|
1
|
Xiao Z, Xie J, Zhao X, Chen X, Lu Y, Xu Y, Wu M, An L, Li Q. Role of Pyroptosis in inflammatory bowel disease. Int Immunopharmacol 2025; 155:114619. [PMID: 40209313 DOI: 10.1016/j.intimp.2025.114619] [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: 01/30/2025] [Revised: 03/21/2025] [Accepted: 04/03/2025] [Indexed: 04/12/2025]
Abstract
Inflammatory bowel disease (IBD) is a serious chronic condition marked by persistent and recurrent intestinal ulcers. Although the exact cause of IBD remains unclear, it is generally accepted that a complex interaction among dietary factors, gut microbiota, and immune responses in genetically predisposed individuals contributes to its development. Pyroptosis, an inflammatory form of programmed cell death activated by inflammasomes, is marked by the rupture of cell membranes and the subsequent release of inflammatory mediators. Emerging evidence indicates that pyroptosis plays a crucial role in the pathogenesis of IBD. Moderate pyroptosis activation can enhance intestinal immune defenses, while excessive inflammasome activation can trigger an inflammatory cascade, resulting in increased damage to intestinal tissues. This article reviews the molecular mechanisms underlying pyroptosis and highlights its role in the onset and progression of IBD. Furthermore, We explore recent advancements in IBD treatment, focusing on small molecule compounds that specifically target and inhibit pyroptosis.
Collapse
Affiliation(s)
- Zhiyi Xiao
- The Clinical Medical College, Guizhou Medical University, Guiyang 550004, China
| | - Jiling Xie
- The Clinical Medical College, Guizhou Medical University, Guiyang 550004, China
| | - Xun Zhao
- Department of Gastroenterology, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China
| | - Xiangjun Chen
- The Clinical Medical College, Guizhou Medical University, Guiyang 550004, China
| | - Yihong Lu
- The Clinical Medical College, Guizhou Medical University, Guiyang 550004, China
| | - Yuanzhao Xu
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China
| | - Manqing Wu
- Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China
| | - Lingyue An
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China.
| | - Qing Li
- Department of Gastroenterology and Surgery, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China.
| |
Collapse
|
|
2
|
Feng X, Zhang M, Zhao T, Cui J, Ye H, Zhou C, Ye L, Zhou L. Polystyrene microplastics trigger colonic inflammation in rats via the TLR4/NF-κB/COX-2 pathway and modulation of intestinal microbiota. Toxicology 2025; 513:154090. [PMID: 39971085 DOI: 10.1016/j.tox.2025.154090] [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: 11/06/2024] [Revised: 02/14/2025] [Accepted: 02/14/2025] [Indexed: 02/21/2025]
Abstract
Polystyrene microplastics (PS-MPs) are common microplastics that pose significant health hazards to humans. Due to multifunctionality in the gut system, MP-associated damage and mechanisms require further exploration. This study was undertaken with the objective of elucidating the impact of PS-MP exposure on colonic inflammation in rats, and to explore its potential mechanisms. Forty-eight specific-pathogen-free Wistar male rats were administered 0, 0.5, 5, and 50 mg/kg/d of PS-MPs for 90 days, after which intestinal flora distribution, inflammatory factor levels in the colon, and TLR4/NF-κB/COX-2 gene levels were examined. To clarify whether PS-MPs directly infiltrate intestinal epithelial cells and induce cytotoxicity, human intestinal epithelial cells (HIECs) were exposed to a range of PS-MP concentrations (0 ∼ 100 μg/mL) for 48 h, and CCK-8 assays were conducted to assess the cell survival rates. In the colon tissue of rats exposed to PS-MP, goblet cells decreased, muscular layer arrangements were disordered, and disrupted and discontinuous crypt structures appeared in colon tissue, while high numbers of inflammatory cells infiltrated the colonic mucosa and submucosa. PS-MPs could accumulate in HIECs, and cell survival rates were decreased. In the colons of rats exposed to PS-MPs, the levels of Interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α were found to be elevated. Additionally, the mRNA and protein levels of TLR4/MyD88 in the colons of PS-MP-exposed rats exhibited a significant increase. Furthermore, the TLR4/NF-κB/COX-2 signaling pathway in rat colons was activated after MP exposure. When the TLR4/NF-κB/COX-2 signaling pathway was inhibited, the significant increases in IL-6 and TNF-α levels caused by PS-MPs were significantly reversed. PS-MP exposure also altered intestinal flora abundance in rats. Compared with the control group, the proportion of Firmicutes, Proteobacteria and Actinobacteria in PS-MPs exposed group was increased. In contrast, the proportion of Bacteroidetes and Verrucomicrobia decreased. Taken together, our results suggest that PS-MP could exert adverse effects on the gastrointestinal health of rats. Pro-inflammatory cytokine (IL-6, IL-1β and TNF-α) levels increased, and the TLR4/NF-κB/COX-2 signaling pathway was triggered. Thus, flora changes and increased intestinal inflammation may interact with each other.
Collapse
Affiliation(s)
- Xuemin Feng
- Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Meng Zhang
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun 130021, China
| | - Tianyang Zhao
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun 130021, China
| | - Jianwei Cui
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun 130021, China
| | - Hui Ye
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun 130021, China
| | - Chunkui Zhou
- Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Lin Ye
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun 130021, China
| | - Liting Zhou
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun 130021, China.
| |
Collapse
|
|
3
|
Ferreira FB, Kaufmann FN, Bastos CR, Xavier J, Aniszewski S, Molina ML, Lara DR, Jansen K, da Silva RA, Souza LDDM, Kaster MP, Ghisleni G. The gain-of-function variant in the NLRP3 gene predicts the effectiveness of brief psychotherapy but not the risk of major depression. Behav Brain Res 2025; 481:115413. [PMID: 39742924 DOI: 10.1016/j.bbr.2024.115413] [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: 07/18/2024] [Revised: 12/16/2024] [Accepted: 12/29/2024] [Indexed: 01/04/2025]
Abstract
Major depressive disorder (MDD) is a highly prevalent psychiatric condition whose pathophysiology has been linked to neuroinflammatory processes involving the NLRP3 inflammasome. To address this point, the study investigated the association of the NLRP3 rs10754558 polymorphism with MDD diagnosis in a young adults population based study and the effectiveness of brief psychotherapies in a randomized clinical trial. A cross-sectional, population-based study was conducted with 1100 individuals aged 18-35 years, including 615 controls and 485 patients with MDD. Diagnosis was determined using the Mini International Neuropsychiatric Interview (M.I.N.I.) based on DSM-IV criteria. Our clinical trial included 227 participants with MDD aged 18-60 years from a randomized clinical trial evaluating the effectiveness of two brief psychotherapies for MDD. Depressive and anxiety symptoms were assessed at baseline, post-treatment (16-18 weeks), and 6-month follow-up using the Beck Depression Inventory-II (BDI-II) and the Beck Anxiety Inventory (BAI). Statistical analyses included logistic regression and generalized estimating equation (GEE) model adjusted for demographic and clinical variables. The results showed no significant association between rs10754558 genotypes and MDD diagnosis. However, when evaluating the efficacy of brief psychotherapies, the GG genotype was associated with poorer treatment outcomes for both depressive and anxiety symptoms compared to the GC/CC genotypes (p < 0.05). Longitudinal analysis revealed significant differences over time, with GG individuals demonstrating less symptom improvement (BDI-II: baseline 36.61 to follow-up 21.75; BAI: baseline 26.32 to follow-up 19.55) compared to GC/CC genotypes (BDI-II: baseline 32.05 to follow-up 20.29; BAI: baseline 22.05 to follow-up 17.96). These findings suggest that the GG genotype, previously characterized as a gain-of-function variant, may contribute to genetic heterogeneity influencing psychotherapy outcomes. This highlights the potential for genetic markers, such as rs10754558, to inform personalized psychiatric treatments and improve therapeutic strategies.
Collapse
Affiliation(s)
| | | | - Clarissa Ribeiro Bastos
- Center of Health Sciences, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil.
| | - Janaína Xavier
- Center of Health Sciences, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil.
| | - Stephanie Aniszewski
- Center of Health Sciences, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil.
| | - Mariane Lopez Molina
- Anhanguera Educational College of Rio Grande, Rio Grande, Rio Grande do Sul, Brazil.
| | - Diogo Rizzato Lara
- Department of Cellular and Molecular Biology, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
| | - Karen Jansen
- Center of Health Sciences, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil.
| | | | | | - Manuella Pinto Kaster
- Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil.
| | - Gabriele Ghisleni
- Center of Health Sciences, Catholic University of Pelotas, Pelotas, Rio Grande do Sul, Brazil.
| |
Collapse
|
|
4
|
Ge J, Cao M, Zhang Y, Wu T, Liu J, Pu J, He H, Guo Z, Ju S, Yu J. Inhibiting NLRP3 enhances cellular autophagy induced by outer membrane vesicles from Pseudomonas aeruginosa. Microbiol Spectr 2025; 13:e0181924. [PMID: 39873509 PMCID: PMC11878092 DOI: 10.1128/spectrum.01819-24] [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: 07/23/2024] [Accepted: 12/27/2024] [Indexed: 01/30/2025] Open
Abstract
The bacterium Pseudomonas aeruginosa is able to invade lung epithelial cells and survive intracellularly. During this process, it secretes outer membrane vesicles (OMVs), however, it is currently unclear how OMVs from P. aeruginosa (PA-OMVs) affect lung epithelial cells and their impact on oxidative stress, autophagy, and other physiological activities of lung epithelial cells. In this study, we found that PA-OMVs activated oxidative stress and autophagy in cells. We demonstrated that the NLRP3 (NLR family, pyrin domain containing 3) inhibitor MCC950 can enhance autophagy induced by PA-OMVs. The main function of NLRP3 is related to the body's immune response and inflammation regulation. MCC950 is the most common inhibitor of NLRP3. Additionally, we showed that PA-OMVs not only enhanced the expression of AMP-activated protein kinase, a key regulator of cellular energy homeostasis, and reactive oxygen species, which play a crucial role in cellular signaling and oxidative stress, but also significantly enhanced the expression of NLRP3. Inhibiting the expression of NLRP3 further enhanced the process of PA-OMVs induced autophagy. These results demonstrate that PA-OMVs activate both autophagy and the NLRP3 inflammasome, with NLRP3 suppressing autophagy to a certain extent, hoping to provide broad ideas for the future applications of PA-OMVs.IMPORTANCEThe discovery that lung epithelial cells exposed to outer membrane vesicles from Pseudomonas aeruginosa (PA-OMVs) activate cellular autophagy and induce protective immunity is significant. Specifically, the addition of an NLRP3 inhibitor, MCC950, has been found to decrease NLRP3 targets while simultaneously enhancing the autophagy activity induced by PA-OMVs. This finding unveils a novel theoretical framework for the development of PA-OMVs vaccines, highlighting new targets for enhancing the body's anti-infective responses. By elucidating the mechanisms through which PA-OMVs trigger autophagy and bolster immune defenses, this research opens avenues for innovative vaccine design strategies aimed at combatting infections effectively.
Collapse
Affiliation(s)
- Jing Ge
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
- Medical School of Nantong University, Nantong, China
| | - Min Cao
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
- Medical School of Nantong University, Nantong, China
| | - Yuyao Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
- Medical School of Nantong University, Nantong, China
| | - Tianqi Wu
- Krieger School of Arts and Science, Johns Hopkins University, Baltimore, Maryland, USA
| | - Jiayi Liu
- Institute of Public Health, Nantong University, Nantong, China
| | - Jiang Pu
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Hongye He
- Institute of Public Health, Nantong University, Nantong, China
| | - Zhibin Guo
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Shaoqing Ju
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Juan Yu
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
- Institute of Public Health, Nantong University, Nantong, China
| |
Collapse
|
|
5
|
Redhwan A, Adnan M, Bakhsh HR, Alshammari N, Surti M, Parashar M, Patel M, Patel M, Manjegowda DS, Sharma S. Computational Identification and Functional Analysis of Potentially Pathogenic nsSNPs in the NLRP3 Gene Linked to Alzheimer's Disease. Cell Biochem Biophys 2025; 83:357-375. [PMID: 39167281 DOI: 10.1007/s12013-024-01465-9] [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] [Accepted: 07/25/2024] [Indexed: 08/23/2024]
Abstract
Single Nucleotide Polymorphisms (SNPs) are key in understanding complex diseases. Nonsynonymous single-nucleotide polymorphisms (nsSNPs) occur in protein-coding regions, potentially altering amino acid sequences, protein structure and function. Computational methods are vital for distinguishing deleterious nsSNPs from neutral ones. We investigated the role of NLRP3 gene in neuroinflammation associated with Alzheimer's disease (AD) pathogenesis. A total of 893 missense (nsSNPs) were obtained from the dbSNP database and subjected to rigorous filtering using bioinformatics tools like SIFT, Align GVGD, PolyPhen-2, and PANTHER to identify potentially damaging variants. Of these, 18 nsSNPs were consistently predicted to have deleterious effects across all tools. Notably, 16 of these variants exhibited reduced protein stability, while only 4 were predicted to be buried within the protein structure. Among the identified nsSNPs, rs180177442 (R262L and R262P), rs201875324 (T659I), and rs139814109 (T897M) were classified as high-risk variants due to their significant deleterious impact, probable damaging effects, and association with decreased protein stability. Molecular docking and simulation analyses were conducted utilizing Memantine, a standard drug utilized in AD treatment, to investigate potential interactions with the altered protein structures. Additional clinical and genetic investigations are necessary to elucidate the underlying mechanisms that link NLRP3 polymorphisms with the initiation of AD.
Collapse
Affiliation(s)
- Alya Redhwan
- Department of Health, College of Health and Rehabilitation Sciences, Princess Nourah bint Abdulrahman University, Riyadh, 11671, Saudi Arabia
| | - Mohd Adnan
- Department of Biology, College of Science, University of Ha'il, Ha'il, Saudi Arabia
| | - Hadeel R Bakhsh
- Department of Rehabilitation Sciences, College of Health and Rehabilitation Sciences, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Nawaf Alshammari
- Department of Health, College of Health and Rehabilitation Sciences, Princess Nourah bint Abdulrahman University, Riyadh, 11671, Saudi Arabia
| | - Malvi Surti
- 4Research and Development Cell, Department of Biotechnology, Parul Institute of Applied Sciences, Parul University, Vadodara, Gujarat, India
| | - Mansi Parashar
- 4Research and Development Cell, Department of Biotechnology, Parul Institute of Applied Sciences, Parul University, Vadodara, Gujarat, India
| | - Mirav Patel
- 4Research and Development Cell, Department of Biotechnology, Parul Institute of Applied Sciences, Parul University, Vadodara, Gujarat, India
| | - Mitesh Patel
- 4Research and Development Cell, Department of Biotechnology, Parul Institute of Applied Sciences, Parul University, Vadodara, Gujarat, India
| | - Dinesh Sosalagere Manjegowda
- 4Department of Human Genetics, School of Basic and Applied Sciences, Dayananda Sagar University, Bangalore, 560078, India
| | - Sameer Sharma
- Department of Bioinformatics, BioNome, Bangalore, India.
| |
Collapse
|
|
6
|
Li L, Xu T, Qi X. Balanced regulation of ROS production and inflammasome activation in preventing early development of colorectal cancer. Immunol Rev 2025; 329:e13417. [PMID: 39523732 DOI: 10.1111/imr.13417] [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] [Indexed: 11/16/2024]
Abstract
Reactive oxygen species (ROS) production and inflammasome activation are the key components of the innate immune response to microbial infection and sterile insults. ROS are at the intersection of inflammation and immunity during cancer development. Balanced regulation of ROS production and inflammasome activation serves as the central hub of innate immunity, determining whether a cell will survive or undergo cell death. However, the mechanisms underlying this balanced regulation remain unclear. Mitochondria and NADPH oxidases are the two major sources of ROS production. Recently, NCF4, a component of the NADPH oxidase complex that primarily contributes to ROS generation in phagocytes, was reported to balance ROS production and inflammasome activation in macrophages. The phosphorylation and puncta distribution of NCF4 shifts from the membrane-bound NADPH complex to the perinuclear region, promoting ASC speck formation and inflammasome activation, which triggers downstream IL-18-IFN-γ signaling to prevent the progression of colorectal cancer (CRC). Here, we review ROS signaling and inflammasome activation studies in colitis-associated CRC and propose that NCF4 acts as a ROS sensor that balances ROS production and inflammasome activation. In addition, NCF4 is a susceptibility gene for Crohn's disease (CD) and CRC. We discuss the evidence demonstrating NCF4's crucial role in facilitating cell-cell contact between immune cells and intestinal cells, and mediating the paracrine effects of inflammatory cytokines and ROS. This coordination of the signaling network helps create a robust immune microenvironment that effectively prevents epithelial cell mutagenesis and tumorigenesis during the early stage of colitis-associated CRC.
Collapse
Affiliation(s)
- Longjun Li
- Key Laboratory for Experimental Teratology of the Ministry of Education, Advanced Medical Research Institute, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Tao Xu
- Key Laboratory for Experimental Teratology of the Ministry of Education, Advanced Medical Research Institute, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xiaopeng Qi
- Key Laboratory for Experimental Teratology of the Ministry of Education, Advanced Medical Research Institute, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- State Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Jinan, Shandong, China
| |
Collapse
|
|
7
|
Samanta Moraes Laranjeira R, Eduarda de Albuquerque Borborema M, Milene Dos Santos Barbosa A, Vieira de Barros Arcoverde J, Albertina Dantas de Lima C, de Rezende Duarte A, Guiomar Sales Gomes da Silva B, de Azevêdo Silva J, Santos N. Investigating the influence of inflammasome complex genes on Turner syndrome. Hum Immunol 2024; 85:111164. [PMID: 39447524 DOI: 10.1016/j.humimm.2024.111164] [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: 05/19/2024] [Revised: 10/05/2024] [Accepted: 10/14/2024] [Indexed: 10/26/2024]
Abstract
Turner syndrome (TS) is associated with an increased susceptibility to inflammatory and autoimmune diseases. This study investigates the association between genetic polymorphisms in the IL1B and NLRP3 genes, as well as the expression profiles of IL1B, NLRP3, and NLRP1, and the risk of inflammatory and autoimmune conditions in TS patients compared to healthy controls. The genetic association analysis included 92 TS patients (case) and 146 healthy controls (HC), evaluating IL1B rs16944, NLRP3 rs10754558 and rs4925659 using TaqMan genotyping assays. In addition, mRNA expression levels of IL1B, NLRP3, and NLRP1 were also compared in 17 TS patients and 17 healthy females (control group) using qPCR-based fluorogenic probes. The study found significant associations with the G allele of rs16944 (p = 0.001) and the GG genotype (p = 0.002) in TS patients, though these were not associated with inflammatory disorders in this group., On the other hand, rs4925659 exhibited a significantly higher frequency of the A allele (p = 0.02) and AA genotype (p = 0.0001) in HC, while the A allele and GA genotype were more common in the TS group (p = 0.0001). Expression analysis revealed a downregulation of IL1B and NLRP3 (fold change: FC = -6.78 and -15.73, respectively) and an upregulation of NLRP1 (FC = 21.5) in TS patients compared to HC. These results indicate a differential distribution of IL1B and NLRP3 polymorphisms in TS patients, and suggest that alterations in the expression of IL1B, NLRP3, and NLRP1 may contribute to an inflammatory imbalance in the Turner syndrome.
Collapse
Affiliation(s)
| | - Maria Eduarda de Albuquerque Borborema
- Departamento de Genética, Universidade Federal de Pernambuco, Recife, PE, Brazil; Laboratório de Imunopatologia Keizo Asami - LIKA, Universidade Federal de Pernambuco, Recife, PE, Brazil
| | | | | | | | - Andréa de Rezende Duarte
- Serviço de Genética Médica, Instituto de Medicina Integral Professor Fernando Figueira, Recife, PE, Brazil
| | | | - Jaqueline de Azevêdo Silva
- Departamento de Genética, Universidade Federal de Pernambuco, Recife, PE, Brazil; Laboratório de Imunopatologia Keizo Asami - LIKA, Universidade Federal de Pernambuco, Recife, PE, Brazil
| | - Neide Santos
- Departamento de Genética, Universidade Federal de Pernambuco, Recife, PE, Brazil
| |
Collapse
|
|
8
|
Muñiz Pedrogo DA, Sears CL, Melia JMP. Colorectal Cancer in Inflammatory Bowel Disease: A Review of the Role of Gut Microbiota and Bacterial Biofilms in Disease Pathogenesis. J Crohns Colitis 2024; 18:1713-1725. [PMID: 38703073 DOI: 10.1093/ecco-jcc/jjae061] [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: 11/17/2023] [Revised: 01/31/2024] [Accepted: 05/03/2024] [Indexed: 05/06/2024]
Abstract
The risk of colorectal cancer [CRC] is increased in patients with inflammatory bowel disease [IBD], particularly in extensive ulcerative colitis [UC] and Crohn's colitis. Gut microbiota have been implicated in the pathogenesis of CRC via multiple mechanisms, including the release of reactive oxygen species and genotoxins, and induction of inflammation, as well as activation of the immune response. Gut microbiota can enhance their carcinogenic and proinflammatory properties by organising into biofilms, potentially making them more resistant to the host's immune system and to antibiotics. Colonic biofilms have the capacity to invade colonic tissue and accelerate tumorigenesis in tumour-prone models of mice. In the context of IBD, the prevalence of biofilms has been estimated to be up to 95%. Although the relationship between chronic inflammation and molecular mediators that contribute to IBD-associated CRC is well established, the role of gut microbiota and biofilms in this sequence is not fully understood. Because CRC can still arise in the absence of histological inflammation, there is a growing interest in identifying chemopreventive agents against IBD-associated CRC. Commonly used in the treatment of UC, 5-aminosalicylates have antimicrobial and anticarcinogenic properties that might have a role in the chemoprevention of CRC via the inhibition or modulation of carcinogenic gut microbiota and potentially of biofilm formation. Whether biologics and other IBD-targeted therapies can decrease the progression towards dysplasia and CRC, via mechanisms independent of inflammation, is still unknown. Further research is warranted to identify potential new microbial targets in therapy for chemoprevention of dysplasia and CRC in IBD.
Collapse
Affiliation(s)
- David A Muñiz Pedrogo
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Cynthia L Sears
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Joanna M P Melia
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| |
Collapse
|
|
9
|
Miyamoto T, Izawa K, Masui S, Yamazaki A, Yamasaki Y, Matsubayashi T, Shiraki M, Ohnishi H, Yasumura J, Kawabe T, Miyamae T, Matsubara T, Arakawa N, Ishige T, Takizawa T, Shimbo A, Shimizu M, Kimura N, Maeda Y, Maruyama Y, Shigemura T, Furuta J, Sato S, Tanaka H, Izumikawa M, Yamamura M, Hasegawa T, Kaneko H, Nakagishi Y, Nakano N, Iida Y, Nakamura T, Wakiguchi H, Hoshina T, Kawai T, Murakami K, Akizuki S, Morinobu A, Ohmura K, Eguchi K, Sonoda M, Ishimura M, Furuno K, Kashiwado M, Mori M, Kawahata K, Hayama K, Shimoyama K, Sasaki N, Ito T, Umebayashi H, Omori T, Nakamichi S, Dohmoto T, Hasegawa Y, Kawashima H, Watanabe S, Taguchi Y, Nakaseko H, Iwata N, Kohno H, Ando T, Ito Y, Kataoka Y, Saeki T, Kaneko U, Murase A, Hattori S, Nozawa T, Nishimura K, Nakano R, Watanabe M, Yashiro M, Nakamura T, Komai T, Kato K, Honda Y, Hiejima E, Yonezawa A, Bessho K, Okada S, Ohara O, Takita J, Yasumi T, Nishikomori R. Clinical Characteristics of Cryopyrin-Associated Periodic Syndrome and Long-Term Real-World Efficacy and Tolerability of Canakinumab in Japan: Results of a Nationwide Survey. Arthritis Rheumatol 2024; 76:949-962. [PMID: 38268504 DOI: 10.1002/art.42808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 01/09/2024] [Accepted: 01/22/2024] [Indexed: 01/26/2024]
Abstract
OBJECTIVE We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. METHODS Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. RESULTS A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)-unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti-tumor necrosis factor-α agents was effective for IBD- and CAPS-associated symptoms not resolved by canakinumab monotherapy. CONCLUSION This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti-IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Tomoyo Matsubara
- Dokkyo Medical University Saitama Medical Center, Saitama, Japan
| | | | | | | | - Asami Shimbo
- Tokyo Medical and Dental University, Tokyo, Japan
| | | | - Naoki Kimura
- Tokyo Medical and Dental University, Tokyo, Japan
| | | | | | | | | | - Satoshi Sato
- Saitama Children's Medical Center, Saitama, Japan
| | | | | | | | | | - Hiroshi Kaneko
- National Center for Global Health and Medicine, Tokyo, Japan
| | | | - Naoko Nakano
- Ehime Prefectural Central Hospital, Matsuyama, Japan
| | | | | | | | - Takayuki Hoshina
- University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Toshinao Kawai
- National Center for Child Health and Development, Tokyo, Japan
| | | | | | | | | | | | | | | | | | | | - Masaaki Mori
- Tokyo Medical and Dental University, Tokyo, Japan, and St. Marianna University School of Medicine, Kawasaki, Japan
| | | | | | | | - Natsuko Sasaki
- University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Taisuke Ito
- Hamamatsu University School of Medicine, Hamamatsu, Japan
| | | | - Tae Omori
- Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
| | | | | | | | | | | | - Yuichiro Taguchi
- Department of Rheumatology, Nagoya Ekisaikai Hospital, Nagoya, Japan
| | | | - Naomi Iwata
- Aichi Children's Health and Medical Center, Obu, Japan
| | - Hiroki Kohno
- Tokyo Women's Medical University Hospital, Tokyo, Japan
| | | | - Yasuhiko Ito
- Nagoya City University West Medical Center, Nagoya, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Osamu Ohara
- Kazusa DNA Research Institute, Kisarazu, Japan
| | | | | | | |
Collapse
|
|
10
|
Li X, Ji LJ, Feng KD, Huang H, Liang MR, Cheng SJ, Meng XD. Emerging role of exosomes in ulcerative colitis: Targeting NOD-like receptor family pyrin domain containing 3 inflammasome. World J Gastroenterol 2024; 30:527-541. [PMID: 38463022 PMCID: PMC10921143 DOI: 10.3748/wjg.v30.i6.527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 11/21/2023] [Accepted: 01/09/2024] [Indexed: 02/05/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic recurrent inflammatory bowel disease. Despite ongoing advances in our understanding of UC, its pathogenesis is yet unelucidated, underscoring the urgent need for novel treatment strategies for patients with UC. Exosomes are nanoscale membrane particles that mediate intercellular communication by carrying various bioactive molecules, such as proteins, RNAs, DNA, and metabolites. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a cytosolic tripartite protein complex whose activation induces the maturation and secretion of proinflammatory cytokines interleukin-1β (IL-1β) and IL-18, triggering the inflammatory response to a pathogenic agent or injury. Growing evidence suggests that exosomes are new modulators of the NLRP3 inflammasome, with vital roles in the pathological process of UC. Here, recent evidence is reviewed on the role of exosomes and NLRP3 inflammasome in UC. First, the dual role of exosomes on NLRP3 inflammasome and the effect of NLRP3 inflammasome on exosome secretion are summarized. Finally, an outlook on the directions of exosome-NLRP3 inflammasome crosstalk research in the context of UC is proposed and areas of further research on this topic are highlighted.
Collapse
Affiliation(s)
- Xin Li
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou Province, China
| | - Li-Jiang Ji
- Department of Anorectal Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu 215500, Jiangsu Province, China
| | - Kai-Di Feng
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Hua Huang
- Department of Anorectal Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu 215500, Jiangsu Province, China
| | - Mei-Rou Liang
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Shi-Jin Cheng
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xiu-Dong Meng
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou Province, China
| |
Collapse
|
|
11
|
Arrè V, Scialpi R, Centonze M, Giannelli G, Scavo MP, Negro R. The 'speck'-tacular oversight of the NLRP3-pyroptosis pathway on gastrointestinal inflammatory diseases and tumorigenesis. J Biomed Sci 2023; 30:90. [PMID: 37891577 PMCID: PMC10612184 DOI: 10.1186/s12929-023-00983-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 10/23/2023] [Indexed: 10/29/2023] Open
Abstract
The NLRP3 inflammasome is an intracellular sensor and an essential component of the innate immune system involved in danger recognition. An important hallmark of inflammasome activation is the formation of a single supramolecular punctum, known as a speck, per cell, which is the site where the pro-inflammatory cytokines IL-1β and IL-18 are converted into their bioactive form. Speck also provides the platform for gasdermin D protein activation, whose N-terminus domain perforates the plasma membrane, allowing the release of mature cytokines alongside with a highly inflammatory form of cell death, namely pyroptosis. Although controlled NLRP3 inflammasome-pyroptosis pathway activation preserves mucosal immunity homeostasis and contributes to host defense, a prolonged trigger is deleterious and could lead, in genetically predisposed subjects, to the onset of inflammatory bowel disease, including Crohn's disease and ulcerative colitis, as well as to gastrointestinal cancer. Experimental evidence shows that the NLRP3 inflammasome has both protective and pathogenic abilities. In this review we highlight the impact of the NLRP3-pyroptosis axis on the pathophysiology of the gastrointestinal tract at molecular level, focusing on newly discovered features bearing pro- and anti-inflammatory and neoplastic activity, and on targeted therapies tested in preclinical and clinical trials.
Collapse
Affiliation(s)
- Valentina Arrè
- Personalized Medicine Laboratory, National Institute of Gastroenterology "S. de Bellis", IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy
| | - Rosanna Scialpi
- Personalized Medicine Laboratory, National Institute of Gastroenterology "S. de Bellis", IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy
| | - Matteo Centonze
- Personalized Medicine Laboratory, National Institute of Gastroenterology "S. de Bellis", IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology "S. de Bellis", IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy
| | - Maria Principia Scavo
- Personalized Medicine Laboratory, National Institute of Gastroenterology "S. de Bellis", IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy
| | - Roberto Negro
- Personalized Medicine Laboratory, National Institute of Gastroenterology "S. de Bellis", IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy.
| |
Collapse
|
|
12
|
Huang J, Dai M, He M, Bu W, Cao L, Jing J, Cao R, Zhang H, Men K. Treatment of Ulcerative Colitis by Cationic Liposome Delivered NLRP3 siRNA. Int J Nanomedicine 2023; 18:4647-4662. [PMID: 37605735 PMCID: PMC10440093 DOI: 10.2147/ijn.s413149] [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: 04/06/2023] [Accepted: 08/09/2023] [Indexed: 08/23/2023] Open
Abstract
Purpose The abnormal activation of NLRP3 inflammasome is related to the occurrence and development of ulcerative colitis (UC). However, the ideal drug and delivery system remain important factors limiting the targeting of NLRP3 inflammasome in UC therapy. Gene therapy by delivering siRNA is effective in treating various diseases. Therefore, delivering siNLRP3 using an ideal vector for UC treatment is necessary. Materials and Methods Nanoparticles delivering siNLRP3 were developed based on cationic liposome (CLP/siNLRP3). Their ability to inhibit NLRP3 inflammasome activation was monitored using Western blot (WB) and Enzyme-linked Immunosorbent Assay (ELISA). The ASC oligomerization in LPS-primed peritoneal macrophages (PMs) was detected by WB and immunofluorescence. Moreover, we assessed the role of CLP/siNLRP3 on dextran sodium sulfate (DSS)-induced UC by examining NLRP3 levels, pro-inflammatory cytokines expression, and disease-associated index (DAI). Flow cytometry (FCM) was used to detect the contents of macrophages and T cells. Finally, we assessed the safety of CLP/siNLRP3. Results The prepared CLP was spherical, with a small particle size (94 nm) and low permeability. The CLP could efficiently protect siNLRP3 from degradation and then deliver siNLRP3 into PMs, inhibiting NLRP3 inflammasome activation. Also, the CLP/siNLRP3 could inhibit the secretion of mature IL-1β and IL-18 from PMs, thereby achieving a favorable anti-inflammation effect. In vivo, CLP/siNLRP3 could effectively alleviate intestinal injury in UC mice, which was attributed to down-regulating levels of IL-1β and IL-18, inhibiting infiltration of macrophages and other immune cells, and the polarization of M1 macrophages. Finally, pathological testing of tissue sections and blood biochemical tests showed no significant toxic effects of CLP/siNLRP3. Conclusion We introduced a prospective approach for the efficient delivery of siRNA in vitro and in vivo with high safety and stability, which was found to have great potential in treating NLRP3-driven diseases in an RNA-silencing manner.
Collapse
Affiliation(s)
- Jing Huang
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, Henan University, Kaifeng, Henan Province, 475004, People’s Republic of China
| | - Mengmeng Dai
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, Henan University, Kaifeng, Henan Province, 475004, People’s Republic of China
| | - Mingxia He
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, Henan University, Kaifeng, Henan Province, 475004, People’s Republic of China
| | - Weicheng Bu
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, Henan University, Kaifeng, Henan Province, 475004, People’s Republic of China
| | - Liwen Cao
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, Henan University, Kaifeng, Henan Province, 475004, People’s Republic of China
| | - Jing Jing
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, Henan University, Kaifeng, Henan Province, 475004, People’s Republic of China
| | - Run Cao
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, Henan University, Kaifeng, Henan Province, 475004, People’s Republic of China
| | - Hailong Zhang
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital, Henan University, Kaifeng, Henan Province, 475004, People’s Republic of China
| | - Ke Men
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610044, People’s Republic of China
| |
Collapse
|
|
13
|
Liu M, Wang Z, Liu X, Xiao H, Liu Y, Wang J, Chen C, Wang X, Liu W, Xiang Z, Yue D. Therapeutic effect of Yiyi Fuzi Baijiang formula on TNBS-induced ulcerative colitis via metabolism and Th17/Treg cell balance. JOURNAL OF ETHNOPHARMACOLOGY 2023; 309:116301. [PMID: 36842724 DOI: 10.1016/j.jep.2023.116301] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/14/2023] [Accepted: 02/16/2023] [Indexed: 06/18/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Yiyi Fuzi Baijiang formula (YFB) is a traditional Chinese medicine prescription composed of Coix seed, Radix Aconiti Lateralis and Patrinia villosa, which has been used to treat ulcerative colitis (UC) for thousands of years. AIM OF THE STUDY To investigate the therapeutic effect and metabolic analysis of YFB formula on UC in rats induced by 2,4,6-trinitro-benzene sulfonic acid (TNBS). MATERIALS AND METHODS Six main alkaloids in the YFB formula were determined by UPLC‒MS/MS. The rat UC model was induced by TNBS, and the therapeutic effect of YFB formula on UC was evaluated by disease activity index (DAI) score and hematoxylin-eosin (HE) staining. UPLC-QTRAP-MS metabolomics technology was used to screen potential biomarkers for YFB treatment of UC in combination with multivariate data statistics and further analyze related metabolic pathways. Western blotting was used to detect the protein levels of NLRP1, NLRP3, NLRC4, ASC, pro-caspase1 and Caspase-1 in rat liver tissues. ELISA and immunohistochemistry were used to detect the contents of interleukin (IL)-17A, IL-21, IL-22, IL-6, TNF-α, IL-1β and IL-18 in rat serum and liver tissues. RESULTS The DAI scores of the YFB groups were significantly reduced, and colon tissue injury was significantly improved (p < 0.01). The results of metabolomics analysis revealed 29 potential biomarkers in serum and 27 potential biomarkers in liver. YFB formula can treat UC by affecting glycerophospholipid metabolism, primary bile acid biosynthesis, glyoxylic acid and dicarboxylic acid metabolism, and arginine and proline metabolism. Compared with the model group, the contents of IL-17A, IL-21, IL-22, IL-6, TNF-α, IL-1β and IL-18 in the YFB groups were decreased in a dose-dependent manner (p < 0.01). Compared with those in the model group, the protein levels of NLRP1, NLRP3, NLRC4, ASC, pro-caspase1 and Caspase-1 in the YFB groups were significantly decreased in a dose-dependent manner (p < 0.01). CONCLUSIONS The therapeutic effect of YFB formula on UC rats was dose dependent, and the effect of the YFB (2.046 g/kg) group was close to that of the positive group. YFB formula has an anti-inflammatory effect on UC by regulating the balance of Th17/Treg cells in rats.
Collapse
Affiliation(s)
- Meihua Liu
- School of Pharmaceutical Science, Liaoning University, China
| | - Zhonghua Wang
- Rongtong Agricultural Development (Shenyang) Co., Ltd., China
| | - Xuan Liu
- Dezhou Xiangxuan Pharmaceutical Technology Co., Ltd., China
| | - Hang Xiao
- Basic Medical College, Shenyang Medical College, China
| | - Yangcheng Liu
- School of Pharmaceutical Science, Liaoning University, China
| | - Jiaqi Wang
- School of Pharmaceutical Science, Liaoning University, China
| | - Changlan Chen
- School of Pharmaceutical Science, Liaoning University, China
| | - Xin Wang
- School of Pharmaceutical Science, Liaoning University, China
| | - Wei Liu
- School of Pharmaceutical Science, Liaoning University, China
| | - Zheng Xiang
- School of Pharmaceutical Science, Liaoning University, China.
| | - Dongmei Yue
- Department of Pediatrics, Shengjing Hospital of China Medical University, China.
| |
Collapse
|
|
14
|
Estrogen receptor β activation inhibits colitis by promoting NLRP6-mediated autophagy. Cell Rep 2022; 41:111454. [DOI: 10.1016/j.celrep.2022.111454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 02/24/2022] [Accepted: 09/14/2022] [Indexed: 11/20/2022] Open
|
|
15
|
Xia P, Shao YQ, Yu CC, Xie Y, Zhou ZJ. NLRP3 inflammasome up-regulates major histocompatibility complex class I expression and promotes inflammatory infiltration in polymyositis. BMC Immunol 2022; 23:39. [PMID: 35965334 PMCID: PMC9375941 DOI: 10.1186/s12865-022-00515-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 08/12/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Objective
This study was designed to investigate the role of the nucleotide-binding-domain -and leucine-rich repeat -containing (NLR) family, pyrin-domain-containing 3 (NLRP3) inflammasome in the pathogenesis of polymyositis (PM).
Methods
Immunochemistry was performed to analyze the NLRP3, caspase-1 and interleukin-1 beta (IL-1β) expression in the muscle tissue of PM patients. Rat model of PM and C2C12 cell were used to investigate the potential role of NLRP3 inflammasome in PM.
Results
The percentage of CD 68+ macrophages, and the expression levels of NLRP3, caspase-1 and IL-1β in the muscle tissue were elevated in 27 PM patients. LPS/ATP treatment resulted in activation of NLRP3 inflammasome and secretion of IL-1β as well as interferons (IFNs) and monocyte chemotactic protein-1 (MCP-1) in the Raw 264.7 macrophages. Meanwhile, LPS/ATP challenged activation of NLRP3 inflammasome induced overexpression of major histocompatibility complex class I (MHC-I), a key molecular of PM in the co-cultured C2C12 cells. The effect was decreased by treatment of NLRP3 inflammasome inhibitor MCC950 or siRNA of NLRP3 inflammasome. These findings suggested certain levels of IL-1β rather than IFNs up-regulated MHC-I expression in C2C12 cells. IL-1β blockade using neutralizing IL-1β monoclonal antibody or siRNA of IL-1β suppressed MHC-I overexpression. In vivo, NLRP3 inflammasome inhibition by MCC950 reduced the expression of NLRP3, IL-1β and MHC-I in the muscle tissue of PM modal rats. Also, it attenuated the intensity of muscle inflammation as well as the CRP, CK, and LDH levels in the serum.
Conclusion
NLRP3/caspase-1/IL-1β axis may play an important role in the development of PM. Inhibition of NLRP3 activation may hold promise in the treatment of PM.
Collapse
|
|
16
|
de Graaf DM, Wang RX, Amo-Aparicio J, Lee JS, Dowdell AS, Tengesdal IW, Marchetti C, Colgan SP, Joosten LAB, Dinarello CA. IL-38 Gene Deletion Worsens Murine Colitis. Front Immunol 2022; 13:840719. [PMID: 35693797 PMCID: PMC9181991 DOI: 10.3389/fimmu.2022.840719] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 04/26/2022] [Indexed: 01/22/2023] Open
Abstract
IL-38 is a recently discovered cytokine and member of the IL-1 Family. In the IL-1 Family, IL-38 is unique because the cytokine is primarily a B lymphocyte product and functions to suppress inflammation. Studies in humans with inflammatory bowel disease (IBD) suggest that IL-38 may be protective for ulcerative colitis or Crohn’s disease, and that IL-38 acts to maintain homeostasis in the intestinal tract. Here we investigated the role of endogenous IL-38 in experimental colitis in mice deficient in IL-38 by deletion of exons 1-4 in C57 BL/6 mice. Compared to WT mice, IL-38 deficient mice subjected to dextran sulfate sodium (DSS) showed greater severity of disease, more weight loss, increased intestinal permeability, and a worse histological phenotype including increased neutrophil influx in the colon. Mice lacking IL-38 exhibited elevated colonic Nlrp3 mRNA and protein levels, increased caspase-1 activation, and the concomitant increased processing of IL-1β precursor into active IL-1β. Expression of IL-1α, an exacerbator of IBD, was also upregulated. Colonic myleloperoxidase protein and Il17a, and Il17f mRNA levels were higher in the IL-38 deficient mice. Daily treatment of IL-38 deficient mice with an NLRP3 inhibitor attenuated diarrhea and weight loss during the recovery phase. These data implicate endogenous IL-38 as an anti-inflammatory cytokine that reduces DSS colitis severity. We propose that a relative deficiency of IL-38 contributes to IBD by disinhibition of the NLRP3 inflammasome.
Collapse
Affiliation(s)
- Dennis M. de Graaf
- Department of Medicine, University of Colorado Denver, Aurora, CO, United States
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
- *Correspondence: Dennis M. de Graaf,
| | - Ruth X. Wang
- Mucosal Inflammation Program, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
- Medical Scientist Training Program, University of Colorado School of Medicine, Aurora, CO, United States
| | - Jesús Amo-Aparicio
- Department of Medicine, University of Colorado Denver, Aurora, CO, United States
| | - J. Scott Lee
- Mucosal Inflammation Program, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
| | - Alexander S. Dowdell
- Mucosal Inflammation Program, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
| | - Isak W. Tengesdal
- Department of Medicine, University of Colorado Denver, Aurora, CO, United States
| | - Carlo Marchetti
- Department of Medicine, University of Colorado Denver, Aurora, CO, United States
| | - Sean P. Colgan
- Mucosal Inflammation Program, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
| | - Leo A. B. Joosten
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
- Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Charles A. Dinarello
- Department of Medicine, University of Colorado Denver, Aurora, CO, United States
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| |
Collapse
|
|
17
|
Macrophages and Epithelial Cells Mutually Interact through NLRP3 to Clear Infection and Enhance the Gastrointestinal Barrier. IMMUNO 2021. [DOI: 10.3390/immuno2010002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Activation of the nod-like receptor protein 3 (NLRP3) leads to the release of the proinflammatory cytokine IL-1β, which then facilitates pathogen control by macrophages. The role of NLRPs in controlling infection of epithelial cells is not well understood. Our hypothesis was that activation of the NLRP3 inflammasome in colonic epithelial cells would promote macrophage-mediated epithelial recovery after infection with the pathogen Citrobacter rodentium. We devised a co-culture model using mouse colonic epithelial cells (CMT-93) and macrophages (J774A.1) during infection with C. rodentium. Inflammasome was activated using LPS and ATP and inhibited by YVAD. We assessed cytokine secretion (ELISA), macrophage recruitment and pathogen penetration (immunofluorescence), and epithelial barrier integrity (transepithelial electrical resistance). Macrophages were recruited to the apical membrane of epithelial cells, associated with tight junctions, promoted epithelial barrier recovery, and displaced C. rodentium. While NLRP3 was expressed in infected epithelial cells, IL-18 or IL-1β secretion remained unchanged. Supernatants from infected epithelial cells promoted infection clearance by macrophage; while this was inflammasome-independent, ATP significantly improved epithelial barrier recovery. The inflammasome appears to promote epithelial barrier function, independent of IL-18 and IL-1β secretion. Inflammasome activation in macrophages plays a dual role of promoting pathogen clearance and improving epithelial barrier integrity.
Collapse
|
|
18
|
Role of NLRP3rs10754558 and NOS3rs1799983 genetic polymorphisms in smoking and nonsmoking COPD patients. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
|
|
19
|
Keshavarz Shahbaz S, Koushki K, Ayati SH, Bland AR, Bezsonov EE, Sahebkar A. Inflammasomes and Colorectal Cancer. Cells 2021; 10:2172. [PMID: 34571825 PMCID: PMC8467678 DOI: 10.3390/cells10092172] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/22/2021] [Accepted: 07/29/2021] [Indexed: 02/07/2023] Open
Abstract
Inflammasomes are important intracellular multiprotein signaling complexes that modulate the activation of caspase-1 and induce levels of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 in response to pathogenic microorganisms and molecules that originated from host proteins. Inflammasomes play contradictory roles in the development of inflammation-induced cancers. Based on several findings, inflammasomes can initiate and promote carcinogenesis. On the contrary, inflammasomes also exhibit anticancer effects by triggering pyroptosis and immunoregulatory functions. Herein, we review extant studies delving into different functions of inflammasomes in colorectal cancer development.
Collapse
Affiliation(s)
- Sanaz Keshavarz Shahbaz
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Science, Qazvin 3419759811, Iran;
| | - Khadijeh Koushki
- Department of Immunology, School of Medicine, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran;
| | - Seyed Hassan Ayati
- Immunobiochemistry Lab, Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran;
| | - Abigail R. Bland
- Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand;
| | - Evgeny E. Bezsonov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, 125315 Moscow, Russia;
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad 1313199137, Iran
- School of Medicine, The University of Western Australia, Perth 6009, Australia
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
| |
Collapse
|
|
20
|
Qin Y, Yu Y, Yang C, Wang Z, Yang Y, Wang C, Zheng Q, Li D, Xu W. Atractylenolide I Inhibits NLRP3 Inflammasome Activation in Colitis-Associated Colorectal Cancer via Suppressing Drp1-Mediated Mitochondrial Fission. Front Pharmacol 2021; 12:674340. [PMID: 34335248 PMCID: PMC8320763 DOI: 10.3389/fphar.2021.674340] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 06/18/2021] [Indexed: 01/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an important high-risk factor that promotes the occurrence and development of colon cancer. Research on the mechanism of regulating NLRP3 can provide potential targets for treating NLRP3 inflammasome–related diseases and changing the inflammatory potential of immune cells. In this study, the effects of atractylenolide I on colitis-associated CRC (caCRC) and inflammasome activation were investigated both in vivo and in vitro. Furthermore, the role of atractylenolide I on Drp1-mediated mitochondrial fission was analyzed via Western blotting and transmission electron microscopy (TEM). Moreover, the Drp1 overexpression lentiviral vector was used to study the role of Drp1 on the signaling mechanisms of atractylenolide I. Atractylenolide I treatment significantly reduced the cell viability of human HCT116 and SW480 cells and induced apoptosis, and effectively inhibited colon tumors in the AOM/DSS mouse model. The reduction of NLRP3 inflammasome activation and excessive fission of mitochondria mediated by Drp1 were associated with the administration of atractylenolide I. Upregulation of Drp1 reversed the inhibitory effect of atractylenolide I on the activation of NLRP3 inflammasomes. Overexpressing the Drp1 expression counteracted the restraint of atractylenolide I on the release of IL-1β of LPS/DSS-stimulated BMDMs. Atractylenolide I inhibited NLRP3 and caspase-1 expression in mice BMDMs, with no influence in the Drp1-overexpressed BMDMs. These results demonstrated that atractylenolide I inhibits NLRP3 inflammasome activation in colitis-associated colorectal cancer via suppressing Drp1-mediated mitochondrial fission.
Collapse
Affiliation(s)
- Yao Qin
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| | - Yanwei Yu
- Yantai Hospital of Traditional Chinese Medicine, Yantai, China
| | - Chendong Yang
- Yantai Hospital of Traditional Chinese Medicine, Yantai, China
| | - Zhuien Wang
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| | - Yi Yang
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| | - Chongxu Wang
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| | - Qiusheng Zheng
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| | - Defang Li
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| | - Wenjuan Xu
- School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, China
| |
Collapse
|
|
21
|
Zhang G, Chen H, Guo Y, Zhang W, Jiang Q, Zhang S, Han L, Chen S, Xue R. Activation of Platelet NLRP3 Inflammasome in Crohn's Disease. Front Pharmacol 2021; 12:705325. [PMID: 34262463 PMCID: PMC8273542 DOI: 10.3389/fphar.2021.705325] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 06/11/2021] [Indexed: 01/04/2023] Open
Abstract
Patients with Crohn's disease (CD) are inclined to have platelet hyperactivity and an increased risk of intestinal micro-thrombosis. However, the mechanisms underlying platelet hyperactivity in CD are not well understood. We investigated the assembly of platelet NLRP3 inflammasome in patients with active CD and its correlation with platelet hyperactivity. In this study, Real-time PCR and western blotting analyses uncovered that ASC, NLRP3, and active caspase-1 were significantly upregulated in platelets from patients with active CD compared with healthy subjects. As revealed by flow cytometry (FCM) and ELISA analyses, the levels of interleukin-1β in both serum and isolated platelets were elevated in patients with active CD. Co-immunoprecipitation and immunofluorescence experiments revealed an increased assembly of NLRP3 inflammasome in platelets from patients with active CD. In addition, higher levels of intracellular reactive oxygen species (ROS) were observed in these platelets by FCM. Furthermore, elevated levels of platelet P-selectin exposure and fibrinogen binding were demonstrated in patients with active CD by FCM. They were positively correlated with the protein levels of NLRP3 inflammasome components. Collectively, our results indicate that the ROS-NLRP3 inflammasome-interleukin-1β axis may contribute to platelet hyperactivity in active CD.
Collapse
Affiliation(s)
- Ge Zhang
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - He Chen
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yifan Guo
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei Zhang
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Qiuyu Jiang
- Shanghai Medical College, Fudan University, Shanghai, China
| | - Si Zhang
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Liping Han
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - She Chen
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ruyi Xue
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
22
|
Biological functions of NLRP3 inflammasome: A therapeutic target in inflammatory bowel disease. Cytokine Growth Factor Rev 2021; 60:61-75. [PMID: 33773897 DOI: 10.1016/j.cytogfr.2021.03.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 03/10/2021] [Indexed: 12/15/2022]
Abstract
Cases of inflammatory bowel disease (IBD), a debilitating intestinal disorder with complex pathological mechanisms, have been increasing in recent years, straining the capacity of healthcare systems. Thus, novel therapeutic targets and innovative agents must be developed. Notably, the NLRP3 inflammasome is upregulated in patients with IBD and/or in animal experimental models. As an innate immune supramolecular assembly, the NLRP3 inflammasome is persistently activated during the pathogenesis of IBD by multiple stimuli. Moreover, this protein complex regulates pro-inflammatory cytokines. Thus, targeting this multiprotein oligomer may offer a feasible way to relieve IBD symptoms and improve clinical outcomes. The mechanisms by which the NLRP3 inflammasome is activated, its role in IBD pathogenesis, and the drugs administered to target this protein complex are reviewed herein. This review establishes that the use of inflammasome-targeting drugs are effective for IBD treatment. Moreover, this review suggests that the value and potential of naturally sourced or derived medicines for IBD treatment must be recognized and appreciated.
Collapse
|
|
23
|
Xu Q, Zhou X, Strober W, Mao L. Inflammasome Regulation: Therapeutic Potential for Inflammatory Bowel Disease. Molecules 2021; 26:molecules26061725. [PMID: 33808793 PMCID: PMC8003415 DOI: 10.3390/molecules26061725] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/16/2021] [Accepted: 03/17/2021] [Indexed: 12/22/2022] Open
Abstract
Inflammasomes are multiprotein complexes formed to regulate the maturation of pro-inflammatory caspases, in response to intracellular or extracellular stimulants. Accumulating studies showed that the inflammasomes are implicated in the pathogenesis of inflammatory bowel disease (IBD), although their activation is not a decisive factor for the development of IBD. Inflammasomes and related cytokines play an important role in the maintenance of gut immune homeostasis, while its overactivation might induce excess immune responses and consequently cause tissue damage in the gut. Emerging studies provide evidence that some genetic abnormalities might induce enhanced NLRP3 inflammasome activation and cause colitis. In these cases, the colonic inflammation can be ameliorated by blocking NLRP3 activation or its downstream cytokine IL-1β. A number of natural products were shown to play a role in preventing colon inflammation in various experimental colitis models. On the other hand, lack of inflammasome function also causes intestinal abnormalities. Thus, an appropriate regulation of inflammasomes might be a promising therapeutic strategy for IBD intervention. This review aims at summarizing the main findings in these studies and provide an outline for further studies that might contribute to our understanding of the role of inflammasomes in the pathogenesis and therapeutic treatment of IBD.
Collapse
Affiliation(s)
- Qiuyun Xu
- Department of Immunology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226019, China; (Q.X.); (X.Z.)
| | - Xiaorong Zhou
- Department of Immunology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226019, China; (Q.X.); (X.Z.)
| | - Warren Strober
- Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Correspondence: (W.S.); (L.M.)
| | - Liming Mao
- Department of Immunology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226019, China; (Q.X.); (X.Z.)
- Basic Medical Research Center, School of Medicine, Nantong University, Nantong 226019, China
- Correspondence: (W.S.); (L.M.)
| |
Collapse
|
|
24
|
Agah E, Nafissi S, Saleh F, Sarraf P, Tafakhori A, Mousavi SV, Saghazadeh A, Sadr M, Sinaei F, Mohebbi B, Mahmoudi M, Shadi H, Rezaei N. Investigating the possible association between NLRP3 gene polymorphisms and myasthenia gravis. Muscle Nerve 2021; 63:730-736. [PMID: 33533549 DOI: 10.1002/mus.27193] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 01/26/2021] [Accepted: 01/31/2021] [Indexed: 01/14/2023]
Abstract
INTRODUCTION In this case-control study, we investigated the association between nucleotide oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) single-nucleotide polymorphisms (SNPs) rs10754558, rs3806265, rs4612666, and rs35829419 and myasthenia gravis (MG). METHODS Samples from MG patients were selected from a previous study conducted in our neuromuscular clinic, which investigated the association between human leukocyte antigen (HLA) class II genes and MG. Genetic data of controls were also available from another study. The NLRP3 SNPs genotyping was performed using the TaqMan method. RESULTS A total of 93 blood samples from eligible Iranian patients with MG and 56 samples from healthy controls were obtained. The NLRP3 rs3806265 "C" allele was significantly more frequent in MG patients (P < .001; odd ratio [OR] = 2.33, 95% confidence interval [CI]: 1.4-4.0) than controls. The "CC" genotype of this SNP was found in 18.27% of patients, but none of the controls (P < .001). The distribution of other SNPs was similar between the groups. DISCUSSION These preliminary results suggest that there might be some associations between the NLRP3 gene polymorphism and MG.
Collapse
Affiliation(s)
- Elmira Agah
- Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.,Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.,NeuroImmunology Research Association (NIRA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Shahriar Nafissi
- Iranian Center for Neurological Research, Department of Neurology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Saleh
- Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.,Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.,NeuroImmunology Research Association (NIRA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Payam Sarraf
- Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Tafakhori
- Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.,NeuroImmunology Research Association (NIRA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Seyed Vahid Mousavi
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.,NeuroImmunology Research Association (NIRA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Amene Saghazadeh
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Maryam Sadr
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Farnaz Sinaei
- Department of Neurology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahareh Mohebbi
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Mahmoudi
- Rheumatology Research Center (RRC), Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamideh Shadi
- Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| |
Collapse
|
|
25
|
Keogh CE, Rude KM, Gareau MG. Role of pattern recognition receptors and the microbiota in neurological disorders. J Physiol 2021; 599:1379-1389. [PMID: 33404072 DOI: 10.1113/jp279771] [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: 09/29/2020] [Accepted: 12/28/2020] [Indexed: 12/12/2022] Open
Abstract
In recent years, the gut microbiota has been increasingly implicated in the development of many extraintestinal disorders, including neurodevelopmental and neurodegenerative disorders. Despite this growing connection, our understanding of the precise mechanisms behind these effects is currently lacking. Pattern recognition receptors (PRRs) are important innate immune proteins expressed on the surface and within the cytoplasm of a multitude of cells, both immune and otherwise, including epithelial, endothelial and neuronal. PRRs comprise four major subfamilies: the Toll-like receptors (TLRs), the nucleotide-binding oligomerization domain leucine rich repeats-containing receptors (NLRs), the retinoic acid inducible gene 1-like receptors and the C-type lectin receptors. Recognition of commensal bacteria by PRRs is critical for maintaining host-microbe interactions and homeostasis, including behaviour. The expression of PRRs on multiple cell types makes them a highly interesting and novel target for regulation of host-microbe signalling, which may lead to gut-brain signalling. Emerging evidence indicates that two of the four known families of PRRs (the NLRs and the TLRs) are involved in the pathogenesis of neurodevelopmental and neurodegenerative disorders via the gut-brain axis. Taken together, increasing evidence supports a role for these PRRs in the development of neurological disorders, including Alzheimer's disease, Parkinson's disease and multiple sclerosis, via the microbiota-gut-brain axis.
Collapse
Affiliation(s)
- Ciara E Keogh
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California, Davis, CA, 95616, USA
| | - Kavi M Rude
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California, Davis, CA, 95616, USA
| | - Mélanie G Gareau
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California, Davis, CA, 95616, USA
| |
Collapse
|
|
26
|
Wagatsuma K, Nakase H. Contradictory Effects of NLRP3 Inflammasome Regulatory Mechanisms in Colitis. Int J Mol Sci 2020; 21:ijms21218145. [PMID: 33143375 PMCID: PMC7662299 DOI: 10.3390/ijms21218145] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 02/08/2023] Open
Abstract
The inflammasome is an intracellular molecular complex, which is mainly involved in innate immunity. Inflammasomes are formed in response to danger signals, associated with infection and injury, and mainly regulate the secretion of interleukin-1β and interleukin-18. Inflammasome dysregulation is known to be associated with various diseases and conditions, and its regulatory mechanisms have become of great interest in recent years. In the colon, inflammasomes have been reported to be associated with autophagy and the microbiota, and their dysregulation contributes to colitis and. However, the detailed role of inflammasomes in inflammatory bowel disease is still under debate because the mechanisms that regulate the inflammasome are complex and the inflammasome components and cytokines show seemingly contradictory multiple effects. Herein, we comprehensively review the literature on inflammasome functioning in the colon and describe the complex interactions of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome components with inflammatory cytokines, autophagy, and the microbiota in experimental colitis models and patients with inflammatory bowel disease.
Collapse
|
|
27
|
Samir P, Malireddi RKS, Kanneganti TD. The PANoptosome: A Deadly Protein Complex Driving Pyroptosis, Apoptosis, and Necroptosis (PANoptosis). Front Cell Infect Microbiol 2020; 10:238. [PMID: 32582562 PMCID: PMC7283380 DOI: 10.3389/fcimb.2020.00238] [Citation(s) in RCA: 305] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 04/24/2020] [Indexed: 01/05/2023] Open
Abstract
Programmed cell death is regulated by evolutionarily conserved pathways that play critical roles in development and the immune response. A newly recognized pathway for proinflammatory programmed cell death called PANoptosis is controlled by a recently identified cytoplasmic multimeric protein complex named the PANoptosome. The PANoptosome can engage, in parallel, three key modes of programmed cell death—pyroptosis, apoptosis, and necroptosis. The PANoptosome components have been implicated in a wide array of human diseases including autoinflammatory diseases, neurodegenerative diseases, cancer, microbial infections, and metabolic diseases. Here, we review putative components of the PANoptosome and present a phylogenetic analysis of their molecular domains and interaction motifs that support complex assembly. We also discuss genetic data that suggest PANoptosis is coordinated by scaffolding and catalytic functions of the complex components and propose mechanistic models for PANoptosome assembly. Overall, this review presents potential mechanisms governing PANoptosis based on evolutionary analysis of the PANoptosome components.
Collapse
Affiliation(s)
- Parimal Samir
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - R K Subbarao Malireddi
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, United States
| | | |
Collapse
|
|
28
|
Oroxindin inhibits macrophage NLRP3 inflammasome activation in DSS-induced ulcerative colitis in mice via suppressing TXNIP-dependent NF-κB pathway. Acta Pharmacol Sin 2020; 41:771-781. [PMID: 31937929 PMCID: PMC7468572 DOI: 10.1038/s41401-019-0335-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 11/18/2019] [Indexed: 12/13/2022]
Abstract
Oroxindin is a flavonoid isolated from the traditional Chinese medicine Huang-Qin, which has shown various pharmacological activities including anti-inflammatory, antitumor, antioxidant, etc. Thus far, the effect of oroxindin on colonic inflammation and the underlying mechanism remain unknown. In this study, we investigated the tissue distribution of oroxindin and its therapeutic effects on ulcerative colitis (UC) as well as the underlying mechanisms. UC model was established in mice by administrating dextran sulfate sodium (DSS) in drinking water for 7 d. We first showed that oroxindin was largely absorbed by the colon as an active ingredient after normal mice received Huang-Qin-Tang, a traditional Chinese medicine decoction. UC mice were then treated with oroxindin (12.5, 25, 50 mg ·kg−1 ·d−1, i.g.) for 10 d. We found that oroxindin treatment greatly suppressed massive macrophages infiltration and attenuated pathological changes in colonic tissue. Furthermore, oroxindin treatment significantly inhibited the generation of IL-1β and IL-18 in the colon via inhibiting the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome formation and activation. In cultured macrophages, LPS induced NLRP3 inflammasome formation and caspase-1 activation, which were suppressed by oroxindin (12.5–50 μM). In LPS-treated macrophages, oroxindin dose-dependently restored the expression of TXNIP protein, leading to suppressing TXNIP-dependent NF-κB activation. In conclusion, these results demonstrate that oroxindin could be absorbed by the colon and attenuate inflammatory responses via inhibiting NLRP3 inflammasome formation and activation, which is related to the inhibitory effect on TXNIP-dependent NF-κB-signaling pathway. Hence, oroxindin has the potential of becoming an effective drug for treating UC.
Collapse
|
|
29
|
Regulatory effects of moxibustion on ubiquitin and NLRP3 proteins in colon of ulcerative colitis rats. JOURNAL OF ACUPUNCTURE AND TUINA SCIENCE 2020. [DOI: 10.1007/s11726-020-1162-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
|
|
30
|
Cambui RAG, do Espírito Santo GF, Fernandes FP, Leal VNC, Galera BB, Fávaro EGP, Rizzo LA, Elias RM, Pontillo A. Double-edged sword of inflammasome genetics in colorectal cancer prognosis. Clin Immunol 2020; 213:108373. [PMID: 32135277 DOI: 10.1016/j.clim.2020.108373] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 11/28/2019] [Accepted: 02/25/2020] [Indexed: 12/12/2022]
Abstract
Inflammation is a colorectal cancer (CRC) hallmark. Inflammasome-dependent cytokines IL-1ß and IL-18 can play a beneficial or detrimental role in tumorigenesis depending on cancer type. Variants in inflammasome genes were associated with tumor development and/or outcome, and have been proposed as potential biomarkers for population screening. In this study, 215 CRC patients followed-up for 10 years were examined for 9 polymorphisms in selected inflammasome genes. Multivariate association analysis and survival analysis were performed to evaluate the association between the polymorphisms and CRC prognosis. Variants associated with lower levels of IL-18 (rs1834481, rs5744256), or with increased activation of inflammasome receptors NLRP1 (rs12150220) and NLRP3 (rs35829419) resulted detrimental to CRC prognosis and may be used as prognostic markers.
Collapse
Affiliation(s)
- Raylane Adrielle Gonçalves Cambui
- Faculdade de Medicina, Universidade Federal de Mato Grosso, Cuiabá, MT, Brazil; Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brazil.
| | | | - Fernanda Pereira Fernandes
- Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brazil
| | | | | | | | | | - Rosa Maria Elias
- Centro Universitário de Várzea Grande, Várzea Grande, MT, Brazil
| | - Alessandra Pontillo
- Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brazil
| |
Collapse
|
|
31
|
Gastrointestinal disorders-induced pain. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2019.100580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
|
|
32
|
Yue B, Luo X, Yu Z, Mani S, Wang Z, Dou W. Inflammatory Bowel Disease: A Potential Result from the Collusion between Gut Microbiota and Mucosal Immune System. Microorganisms 2019; 7:microorganisms7100440. [PMID: 31614539 PMCID: PMC6843348 DOI: 10.3390/microorganisms7100440] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/02/2019] [Accepted: 10/09/2019] [Indexed: 12/11/2022] Open
Abstract
Host health depends on the intestinal homeostasis between the innate/adaptive immune system and the microbiome. Numerous studies suggest that gut microbiota are constantly monitored by the host mucosal immune system, and any slight disturbance in the microbial communities may contribute to intestinal immune disruption and increased susceptibility to inflammatory bowel disease (IBD), a chronic relapsing inflammatory condition of the gastrointestinal tract. Therefore, maintaining intestinal immune homeostasis between microbiota composition and the mucosal immune system is an effective approach to prevent and control IBD. The overall theme of this review is to summarize the research concerning the pathogenesis of IBD, with particular focus on the factors of gut microbiota-mucosal immune interactions in IBD. This is a comprehensive and in-depth report of the crosstalk between gut microbiota and the mucosal immune system in IBD pathogenesis, which may provide insight into the further evaluation of the therapeutic strategies for IBD.
Collapse
Affiliation(s)
- Bei Yue
- Shanghai Key Laboratory of Formulated Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai 201203, China.
| | - Xiaoping Luo
- Shanghai Key Laboratory of Formulated Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai 201203, China.
| | - Zhilun Yu
- Shanghai Key Laboratory of Formulated Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai 201203, China.
| | - Sridhar Mani
- Departments of Medicine and Genetics, Albert Einstein College of Medicine, The Bronx, NY 10461, USA.
| | - Zhengtao Wang
- Shanghai Key Laboratory of Formulated Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai 201203, China.
| | - Wei Dou
- Shanghai Key Laboratory of Formulated Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai 201203, China.
| |
Collapse
|
|
33
|
Tourkochristou E, Aggeletopoulou I, Konstantakis C, Triantos C. Role of NLRP3 inflammasome in inflammatory bowel diseases. World J Gastroenterol 2019; 25:4796-4804. [PMID: 31543674 PMCID: PMC6737309 DOI: 10.3748/wjg.v25.i33.4796] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 07/30/2019] [Accepted: 08/07/2019] [Indexed: 02/06/2023] Open
Abstract
Inflammasomes are multiprotein intracellular complexes which are responsible for the activation of inflammatory responses. Among various subtypes of inflammasomes, NLRP3 has been a subject of intensive investigation. NLRP3 is considered to be a sensor of microbial and other danger signals and plays a crucial role in mucosal immune responses, promoting the maturation of proinflammatory cytokines interleukin 1β (IL-1β) and IL-18. NLRP3 inflammasome has been associated with a variety of inflammatory and autoimmune conditions, including inflammatory bowel diseases (IBD). The role of NLRP3 in IBD is not yet fully elucidated as it seems to demonstrate both pathogenic and protective effects. Studies have shown a relationship between genetic variants and mutations in NLRP3 gene with IBD pathogenesis. A complex interaction between the NLRP3 inflammasome and the mucosal immune response has been reported. Activation of the inflammasome is a key function mediated by the innate immune response and in parallel the signaling through IL-1β and IL-18 is implicated in adaptive immunity. Further research is needed to delineate the precise mechanisms of NLRP3 function in regulating immune responses. Targeting NLRP3 inflammasome and its downstream signaling will provide new insights into the development of future therapeutic strategies.
Collapse
Affiliation(s)
- Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Christos Konstantakis
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| |
Collapse
|
|
34
|
Wu MF, Shu CC, Wang JY, Yan BS, Lai HC, Chiang BL, Wu LSH, Yu CJ. NLRP3 inflammasome is attenuated in patients with Mycobacterium avium complex lung disease and correlated with decreased interleukin-1β response and host susceptibility. Sci Rep 2019; 9:12534. [PMID: 31467293 PMCID: PMC6715708 DOI: 10.1038/s41598-019-47609-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 06/28/2019] [Indexed: 01/30/2023] Open
Abstract
The incidence of nontuberculous mycobacteria lung disease (NTM-LD) is increasing in patients without human immunodeficiency virus. Mycobacterium avium complex (MAC) is one of the most common pathogenic species. The presence of MAC has a clinical relevance of around 35~42%, indicating the possibility of host susceptibility. Previous studies have shown that interleukin (IL)-1β and IL-1-receptor knock-out mice are susceptible to mycobacterial infections; however, the role of inflammasome-driven interleukin (IL)-1β has not been studied in MAC-LD. We enrolled patients with MAC-LD and healthy controls. Peripheral blood mononuclear cells (PBMCs), monocytes, and monocyte-derived macrophages were stimulated by MAC bacilli. The responses of interleukin(IL)-1β and the expression of inflammasome and toll-like receptors (TLRs) were measured. Single nucleotide polymorphisms (SNPs) were also examined for NLRP3 and TLR2 genes. In the patients with MAC-LD, the IL-1β responses decreased in PBMCs, monocytes, and macrophages assayed by MAC bacilli in comparison to the healthy controls. In addition, the level of caspase-1 after stimulation was lower in the MAC-LD group, although the mRNA level of IL-1β was not significantly lower. In surveying the activation of IL-1β, the MAC-LD group had an attenuated mRNA level of NLRP3 but similar levels of AIM2 and ASC compared with the controls. The SNPs rs3806268 and rs34298354 in NLRP3 for females and rs3804100 in TLR2 for males were associated with MAC-LD. In conclusion, our patients with MAC-LD had attenuated IL-1β production, which may have been due to lower activation of the NLRP3-caspase-1 axis. Two SNPs of NLRP3 and one of TLR2 were correlated with MAC-LD, possibly indicating host susceptibility.
Collapse
Affiliation(s)
- Ming-Fang Wu
- Institute of Statistical Sciences, Academia Sinica, Taipei, Taiwan.,Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chin-Chung Shu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jann-Yuan Wang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Bo-Shiun Yan
- Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hsin-Chih Lai
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, and Research Center for Chinese Herbal Medicine and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan
| | - Bor-Luen Chiang
- College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Lawrence Shih-Hsin Wu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
| | - Chong-Jen Yu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. .,College of Medicine, National Taiwan University, Taipei, Taiwan.
| |
Collapse
|
|
35
|
Shao BZ, Wang SL, Pan P, Yao J, Wu K, Li ZS, Bai Y, Linghu EQ. Targeting NLRP3 Inflammasome in Inflammatory Bowel Disease: Putting out the Fire of Inflammation. Inflammation 2019; 42:1147-1159. [PMID: 30937839 DOI: 10.1007/s10753-019-01008-y] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, comprised of ulcerative colitis and Crohn's disease. Among the complicated pathogenic factors of IBD, the overaction of inflammatory and immune reaction serves as an important factor. Inflammasome is a form of innate immunity as well as inflammation. Among all kinds of inflammasomes, the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is the most studied one, and has been revealed to be involved in the pathogenesis and progression of IBD. Here, in this review, the association between the NLRP3 inflammasome and IBD will be discussed. Furthermore, several NLRP3 inflammasome inhibitors which have been demonstrated to be effective in the alleviation of IBD will be described in this review.
Collapse
Affiliation(s)
- Bo-Zong Shao
- Department of Gastroenterology, General Hospital of the Chinese People's Liberation Army, Beijing, China.
| | - Shu-Ling Wang
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China
| | - Peng Pan
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China
| | - Jun Yao
- Department of Gastroenterology, The Second Clinical Medical College, Jinan University, Shenzhen, Guangdong, China
| | - Kai Wu
- Department of Gastroenterology, General Hospital of the Chinese People's Liberation Army, Beijing, China
| | - Zhao-Shen Li
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China.
| | - Yu Bai
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China.
| | - En-Qiang Linghu
- Department of Gastroenterology, General Hospital of the Chinese People's Liberation Army, Beijing, China.
| |
Collapse
|
|
36
|
Liu B, Liu L, Zang A, Song Z, Yang H, Wang Z, Shang Y, Ma T, Zhang Y. Tanshinone IIA inhibits proliferation and induces apoptosis of human nasopharyngeal carcinoma cells via p53-cyclin B1/CDC2. Oncol Lett 2019; 18:3317-3322. [PMID: 31452810 DOI: 10.3892/ol.2019.10658] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2015] [Accepted: 03/21/2019] [Indexed: 12/21/2022] Open
Abstract
Tanshinone IIA exhibits natural antioxidative and antineoplastic activity. However, to the best of our knowledge, the effects of tanshinone IIA on human nasopharyngeal carcinoma cells remains unknown. The present study aimed to investigate whether tanshinone IIA inhibits proliferation and induces apoptosis of human nasopharyngeal carcinoma cells via p53-cyclin B1/cell division cycle gene 2 (CDC2). Cell proliferation, cytotoxicity and apoptosis of 13-9B cells were evaluated by an MTT assay, lactate dehydrogenase assay and flow cytometry, respectively. ELISA and western blot analysis were used to analyze caspase-3 activity and poly (ADP-ribose) polymerase (PARP), p53, cyclin B1 and CDC2 protein expression in 13-9B cells. Treatment of 13-9B cells with tanshinone IIA significantly suppressed cell proliferation and significantly induced cytotoxicity and apoptosis of 13-9B cells. Furthermore, tanshinone IIA significantly increased caspase-3 activity, and significantly increased the protein expression levels of PARP, p53, cyclin B1 and CDC2 in 13-9B cells. In summary, the current results indicate that tanshinone IIA inhibits proliferation and induces apoptosis of human nasopharyngeal carcinoma cells via PARP, p53, cyclin B1/CDC2 and caspase-3-mediated signaling.
Collapse
Affiliation(s)
- Bin Liu
- Department of Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| | - Lixia Liu
- Department of Functions Branch, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| | - Aimin Zang
- Department of Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| | - Zizheng Song
- Department of Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| | - Hua Yang
- Department of Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| | - Zhiyu Wang
- Department of Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| | - Yanhong Shang
- Department of Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| | - Tao Ma
- Department of Surgery, Baoding No.1 Central Hospital, Baoding, Hebei 071000, P.R. China
| | - Yonggang Zhang
- Department of Surgery, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| |
Collapse
|
|
37
|
Associations of a NLRP3 rs10754558 Polymorphism with Helicobacter pylori-Infected Patients with Gastritis and Peptic Ulcer Disease. Jundishapur J Microbiol 2019. [DOI: 10.5812/jjm.88231] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
|
|
38
|
Abstract
NLRP3 inflammasome can be widely found in epithelial cells and immune cells. The NOD-like receptors (NLRs) family member NLRP3 contains a central nucleotide-binding and oligomerization (NACHT) domain which facilitates self-oligomerization and has ATPase activity. The C-terminal conserves a leucine-rich repeats (LRRs) domain which can modulate NLRP3 activity and sense endogenous alarmins and microbial ligands. In contrast, the N-terminal pyrin domain (PYD) can account for homotypic interactions with the adaptor protein-ASC of NLRP3 inflammasome. These characters enable it function in innate immunity. Its downstream effector proteins include caspase-1 and IL-1β etc. which exhibit protective or detrimental roles in mucosal immunity in different studies. Here, we comprehensively review the current literature regarding the physiology of NLRP3 inflammasome and its potential roles in the pathogenesis of IBD. We also discuss about the complex interactions among the NLRP3 inflammasome, mucosal immune response, and gut homeostasis as found in experimental models and IBD patients.
Collapse
Affiliation(s)
- Yu Zhen
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- The Centre of Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- The Centre of Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
39
|
Bai Y, Liu Y, Jin S, Su K, Zhang H, Ma S. Expression of microRNA‑27a in a rat model of osteonecrosis of the femoral head and its association with TGF‑β/Smad7 signalling in osteoblasts. Int J Mol Med 2018; 43:850-860. [PMID: 30535438 PMCID: PMC6317694 DOI: 10.3892/ijmm.2018.4007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 10/22/2018] [Indexed: 12/16/2022] Open
Abstract
The present study assessed whether microRNA (miR)-27a is an influential factor in steroid-induced osteonecrosis of the femoral head (ONFH) and investigated the underlying mechanism of action. The results indicated that serum miR-27a was decreased in a rat model of ONFH compared with that in control rats. It was also observed that increased miR-27a expression promoted osteogenic differentiation and cell proliferation, inhibited caspase-3/9 and B-cell lymphoma-2-associated X protein expression and induced alkaline phosphatase (ALP) activity and bone morphogenetic protein (BMP)-2, runt-related transcription factor (Runx)2 and osteonectin mRNA expression in osteoblastic MC3T3-E1 cells. miR-27a mimics also induced transforming growth factor (TGF)-β and Smad7 protein expression in MC3T3-E1 cells. Furthermore, transfection with TGF-β expression plasmid was able to enhance the effects of miR-27a mimics on osteoblastic differentiation, cell proliferation, ALP activity, BMP-2, Runx2 and osteonectin mRNA expression, and Smad7 protein expression in the MC3T3-E1 cells. Transfection with a TGF-β or Smad7 expression plasmid also enhanced the effects of miR-27a mimics on osteoblastic differentiation, cell proliferation, ALP activity and osteonectin mRNA expression in the MC3T3-E1 cells. Taken together, the results of the present study suggested that the induction of TGF-β/Smad7 signaling in osteoblasts may be a potential mechanism by which miR-27a regulates steroid-induced ONFH.
Collapse
Affiliation(s)
- Yuming Bai
- Second Department of Orthopaedics, Cangzhou Central Hospital, Cangzhou, Hebei 061000, P.R. China
| | - Ying Liu
- Department of Surgery, Cangzhou People's Hospital, Cangzhou, Hebei 061000, P.R. China
| | - Shengli Jin
- Second Department of Orthopaedics, Cangzhou Central Hospital, Cangzhou, Hebei 061000, P.R. China
| | - Ke Su
- Second Department of Orthopaedics, Cangzhou Central Hospital, Cangzhou, Hebei 061000, P.R. China
| | - Haisen Zhang
- Second Department of Orthopaedics, Cangzhou Central Hospital, Cangzhou, Hebei 061000, P.R. China
| | - Shiyun Ma
- Second Department of Orthopaedics, Cangzhou Central Hospital, Cangzhou, Hebei 061000, P.R. China
| |
Collapse
|
|
40
|
Gong Z, Zhao S, Zhou J, Yan J, Wang L, Du X, Li H, Chen Y, Cai W, Wu J. Curcumin alleviates DSS-induced colitis via inhibiting NLRP3 inflammsome activation and IL-1β production. Mol Immunol 2018; 104:11-19. [PMID: 30396035 DOI: 10.1016/j.molimm.2018.09.004] [Citation(s) in RCA: 142] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 09/03/2018] [Accepted: 09/04/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND NLRP3 inflammasome mediates IL-1β maturation, therefore plays a vital role in the development of IBD. Curcumin is known for possessing strong anti-inflammatory property. OBJECTIVE The present study was to investigate the protective effects of curcumin on dextran sulfate sodium (DSS)-induced colitis through inhibiting NLRP3 inflammasome activation and IL-1β production. METHODS LPS-primed macrophages were treated with curcumin prior to DSS triggering NLRP3 inflammasome activation, IL-1β secretion and ASC oligomerization were observed. The mechanisms of curcumin in the inhibition of DSS-induced inflammasome activation were explored. Curcumin or caspase-1/NLRP3 inhibitor was administrated respectively in DSS-induced colitis mouse model. The changes of body weight, disease activity index, colon length were measured. Additionally, mature IL-1β and other inflammatory cytokines, MPO activity and histopathological damage were analyzed for the evaluation of colitis severity. RESULTS NLRP3 inflammasome activation was dramatically inhibited by curcumin in DSS-stimulated macrophages, as evidenced by decreased IL-1β secretion, less caspase-1 activation and ASC specks. Mechanistically, curcumin prevented DSS-induced K+ efflux, intracellular ROS formation and cathepsin B release, three major cellular events mediating NLRP3 inflammasome activation. In DSS-induced colitis, curcumin administration significantly ameliorated colitis symptoms by reducing weight loss, DAI and colon length shortening. Meanwhile, curcumin significantly decreased the expression of multiple inflammatory cytokines (including mature IL-1β, IL-6, MCP-1), MPO activity, caspase-1 activity as well as histopathological damage. Furthermore, blockage of NLRP3 inflammasome activation in vivo with specific NLRP3 inhibitor abrogated the further inhibitory effect of curcumin on DSS-induced colitis. CONCLUSION Curcumin could strongly suppress DSS-induced NLRP3 inflammsome activation and alleviate DSS-induced colitis in mice, thus it may be a promising candidate drug in clinical application for IBD therapy.
Collapse
Affiliation(s)
- Zizhen Gong
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Shengnan Zhao
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Jiefei Zhou
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Junkai Yan
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Lingyu Wang
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Xixi Du
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Hui Li
- Department of Pathology, Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Yingwei Chen
- Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Wei Cai
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
| | - Jin Wu
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
| |
Collapse
|
|
41
|
Han X, Zheng J, Wang Y, Gao Z. miRNA-29a inhibits colon cancer growth by regulation of the PTEN/Akt/GSK3β and Wnt/β-catenin signaling pathways. Oncol Lett 2018; 16:2638-2644. [PMID: 30013659 DOI: 10.3892/ol.2018.8905] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Accepted: 03/19/2018] [Indexed: 12/13/2022] Open
Abstract
In the present study, the effects of microRNA-29a (miRNA-29a) on colon cancer cell viability and the molecular mechanisms underlying the effects were investigated. The expression of miRNA-29a in colon cancer serum samples was notably downregulated, compared with in the normal group. First, miRNA-29a mimic was used to increase the expression of miRNA-29a in HCT-116 cells. Furthermore, upregulation of miRNA-29a suppressed cell viability, increased lactate dehydrogenase levels and apoptosis, and promoted caspase-3/9 activities and B-cell lymphoma 2-associated X protein and phosphatase and tensin homolog (PTEN) protein expression in colon cancer cells. Furthermore, upregulation of miRNA-29a decreased phosphoinositide 3-kinase, phosphorylated (p)-protein kinase B (Akt) and p-glycogen synthase kinase 3β (GSK3β) protein expression and suppressed the Wnt/β-catenin signaling pathway in colon cancer cells. The results of the present study verified that the protective effects of miRNA-29a suppress the PTEN/Akt/GSK3β and Wnt/β-catenin signaling pathways in colon cancer.
Collapse
Affiliation(s)
- Xiaofeng Han
- Department of General Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100043, P.R. China
| | - Jianwei Zheng
- Department of General Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100043, P.R. China
| | - Yunlei Wang
- Department of General Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100043, P.R. China
| | - Zhigang Gao
- Department of General Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100043, P.R. China
| |
Collapse
|
|
42
|
Hanaei S, Sadr M, Rezaei A, Shahkarami S, Ebrahimi Daryani N, Bidoki AZ, Rezaei N. Association of NLRP3 single nucleotide polymorphisms with ulcerative colitis: A case-control study. Clin Res Hepatol Gastroenterol 2018; 42:269-275. [PMID: 29102545 DOI: 10.1016/j.clinre.2017.09.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2017] [Revised: 08/30/2017] [Accepted: 09/07/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND Ulcerative colitis (UC) is inflammatory bowel disease (IBD), characterized by chronic inflammation episodes within mucosal layer of the intestine mostly affecting colon and rectum. As the role of innate immunity in pathogenesis of disease and important role of NLRP3, the aim of this study is to investigate the association of NLRP3 SNPs with UC in Iranian patients. METHODS Blood samples from 45 UC patients and 56 healthy subjects were tested for single nucleotide polymorphisms in rs10754558, rs3806265, rs4612666, and rs35829419 of NLRP3 gene, using real-time PCR method. RESULTS Among the investigated SNPs, "GG" genotype of rs10754558 have been 2.48 times more common among UC patients (P=0.04), while "CG" genotype has indicated protective effect against UC, as more frequently found in healthy subjects. CONCLUSION Despite no significant association between three investigated SNPs and disease, "GG" and "CG" genotypes of rs10754558 have been significantly associated with disease.
Collapse
Affiliation(s)
- S Hanaei
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - M Sadr
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - A Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - S Shahkarami
- Department of Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Medical Genetics Network (MeGeNe), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - N Ebrahimi Daryani
- Department of Internal Medicine, Division of Gastroenterology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - A Z Bidoki
- The John Curtin School of Medical Research, Australian National University, Canberra 2601, Australia; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Canberra, Australia
| | - N Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Sheffield, UK.
| |
Collapse
|
|
43
|
Liu J, Tang LY, Wang YG, Lu SY, Zhang EN, Wang ZG, Zhang HX. Identification of MAVS as a Novel Risk Factor for the Development of Osteoarthritis. Aging Dis 2018; 9:40-50. [PMID: 29392080 PMCID: PMC5772857 DOI: 10.14336/ad.2017.0308] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 03/08/2017] [Indexed: 11/03/2022] Open
Abstract
Evidence indicated that inflammatory response and some pattern-recognition receptors play important roles in the occurrence and progression of osteoarthritis. This study is conducted to evaluate the role of RIG-I and its adaptor protein MAVS in the pathogenesis of osteoarthritis. Four SNPs in RIG-I gene and four in MAVS gene were genotyped in 1056 Chinese Han population. We also overexpressed MAVS in murine chondrogenic ATDC5 cells and analyzed the cell viability and apoptosis. Rs11795343 (P-allele: 0.063394) in RIG-I, rs17857295 (P-allele: 0.073518) and rs7262903 (P-allele: 0.054052, P-genotype: 0.067930) in MAVS were marginally associated with OA. Rs7269320 (P-allele: 0.014783, P-genotype: 0.03272) in MAVS was significant associated with OA. Further analyses in different genders indicated that rs7262903 (P-allele: 0.017256, P-genotype: 0.045683) and rs7269320 (P-allele: 0.013073, P-genotype: 0.038881) are significantly associated with OA in female group. Haplotype analyses indicated G-C-G (χ2: 4.328, P-value: 0.037503) in rs10813821-rs11795343-rs659527 block of RIG-I, G-C-A-T (χ2: 4.056, P-value: 0.044028) and G-C-C-C (χ2: 14.295, P-value: 0.000158) in rs17857295-rs2326369-rs7262903-rs7269320 block of MAVS were significantly associated with OA. Furthermore, forced expression of MAVS could suppress the viability and promote the apoptosis of ATDC5 chondrogenic cells. In conclusion, this study indicated that RIG-I and MAVS are probably associated with OA in the females of Chinese Han population. And MAVS might be a novel risk factor for OA which may involve in growth of chondrocytes and cartilage homeostasis.
Collapse
Affiliation(s)
- Jie Liu
- 1Shanghai Institute of Orthopaedics and Traumatology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ling-Yun Tang
- 2State Key Laboratory of Medical Genomics, Research center for experimental medicine, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yan-Gui Wang
- 3Department of Clinical Laboratory, Yantaishan Hospital, Yantai, Shandong, 264008, China
| | - Shun-Yuan Lu
- 2State Key Laboratory of Medical Genomics, Research center for experimental medicine, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - En-Ning Zhang
- 4Department of Medical Oncology, Yantaishan Hospital, Yantai, 264000, China
| | - Zhu-Gang Wang
- 2State Key Laboratory of Medical Genomics, Research center for experimental medicine, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Hong-Xin Zhang
- 2State Key Laboratory of Medical Genomics, Research center for experimental medicine, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| |
Collapse
|
|
44
|
Wu D, Wu K, Zhu Q, Xiao W, Shan Q, Yan Z, Wu J, Deng B, Xue Y, Gong W, Lu G, Ding Y. Formononetin Administration Ameliorates Dextran Sulfate Sodium-Induced Acute Colitis by Inhibiting NLRP3 Inflammasome Signaling Pathway. Mediators Inflamm 2018; 2018:3048532. [PMID: 29507526 PMCID: PMC5817291 DOI: 10.1155/2018/3048532] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 09/29/2017] [Accepted: 10/22/2017] [Indexed: 02/05/2023] Open
Abstract
Formononetin is a kind of isoflavone compound and has been reported to possess anti-inflammatory properties. In this present study, we aimed to explore the protective effects of formononetin on dextran sulfate sodium- (DSS-) induced acute colitis. By intraperitoneal injection of formononetin in mice, the disease severity of colitis was attenuated in a dose-dependent manner, mainly manifesting as relieved clinical symptoms of colitis, mitigated colonic epithelial cell injury, and upregulations of colonic tight junction proteins levels (ZO-1, claudin-1, and occludin). Meanwhile, our study found that formononetin significantly prevented acute injury of colonic cells induced by TNF-α in vitro, specifically manifesting as the increased expressions of colonic tight junction proteins (ZO-1, claudin-1, and occludin). In addition, the result showed that formononetin could reduce the NLRP3 pathway protein levels (NLRP3, ASC, IL-1β) in vivo and vitro, and MCC950, the NLRP3 specific inhibitor, could alleviate the DSS-induced mice acute colitis. Furthermore, in the foundation of administrating MCC950 to inhibit activation of NLRP3 inflammasome, we failed to observe the protective effects of formononetin on acute colitis in mice. Collectively, our study for the first time confirmed the protective effects of formononetin on DSS-induced acute colitis via inhibiting the NLRP3 inflammasome pathway activation.
Collapse
Affiliation(s)
- Dacheng Wu
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
- Laboratory of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Keyan Wu
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
- Laboratory of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Qingtian Zhu
- Laboratory of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Weiming Xiao
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
- Laboratory of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Qing Shan
- Laboratory of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Zhigang Yan
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
- Laboratory of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Jian Wu
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
- Laboratory of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Bin Deng
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
- Laboratory of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Yan Xue
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
- Laboratory of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Weijuan Gong
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
- Laboratory of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
- Department of Immunology, School of Medicine, Yangzhou University, Yangzhou, China
| | - Guotao Lu
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
- Laboratory of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Yanbing Ding
- Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
- Laboratory of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| |
Collapse
|
|
45
|
da Silva WC, Reis EC, Oshiro TM, Pontillo A. Genetics of Inflammasomes. EXPERIENTIA SUPPLEMENTUM (2012) 2018; 108:321-341. [PMID: 30536178 DOI: 10.1007/978-3-319-89390-7_14] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Mutations in inflammasome genes are responsible for rare monogenic and polygenic autoinflammatory diseases. On the other side, genetic polymorphisms in the same molecules contribute to the development of common multifactorial diseases (i.e., autoimmune diseases, cardiovascular pathologies, cancer). In this chapter we depicted the current knowledge about inflammasome genetics.
Collapse
Affiliation(s)
- Wanessa Cardoso da Silva
- Laboratório de Investigação em Dermatologia e Imunodeficiências, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
- Avenida Dr. Enéas de Carvalho Aguiar, 470 - Instituto de Medicina Tropical (IMT) Prédio 2 - 3° andar, São Paulo, SP, Brasil.
| | - Edione C Reis
- Laboratório de Imunogenética, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brasil
- Avenida Prof. Lineu Prestes, 1730 - 05508-000 Cidade Universitária, São Paulo, SP, Brasil
| | - Telma M Oshiro
- Laboratório de Investigação em Dermatologia e Imunodeficiências, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
- Avenida Dr. Enéas de Carvalho Aguiar, 470 - Instituto de Medicina Tropical (IMT) Prédio 2 - 3° andar, São Paulo, SP, Brasil
| | - Alessandra Pontillo
- Laboratório de Imunogenética, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brasil
- Avenida Prof. Lineu Prestes, 1730 - 05508-000 Cidade Universitária, São Paulo, SP, Brasil
| |
Collapse
|
|
46
|
Yue C, Yang X, Li J, Chen X, Zhao X, Chen Y, Wen Y. Trimethylamine N-oxide prime NLRP3 inflammasome via inhibiting ATG16L1-induced autophagy in colonic epithelial cells. Biochem Biophys Res Commun 2017. [PMID: 28629999 DOI: 10.1016/j.bbrc.2017.06.075] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Recently, the intricate relationship between Trimethylamine N-oxide (TMAO) and inflammatory bowel disease (IBD) is of growing interest. The NLRP3 inflammasome plays crucial roles in gut homeostasis and determining the severity of inflammation in IBD, however, the precise roles of the NLRP3 inflammasome in IBD are still debated. ATG16L1 mediates the cellular degradative process of autophagy and is considered a critical regulator of inflammation based on its genetic association with IBD. Whether TMAO prime NLRP3 inflammasome via ATG16L1-induced autophagy remains unclear. This study observed the expression of ATG16L1, LC3-II and p62 and activation of NLRP3 inflammasome stimulated by TMAO in fetal human colon cells (FHCs), aiming to elucidate the mechanism by which the TMAO may contribute to colonic epithelial inflammation. Our results demonstrated that TMAO significantly inhibited ATG16L1, LC3-II and p62 expression, and triggered the activated NLRP3 inflammasome and production of ROS in a dose- and time-dependent manner. Furthermore, TMAO-mediated effects were observably reversed by over-expression ATG16L1 and siRNA-mediated knockdown NLRP3.The present results support the hypothesis that TMAO may be involved in the pathogenesis of IBD by impacting ATG16L1-induced autophagy and activating NLRP3 inflammasome, suggesting a potential therapeutic targets for the treatment of IBD and TMAO-associated complications.
Collapse
Affiliation(s)
- Chaochi Yue
- Graduate School of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, China; Department of Traditional Chinese Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Xiangdong Yang
- Chengdu Rectum Faculty Hospital, Chengdu, Sichuan, 610015, China.
| | - Jun Li
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Xiaochao Chen
- Chengdu Rectum Faculty Hospital, Chengdu, Sichuan, 610015, China
| | - Xiangdong Zhao
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Ye Chen
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Yong Wen
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| |
Collapse
|
|
47
|
Yang Z, Cao J, Yang Q, Zhang Y, Han L. NLRP3 p.Q705K and CARD8 p.C10X single nucleotide polymorphisms are not associated with susceptibility to rheumatoid arthritis: a meta-analysis. Int J Rheum Dis 2017; 20:1481-1491. [PMID: 28185410 DOI: 10.1111/1756-185x.13016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Affiliation(s)
- Zhaowen Yang
- Department of Immunology; Shandong University School of Medicine; Ji'nan China
- Department of Rheumatology; Jinan Central Hospital affiliated to Shandong University; Ji'nan China
| | - Jin Cao
- Department of Rheumatology; Provincial Hospital affiliated to Shandong University; Ji'nan China
| | - Qingrui Yang
- Department of Rheumatology; Provincial Hospital affiliated to Shandong University; Ji'nan China
| | - Yuanchao Zhang
- Department of Rheumatology; Provincial Hospital affiliated to Shandong University; Ji'nan China
| | - Lihui Han
- Department of Immunology; Shandong University School of Medicine; Ji'nan China
| |
Collapse
|
|
48
|
Zhao S, Chen H, Wu G, Zhao C. The association of NLRP3 and TNFRSF1A polymorphisms with risk of ankylosing spondylitis and treatment efficacy of etanercept. J Clin Lab Anal 2017; 31. [PMID: 28116820 DOI: 10.1002/jcla.22138] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 12/13/2016] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND To discover how NLRP3 and TNFRSF1A polymorphisms affect the efficacy of traditional medicine and etanercept for ankylosing spondylitis (AS) patients. METHODS Single nucleotide polymorphism (SNP) and haplotype analyses were conducted based on determined NLRP3 and TNFRSF1A among AS patients. We subsequently analyzed the relationship between relevant clinical indexes and polymorphisms of NLRP3 and TNFRSF1A. RESULTS The 4 SNP loci on NLRP3 and 3 SNP loci on TNFRSF1A showed significant linkage disequilibrium, respectively. The T allele of NLRP3 rs4612666 and the T allele of TFRSF1A rs4149570 are both associated with AS (P<.05). The T-A-C-T haplotype of NLRP3 as well as the G-C-C, T-C-C, T-C-T, and T-T-T haplotypes of TFRSF1A are associated with AS (P<.05). The morning stiffness time, BASDAI scoring, and ESR of patients receiving etanercept were significantly higher than those receiving traditional medicine. T allele of NLRP3 rs4612666 had a significantly greater negative impact on the ASAS20 improvement than C allele. Whereas the A allele of NLRP3 rs3806268 had a significantly greater positive impact on the ASAS20 improvement than G allele. There is no significant association between SNP and efficacy of traditional medicine in the treatment of AS. CONCLUSION NLRP3 and TFRSF1A (rs4149570) are associated with AS susceptibility. There is a significant association between NLRP3 polymorphisms and treatment of etanercept.
Collapse
Affiliation(s)
- Shengchun Zhao
- Second Department of Orthopaedics, Yiwu City Central Hospital, Yiwu, Zhejiang, China
| | - Hongwei Chen
- Department of Orthopaedics, Yiwu City Central Hospital, Yiwu, Zhejiang, China
| | - Guolin Wu
- Department of Orthopaedics, Yiwu City Central Hospital, Yiwu, Zhejiang, China
| | - Chen Zhao
- Department of Orthopaedics, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China
| |
Collapse
|
|
49
|
Zhu Z, Yan J, Geng C, Wang D, Li C, Feng S, Wang H. A Polymorphism Within the 3'UTR of NLRP3 is Associated with Susceptibility for Ischemic Stroke in Chinese Population. Cell Mol Neurobiol 2016; 36:981-988. [PMID: 26689701 PMCID: PMC11482513 DOI: 10.1007/s10571-015-0288-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 10/08/2015] [Indexed: 01/10/2023]
Abstract
Stroke was regarded as a severe disorder with high morbidity and high mortality worldwide, ischemic stroke (IS) accounts for 85 to 90 % of new increased stroke cases. Partial mechanisms were elucidated by genetic factors including genomic instability such as single nucleotide polymorphism (SNP). Previous reports demonstrated that inflammation was involved in IS, NLRP3 [nucleotide-binding domain (NOD)-like receptor protein 3], acting as a specific inflammatory gene, however, its function and influence on IS was not well clarified. In this study, a case-control study including 1102 IS patients and 1610 healthy controls was conducted to investigate the association between IS susceptibility with a SNP (rs10754558) in 3'UTR of NLRP3. Logistic regression analysis showed that the heterozygote and the homozygote GG confer a significantly increased risk of CRC after controlling for other covariates (adjusted OR = 1.52, 95 % C.I. 1.19-1.97, P = 0.002; adjusted OR = 2.22, 95 % C.I. 2.18-3.67, P < 0.001, respectively). Carriage of G allele was associated with a greatly increased risk of developing the disease (OR = 1.69, 95 % C.I. 1.31-1.83, P < 0.001). Stratification analysis found that hypertension had interaction with rs10754558 to modulate IS risk. Further in vitro assay revealed that rs10754558 can affect mRNA level of NLRP3, suggesting its possible functional significance. Our data suggested that genetic polymorphisms in NLRP3 may influence IS risk in Chinese population. Replication of our studies in other populations and further functional studies are required for complete comprehension of the roles of NLRP3 polymorphisms in IS risk.
Collapse
Affiliation(s)
- Zhansheng Zhu
- Department of Pathology, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, People's Republic of China
| | - Jing Yan
- Center of Emergency, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221002, Jiangsu, People's Republic of China
| | - Chunsong Geng
- Department of Laboratory, Suzhou Kowloon Hospital Shanghai Jiao Tong University School of Medicine, Suzhou, 215000, Jiangsu, People's Republic of China
| | - Dagang Wang
- Department of Laboratory, Beijing 302 Military Hospital of China, Beijing, 100039, People's Republic of China
| | - Chaoyang Li
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221002, Jiangsu, People's Republic of China
| | - Shuai Feng
- Department of Respiratory Diseases, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221002, Jiangsu, People's Republic of China
| | - Huiping Wang
- Department of Genetics, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, People's Republic of China.
| |
Collapse
|
|
50
|
Lee YH, Bae SC. Association between functional NLRP3 polymorphisms and susceptibility to autoimmune and inflammatory diseases: a meta-analysis. Lupus 2016; 25:1558-1566. [PMID: 27060062 DOI: 10.1177/0961203316644336] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 03/22/2016] [Indexed: 12/26/2022]
Abstract
OBJECTIVE This study determined whether NLRP3 polymorphisms rs35829419 C/A and rs10754558 C/G were associated with autoimmune and inflammatory diseases. METHODS An association between the NLRP3 rs35829419 C/A and rs10754558 C/G polymorphisms and autoimmune and inflammatory diseases was determined by performing a meta-analysis by using (1) allele contrast, (2) recessive, (3) dominant, and (4) co-dominant models. RESULTS Thirty comparative studies involving 8069 patients and 8824 controls were included in the meta-analysis. No association was observed between autoimmune and inflammatory diseases and NLRP3 rs35829419 C allele (OR = 1.020, 95% CI = 0.804-1.295, p = 0.869). Stratification by ethnicity showed no association between the NLRP3 rs35829419 C allele and autoimmune and inflammatory diseases in European, Latin American, and Polynesian populations. Stratification by disease type showed no association between the NLRP3 rs35829419 C allele and gout, SLE, RA, celiac disease, and Crohn's disease. Moreover, no association was observed between autoimmune and inflammatory diseases and the NLRP3 rs10754558 C allele (OR = 1.057, 95% CI = 0.950-1.177, p = 0.310). However, stratification by ethnicity showed an association between the NLRP3 rs10754558 C allele and autoimmune and inflammatory diseases in the Latin American (OR = 1.399, 95% CI = 1.201-1.630, p = 1.6 × 10-6) but not in European and Asian populations. Further, stratification by disease type showed a significant association of the NLRP3 rs10754558 C allele with SLE (OR = 1.465 95% CI = 1.144-1.875, p = 0.002) but not with gout and celiac disease. The same pattern was observed for the NLRP3 rs10754558 C allele in the recessive model. CONCLUSIONS Our results indicated that the NLRP3 rs10754558 C/G polymorphism was associated with susceptibility to SLE and with autoimmune and inflammatory diseases in Latin American individuals.
Collapse
Affiliation(s)
- Y H Lee
- Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - S-C Bae
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
| |
Collapse
|