowa G. Elevated postischemic tissue injury and leukocyte-endothelial adhesive interactions in mice with global deficiency in caveolin-2: role of PAI-1. Am J Physiol Heart Circ Physiol 2021; 320:H1185-H1198. [PMID: 33416452 PMCID: PMC8362680 DOI: 10.1152/ajpheart.00682.2020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 01/13/2023]
Abstract
Ischemia/reperfusion (I/R)-induced rapid inflammation involving activation of leukocyte-endothelial adhesive interactions and leukocyte infiltration into tissues is a major contributor to postischemic tissue injury. However, the molecular mediators involved in this pathological process are not fully known. We have previously reported that caveolin-2 (Cav-2), a protein component of plasma membrane caveolae, regulated leukocyte infiltration in mouse lung carcinoma tumors. The goal of the current study was to examine if Cav-2 plays a role in I/R injury and associated acute leukocyte-mediated inflammation. Using a mouse small intestinal I/R model, we demonstrated that I/R downregulates Cav-2 protein levels in the small bowel. Further study using Cav-2-deficient mice revealed aggravated postischemic tissue injury determined by scoring of villi length in H&E-stained tissue sections, which correlated with increased numbers of MPO-positive tissue-infiltrating leukocytes determined by IHC staining. Intravital microscopic analysis of upstream events relative to leukocyte transmigration and tissue infiltration revealed that leukocyte-endothelial cell adhesive interactions in postcapillary venules, namely leukocyte rolling and adhesion were also enhanced in Cav-2-deficient mice. Mechanistically, Cav-2 deficiency increased plasminogen activator inhibitor-1 (PAI-1) protein levels in the intestinal tissue and a pharmacological inhibition of PAI-1 had overall greater inhibitory effect on both aggravated I/R tissue injury and enhanced leukocyte-endothelial interactions in postcapillary venules in Cav-2-deficient mice. In conclusion, our data suggest that Cav-2 protein alleviates tissue injury in response to I/R by dampening PAI-1 protein levels and thereby reducing leukocyte-endothelial adhesive interactions.NEW & NOTEWORTHY The role of caveolin-2 in regulating ischemia/reperfusion (I/R) tissue injury and the mechanisms underlying its effects are unknown. This study uses caveolin-2-deficient mouse and small intestinal I/R injury models to examine the role of caveolin-2 in the leukocyte-dependent reperfusion injury. We demonstrate for the first time that caveolin-2 plays a protective role from the I/R-induced leukocyte-dependent reperfusion injury by reducing PAI-1 protein levels in intestinal tissue and leukocyte-endothelial adhesive interactions in postcapillary venules.
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Affiliation(s)
- Yajun Liu
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - Meifang Wang
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - Derek Wang
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - William P Fay
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
- Department of Medicine, University of Missouri, Columbia, Missouri
| | - Ronald J Korthuis
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
- The Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| | - Grzegorz Sowa
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
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Milligan G, Barki N, Tobin AB. Chemogenetic Approaches to Explore the Functions of Free Fatty Acid Receptor 2. Trends Pharmacol Sci 2021; 42:191-202. [PMID: 33495026 DOI: 10.1016/j.tips.2020.12.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 12/08/2020] [Accepted: 12/16/2020] [Indexed: 12/15/2022]
Abstract
Short-chain fatty acids are generated in large amounts by the intestinal microbiota. They activate both the closely related G protein-coupled receptors free fatty acid receptor 2 (FFA2) and free fatty acid receptor 3 (FFA3) that are considered therapeutic targets in diseases of immuno-metabolism. Limited and species-selective small-molecule pharmacology has restricted our understanding of the distinct roles of these receptors. Replacement of mouse FFA2 with a designer receptor exclusively activated by designer drug form of human FFA2 (hFFA2-DREADD) has allowed definition of specific roles of FFA2 in pharmacological and physiological studies conducted both ex vivo and in vivo, whilst overlay of murine disease models offers opportunities for therapeutic validation prior to human studies. Similar approaches can potentially be used to define roles of other poorly characterised receptors.
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Affiliation(s)
- Graeme Milligan
- Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
| | - Natasja Barki
- Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
| | - Andrew B Tobin
- Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
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Wu MCL, Lee JD, Ruitenberg MJ, Woodruff TM. Absence of the C5a Receptor C5aR2 Worsens Ischemic Tissue Injury by Increasing C5aR1-Mediated Neutrophil Infiltration. THE JOURNAL OF IMMUNOLOGY 2020; 205:2834-2839. [PMID: 33028618 DOI: 10.4049/jimmunol.2000778] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/16/2020] [Indexed: 02/06/2023]
Abstract
Neutrophil infiltration to ischemic tissues following reperfusion worsens injury. A key driver of neutrophil recruitment and activation is the complement factor C5a, which signals through two receptors, C5aR1 and C5aR2. In this study, we used a neutrophil-dependent mouse model of intestinal ischemia-reperfusion (IR) injury to investigate the underexplored role of C5aR2 in neutrophil mobilization, recruitment, and disease outcomes. We show that intestinal IR induces rapid neutrophil mobilization along with a concomitant reduction in plasma C5a levels that is driven by both C5aR1 and C5aR2. Intestinal IR in C5aR2-/- mice led to worsened intestinal damage and increased neutrophil infiltration. Inhibition of C5aR1 signaling in C5aR2-/- mice with PMX53 prevented neutrophil accumulation and reduced IR pathology, suggesting a key requirement for enhanced neutrophil C5aR1 activation in the absence of C5aR2 signaling. Interestingly, C5aR2 deficiency also reduced circulating neutrophil numbers after IR, as well as following G-CSF-mediated bone marrow mobilization, which was independent of C5aR1, demonstrating that C5aR2 has unique and distinct functions from C5aR1 in neutrophil egress. Despite enhanced tissue injury in C5aR2-/- IR mice, there were significant reductions in intestinal proinflammatory cytokines, highlighting complicated dual protective/pathogenic roles for C5aR2 in pathophysiology. Collectively, we show that C5aR2 is protective in intestinal IR by inhibiting C5aR1-mediated neutrophil recruitment to the ischemic tissue. This is despite the potentially local pathogenic effects of C5aR2 in increasing intestinal proinflammatory cytokines and enhancing circulating neutrophil numbers in response to mobilizing signals. Our data therefore suggest that this balance between the dual pro- and anti-inflammatory roles of C5aR2 ultimately dictates disease outcomes.
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Affiliation(s)
- Mike C L Wu
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Queensland 4072, Australia
| | - John D Lee
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Queensland 4072, Australia
| | - Marc J Ruitenberg
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Queensland 4072, Australia
| | - Trent M Woodruff
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Queensland 4072, Australia
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