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Ayoub M, Chmouni YA, Damaa N, Eter A, Medawar H, Ghadieh HE, Bazzi S, Khattar ZA, Azar S, Harb F. Genetic and immunological regulation of gut Microbiota: The Roles of TLRs, CLRs, and key proteins in microbial homeostasis and disease. Gene 2025; 955:149469. [PMID: 40189163 DOI: 10.1016/j.gene.2025.149469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 03/26/2025] [Accepted: 04/01/2025] [Indexed: 04/10/2025]
Abstract
The gut microbiota plays a crucial role in human health, influencing metabolism, immune regulation, and neurological function. This review examines the genetic and immunological mechanisms governing microbiota composition, with a focus on key pattern recognition receptors, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and signaling proteins such as CARD9 and NOD2. We discuss how genetic polymorphisms in these receptors contribute to gut dysbiosis and disease susceptibility, particularly in inflammatory bowel disease (IBD) and neurodegenerative disorders like Parkinson's disease. Additionally, we explore emerging microbiota-targeted therapeutic strategies, including probiotics and precision medicine approaches. By synthesizing recent advancements, this review examines how genetic and immunological mechanisms regulate gut microbiota and influence disease susceptibility, emphasizing key therapeutic implications.
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Affiliation(s)
- Marylyn Ayoub
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al Kurah, P.O. Box 100, Kalhat, Lebanon
| | - Yara Abi Chmouni
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al Kurah, P.O. Box 100, Kalhat, Lebanon
| | - Norman Damaa
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al Kurah, P.O. Box 100, Kalhat, Lebanon
| | - Alaa Eter
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al Kurah, P.O. Box 100, Kalhat, Lebanon
| | - Hilmi Medawar
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al Kurah, P.O. Box 100, Kalhat, Lebanon
| | - Hilda E Ghadieh
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al Kurah, P.O. Box 100, Kalhat, Lebanon
| | - Samer Bazzi
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al Kurah, P.O. Box 100, Kalhat, Lebanon
| | - Ziad Abi Khattar
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al Kurah, P.O. Box 100, Kalhat, Lebanon
| | - Sami Azar
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al Kurah, P.O. Box 100, Kalhat, Lebanon
| | - Frederic Harb
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al Kurah, P.O. Box 100, Kalhat, Lebanon.
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Peng S, Zhao Y, Jiang W, Long Y, Hu T, Li M, Hu J, Shen Y. MAPK signaling mediated intestinal inflammation induced by endoplasmic reticulum stress and NOD2. Mol Cell Biochem 2025; 480:3709-3717. [PMID: 39806198 DOI: 10.1007/s11010-025-05212-3] [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: 08/10/2024] [Accepted: 01/06/2025] [Indexed: 01/16/2025]
Abstract
Endoplasmic reticulum (ER) stress is crucially involved in inflammatory bowel disease (IBD), but the mechanisms remain incompletely understood. This study aimed to elucidate how ER stress promotes inflammation in IBD. ER stress marker Grp78 and NOD2 in colon tissues of Crohn's disease (CD) patients and IBD model mice were detected by immunohistochemical analysis. THP-1 cells were exposed to ER stress and the expression of NOD2 and inflammatory cytokines was detected by PCR. We found that ER stress markers Grp78 and NOD2 were upregulated in intestinal tissues of CD patients and in THP-1 cells exposed to ER stress. ER stress inhibitor reduced Grp78 and NOD2 expression in colitis model mice and alleviated colitis. ER stress inducer cooperated with NOD2 ligand MDP to upregulate TNF-α, IL-8 and IL-1β, and activate MAPK signaling in THP-1 cells. Moreover, inhibitors of MAPK signaling led to the downregulation of IL-1β, IL-8 and TNF-α in THP-1 cells stimulated by ER stress inducer and MDP. In conclusion, ER stress upregulates NOD2 and promotes inflammation in IBD, at least partially due to the activation of MAPK pathway.
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Affiliation(s)
- Siyuan Peng
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Yan Zhao
- Department of Pathology, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Wang Jiang
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Yan Long
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Tian Hu
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Mengling Li
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Jinyue Hu
- Medical Research Center, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China
| | - Yueming Shen
- Department of Digestive Diseases, Changsha Central Hospital Affiliated to University of South China, No.161 Shaoshan Nanlu, Changsha, Hunan, China.
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Shi X, Deng J, Zhang J, Zhao X, Zhao Y, Li L, Gao F, Kuang W, Wang J, Tan X, Li C, Li S, Li C. Long-term prognosis of 47 pediatric patients with Blau syndrome in China. BMC Pediatr 2025; 25:374. [PMID: 40350497 PMCID: PMC12066035 DOI: 10.1186/s12887-025-05584-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 03/11/2025] [Indexed: 05/14/2025] Open
Abstract
OBJECTIVES Blau syndrome (BS) is a rare autoinflammatory disease characterized by a clinical triad of uveitis, dermatitis and arthritis. The aim of our study was to summarize organ involvement, predict disease prognosis and evaluate treatment response. METHODS Clinical data of 47 Chinese children who were diagnosed with Blau syndrome in Beijing Children's hospital, Capital Medical University was retrospectively analyzed. Direct sequencing of NOD2 gene was performed by sanger sequencing. Data were analyzed through SPSS 21.0. A Bayesian network was constructed to integrate prediction algorithms of genetic mutations and clinical manifestations, exploring the complex relationship between genotype and phenotype through R (Version 4.4.1, R Core Development Team). P value < 0.05 was significant. RESULTS The 47 patients included 26 males and 21 females. Median age of disease onset was 13.64 months, ranging from 1 to 51 months. At baseline, incidence of fever, arthritis, rash, dermatitis and uveitis were 34%, 93.6%, 72.3% and 31.9%. Nearly 30% patients (14 patients) presented with characteristic triad. Incidence of vasculitis and interstitial lung disease were 27.7% and 17.0%, respectively. Inflammatory indices (e.g., erythrocyte sedimentation rate and C reactive protein) were above normal range. Twelve different NOD2 mutations were identified. R334Q was associated with arthritis, rash, uveitis and fever, whereas R334W was associated with arthritis, rash and fever. Approximately 95.7% patients (45 patients) were treated with combination of prednisolone and methotrexate and 42.6% patients (20 patients) were treated with tumor necrosis factor inhibitors. At the most recent follow-up visit, 34 patients (72.3%) achieved disease control. Patients treated with TNF-α inhibitors had a higher remission rate. CONCLUSIONS Clinical manifestations of Blau syndrome in this study were various. TNF-α inhibitors were effective in inducing remission rate of Blau syndrome.
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Affiliation(s)
- Xinwei Shi
- Department of Rheumatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Jianghong Deng
- Department of Rheumatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Junmei Zhang
- Department of Rheumatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Xiaozhen Zhao
- Department of Rheumatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Yinan Zhao
- Department of Rheumatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Li Li
- Department of Rheumatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Fengqiao Gao
- Department of Rheumatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Weiying Kuang
- Department of Rheumatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Jiang Wang
- Department of Rheumatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Xiaohua Tan
- Department of Rheumatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Chao Li
- Department of Rheumatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Shipeng Li
- Department of Rheumatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Caifeng Li
- Department of Rheumatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China.
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Zhang C, Han L, Dong K, Zhang Q, Liu Z. Reply to: LRRK2 is not required for lysozyme expression in Paneth cells. Nat Immunol 2024; 25:2040-2042. [PMID: 39379659 DOI: 10.1038/s41590-024-01968-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 08/29/2024] [Indexed: 10/10/2024]
Affiliation(s)
- Chengye Zhang
- Institute of Immunology, School of Basic Medicine, Tsinghua University, Beijing, China
| | - Lizhuang Han
- Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Kemeng Dong
- Institute of Immunology, School of Basic Medicine, Tsinghua University, Beijing, China
| | - Qin Zhang
- Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
| | - Zhihua Liu
- Institute of Immunology, School of Basic Medicine, Tsinghua University, Beijing, China.
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Caruso R, Lo BC, Chen GY, Núñez G. Host-pathobiont interactions in Crohn's disease. Nat Rev Gastroenterol Hepatol 2024:10.1038/s41575-024-00997-y. [PMID: 39448837 DOI: 10.1038/s41575-024-00997-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/23/2024] [Indexed: 10/26/2024]
Abstract
The mammalian intestine is colonized by trillions of microorganisms that are collectively referred to as the gut microbiota. The majority of symbionts have co-evolved with their host in a mutualistic relationship that benefits both. Under certain conditions, such as in Crohn's disease, a subtype of inflammatory bowel disease, some symbionts bloom to cause disease in genetically susceptible hosts. Although the identity and function of disease-causing microorganisms or pathobionts in Crohn's disease remain largely unknown, mounting evidence from animal models suggests that pathobionts triggering Crohn's disease-like colitis inhabit certain niches and penetrate the intestinal tissue to trigger inflammation. In this Review, we discuss the distinct niches occupied by intestinal symbionts and the evidence that pathobionts triggering Crohn's disease live in the mucus layer or near the intestinal epithelium. We also discuss how Crohn's disease-associated mutations in the host disrupt intestinal homeostasis by promoting the penetration and accumulation of pathobionts in the intestinal tissue. Finally, we discuss the potential role of microbiome-based interventions in precision therapeutic strategies for the treatment of Crohn's disease.
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Affiliation(s)
- Roberta Caruso
- Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Bernard C Lo
- Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Grace Y Chen
- Department of Internal Medicine and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Gabriel Núñez
- Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
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Ma C, Haritunians T, Gremida AK, Syal G, Shah J, Yang S, Ramos Del Aguila de Rivers C, Storer CE, Chen L, Mengesha E, Mujukian A, Hanna M, Fleshner P, Binion DG, VanDussen KL, Stappenbeck TS, Head RD, Ciorba MA, McGovern DPB, Liu TC. Ileal Paneth Cell Phenotype is a Cellular Biomarker for Pouch Complications in Ulcerative Colitis. J Crohns Colitis 2024; 18:jjae105. [PMID: 38953127 PMCID: PMC11637519 DOI: 10.1093/ecco-jcc/jjae105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Indexed: 07/03/2024]
Abstract
BACKGROUND & AIMS Biomarkers that integrate genetic and environmental factors and predict outcome in complex immune diseases such as inflammatory bowel disease (IBD; including Crohn's disease [CD] and ulcerative colitis [UC]) are needed. We showed that morphologic patterns of ileal Paneth cells (Paneth cell phenotype [PCP]; a surrogate for PC function) is one such cellular biomarker for CD. Given the shared features between CD and UC, we hypothesized that PCP is also associated with molecular/genetic features and outcome in UC. Because PC density is highest in the ileum, we further hypothesized that PCP predicts outcome in UC subjects who underwent total colectomy and ileal pouch-anal anastomosis (IPAA). METHODS Uninflamed ileal resection margins from UC subjects with colectomy and IPAA were used for PCP and transcriptomic analyses. PCP was defined using defensin 5 immunofluorescence. Genotyping was performed using Immunochip. UC transcriptomic and genotype associations of PCP were incorporated with data from CD subjects to identify common IBD-related pathways and genes that regulate PCP. RESULTS The prevalence of abnormal ileal PCP was 27%, comparable to that seen in CD. Combined analysis of UC and CD subjects showed that abnormal PCP was associated with transcriptomic pathways of secretory granule maturation and polymorphisms in innate immunity genes. Abnormal ileal PCP at the time of colectomy was also associated with pouch complications including de novo CD in the pouch and time to first episode of pouchitis. CONCLUSIONS Ileal PCP is biologically and clinically relevant in UC and can be used as a biomarker in IBD.
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Affiliation(s)
- Changqing Ma
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Talin Haritunians
- F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Anas K Gremida
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Gaurav Syal
- F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Janaki Shah
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Shaohong Yang
- F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | - Chad E Storer
- Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
| | - Ling Chen
- Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA
| | - Emebet Mengesha
- F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Angela Mujukian
- F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Mary Hanna
- F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Phillip Fleshner
- F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - David G Binion
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Kelli L VanDussen
- Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Thaddeus S Stappenbeck
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA
| | - Richard D Head
- Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
| | - Matthew A Ciorba
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Dermot P B McGovern
- F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ta-Chiang Liu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
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Tian K, Jing D, Lan J, Lv M, Wang T. Commensal microbiome and gastrointestinal mucosal immunity: Harmony and conflict with our closest neighbor. Immun Inflamm Dis 2024; 12:e1316. [PMID: 39023417 PMCID: PMC11256888 DOI: 10.1002/iid3.1316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 05/06/2024] [Accepted: 06/03/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUND The gastrointestinal tract contains a wide range of microorganisms that have evolved alongside the immune system of the host. The intestinal mucosa maintains balance within the intestines by utilizing the mucosal immune system, which is controlled by the complex gut mucosal immune network. OBJECTIVE This review aims to comprehensively introduce current knowledge of the gut mucosal immune system, focusing on its interaction with commensal bacteria. RESULTS The gut mucosal immune network includes gut-associated lymphoid tissue, mucosal immune cells, cytokines, and chemokines. The connection between microbiota and the immune system occurs through the engagement of bacterial components with pattern recognition receptors found in the intestinal epithelium and antigen-presenting cells. This interaction leads to the activation of both innate and adaptive immune responses. The interaction between the microbial community and the host is vital for maintaining the balance and health of the host's mucosal system. CONCLUSION The gut mucosal immune network maintains a delicate equilibrium between active immunity, which defends against infections and damaging non-self antigens, and immunological tolerance, which allows for the presence of commensal microbiota and dietary antigens. This balance is crucial for the maintenance of intestinal health and homeostasis. Disturbance of gut homeostasis leads to enduring or severe gastrointestinal ailments, such as colorectal cancer and inflammatory bowel disease. Utilizing these factors can aid in the development of cutting-edge mucosal vaccines that have the ability to elicit strong protective immune responses at the primary sites of pathogen invasion.
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Affiliation(s)
- Kexin Tian
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical SchoolNanjing UniversityNanjingChina
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical SchoolNanjing UniversityNanjingChina
| | - Dehong Jing
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical SchoolNanjing UniversityNanjingChina
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical SchoolNanjing UniversityNanjingChina
| | - Junzhe Lan
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical SchoolNanjing UniversityNanjingChina
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical SchoolNanjing UniversityNanjingChina
| | - Mingming Lv
- Department of BreastWomen's Hospital of Nanjing Medical University, Nanjing Maternity, and Child Health Care HospitalNanjingChina
| | - Tingting Wang
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical SchoolNanjing UniversityNanjingChina
- Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical SchoolNanjing UniversityNanjingChina
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Sundaram B, Tweedell RE, Prasanth Kumar S, Kanneganti TD. The NLR family of innate immune and cell death sensors. Immunity 2024; 57:674-699. [PMID: 38599165 PMCID: PMC11112261 DOI: 10.1016/j.immuni.2024.03.012] [Citation(s) in RCA: 48] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/07/2024] [Accepted: 03/12/2024] [Indexed: 04/12/2024]
Abstract
Nucleotide-binding oligomerization domain (NOD)-like receptors, also known as nucleotide-binding leucine-rich repeat receptors (NLRs), are a family of cytosolic pattern recognition receptors that detect a wide variety of pathogenic and sterile triggers. Activation of specific NLRs initiates pro- or anti-inflammatory signaling cascades and the formation of inflammasomes-multi-protein complexes that induce caspase-1 activation to drive inflammatory cytokine maturation and lytic cell death, pyroptosis. Certain NLRs and inflammasomes act as integral components of larger cell death complexes-PANoptosomes-driving another form of lytic cell death, PANoptosis. Here, we review the current understanding of the evolution, structure, and function of NLRs in health and disease. We discuss the concept of NLR networks and their roles in driving cell death and immunity. An improved mechanistic understanding of NLRs may provide therapeutic strategies applicable across infectious and inflammatory diseases and in cancer.
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Affiliation(s)
- Balamurugan Sundaram
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Rebecca E Tweedell
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
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Zhang J, Luo Y, Wu B, Huang X, Zhao M, Wu N, Miao J, Li J, Zhu L, Wu D, Shen M. Identifying functional dysregulation of NOD2 variant Q902K in patients with Yao syndrome. Arthritis Res Ther 2024; 26:58. [PMID: 38395960 PMCID: PMC10885518 DOI: 10.1186/s13075-024-03286-w] [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: 10/07/2023] [Accepted: 02/09/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND AND OBJECTIVES The study investigated the pathogenesis of Yao syndrome (YAOS), a rare systemic autoinflammatory disease associated with the nucleotide-binding oligomerization domain containing 2 (NOD2) gene variants. METHODS RNA sequencing analyses were used to detect transcriptomic profile changes. Immunoblot and immunohistochemistry were used to examine the NOD2-mediated inflammatory signaling pathways and ELISA was used to detect cytokines. RESULTS Transcriptome analysis of YAOS revealed NOD-like receptor signaling pathway enrichment. Compared with HCs, P-RIP2, p-p65, p-p38, p-ERK, and p-JNK notably increased in PBMCs of a patient with YAOS. P-RIP2, p-p65, and p-p38 elevated in small intestinal mucosa tissues. P-p65 and p-p38 in synovial tissues from YAOS were higher than those in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Serum interleukin (IL)-6 level along with tumor necrosis factor (TNF)-α and IL-6 secreted from PBMCs were markedly higher in patients with YAOS in comparison to healthy controls (HCs). The supernatants of synovial cells from a patient with YAOS showed substantially higher IL-1β and IL-6 levels than those of RA and OA. Canakinumab therapy of a Q902K heterozygous patient with YAOS resulted in notable clinical improvement. CONCLUSION Overproduction of pro-inflammatory cytokines and the hyperactivation of NOD2-mediated signaling pathways were found in the NOD2 variant Q902K patient with YAOS. NOD2-RIP2-MAPK pathway might play a pivotal role in the pathogenesis of YAOS. These results provide new perspectives for targeted therapies in YAOS.
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Affiliation(s)
- Jingyuan Zhang
- Department of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China
| | - Yi Luo
- Department of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China
| | - Bingxuan Wu
- Department of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China
| | - Xin Huang
- Department of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China
| | - Mengzhu Zhao
- Department of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China
| | - Na Wu
- Department of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China
| | - Junke Miao
- Department of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China
| | - Ji Li
- Department of Gastroenterology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Lei Zhu
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.
| | - Di Wu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; State Key Laboratory of Complex Severe and Rare Diseases; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
| | - Min Shen
- Department of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
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Orsini Delgado ML, Gamelas Magalhaes J, Morra R, Cultrone A. Muropeptides and muropeptide transporters impact on host immune response. Gut Microbes 2024; 16:2418412. [PMID: 39439228 PMCID: PMC11509177 DOI: 10.1080/19490976.2024.2418412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 10/04/2024] [Accepted: 10/10/2024] [Indexed: 10/25/2024] Open
Abstract
In bacteria, the cell envelope is the key element surrounding and protecting the bacterial content from mechanical or osmotic damages. It allows the selective interchanges of solutes, ions, cellular debris, and drugs between the cellular compartments and the external environment, thanks to the presence of transmembrane proteins called transporters. The major component of the cell envelope is the peptidoglycan, consisting of long linear glycan strands cross-linked by short peptide stems. During cell growth or under stress conditions, peptidoglycan fragments, the muropeptides, are released by bacteria and recognized by the host Pattern Recognition Receptor, promoting the activation of their innate defense mechanisms. The review sums up the salient aspects of microbiota-host interaction with a focus on the NOD-dependent immune response to bacterial peptidoglycan and on the accountability of muropeptide transporters in the crosstalk with the host and in antibiotic resistance. Furthermore, it retraces the discoveries and applications of microorganisms-derived components such as vaccines or vaccine adjuvants.
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11
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Schumacher MA. The emerging roles of deep crypt secretory cells in colonic physiology. Am J Physiol Gastrointest Liver Physiol 2023; 325:G493-G500. [PMID: 37697924 PMCID: PMC10887841 DOI: 10.1152/ajpgi.00093.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/18/2023] [Accepted: 09/03/2023] [Indexed: 09/13/2023]
Abstract
Deep crypt secretory (DCS) cells are a population of epithelial cells located at the colonic crypt base that share some similarities to Paneth and goblet cells. They were initially defined as c-Kit expressing cells, though subsequent work showed that they are more specifically marked by Reg4 in the murine colon. The best-understood function of DCS cells at present is supporting the stem cell niche by generating Notch and EGF ligands. However, as these cells also express immunoregulatory (e.g., Ccl6) and host defense (e.g., Retnlb) genes, it is likely they have additional functions in maintaining colonic health outside of maintenance of the stem niche. Recent advances in single-cell transcriptomic profiling hint at additional epithelial and immune roles that may exist for these cells and have aided in elucidating their developmental lineage. This review highlights the emerging evidence supporting a crucial role for DCS cells in intestinal physiology, the current understanding of how these cells are regulated, and their potential role(s) in colonic disease.
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Affiliation(s)
- Michael A Schumacher
- Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, California, United States
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, United States
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12
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Zhou RW, Harpaz N, Itzkowitz SH, Parsons RE. Molecular mechanisms in colitis-associated colorectal cancer. Oncogenesis 2023; 12:48. [PMID: 37884500 PMCID: PMC10603140 DOI: 10.1038/s41389-023-00492-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/30/2023] [Accepted: 09/11/2023] [Indexed: 10/28/2023] Open
Abstract
Sustained chronic inflammation of the large intestine leads to tissue damage and repair, which is associated with an increased incidence of colitis-associated colorectal cancer (CAC). The genetic makeup of CAC is somewhat similar to sporadic colorectal carcinoma (sCRC), but there are differences in the sequence and timing of alterations in the carcinogenesis process. Several models have been developed to explain the development of CAC, particularly the "field cancerization" model, which proposes that chronic inflammation accelerates mutagenesis and selects for the clonal expansion of phenotypically normal, pro-tumorigenic cells. In contrast, the "Big Bang" model posits that tumorigenic clones with multiple driver gene mutations emerge spontaneously. The details of CAC tumorigenesis-and how they differ from sCRC-are not yet fully understood. In this Review, we discuss recent genetic, epigenetic, and environmental findings related to CAC pathogenesis in the past five years, with a focus on unbiased, high-resolution genetic profiling of non-dysplastic field cancerization in the context of inflammatory bowel disease (IBD).
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Affiliation(s)
- Royce W Zhou
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Molecular Medicine Program, Internal Medicine Residency Program, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Noam Harpaz
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Steven H Itzkowitz
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Ramon E Parsons
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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13
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Alula KM, Theiss AL. Autophagy in Crohn's Disease: Converging on Dysfunctional Innate Immunity. Cells 2023; 12:1779. [PMID: 37443813 PMCID: PMC10341259 DOI: 10.3390/cells12131779] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/29/2023] [Accepted: 06/30/2023] [Indexed: 07/15/2023] Open
Abstract
Crohn's disease (CD) is a chronic inflammatory bowel disease marked by relapsing, transmural intestinal inflammation driven by innate and adaptive immune responses. Autophagy is a multi-step process that plays a critical role in maintaining cellular homeostasis by degrading intracellular components, such as damaged organelles and invading bacteria. Dysregulation of autophagy in CD is revealed by the identification of several susceptibility genes, including ATG16L1, IRGM, NOD2, LRRK2, ULK1, ATG4, and TCF4, that are involved in autophagy. In this review, the role of altered autophagy in the mucosal innate immune response in the context of CD is discussed, with a specific focus on dendritic cells, macrophages, Paneth cells, and goblet cells. Selective autophagy, such as xenophagy, ERphagy, and mitophagy, that play crucial roles in maintaining intestinal homeostasis in these innate immune cells, are discussed. As our understanding of autophagy in CD pathogenesis evolves, the development of autophagy-targeted therapeutics may benefit subsets of patients harboring impaired autophagy.
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Affiliation(s)
| | - Arianne L. Theiss
- Division of Gastroenterology & Hepatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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14
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Richard N, Savoye G, Leboutte M, Amamou A, Ghosh S, Marion-Letellier R. Crohn’s disease: Why the ileum? World J Gastroenterol 2023; 29:3222-3240. [PMID: 37377591 PMCID: PMC10292140 DOI: 10.3748/wjg.v29.i21.3222] [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: 12/28/2022] [Revised: 01/23/2023] [Accepted: 05/08/2023] [Indexed: 06/01/2023] Open
Abstract
Crohn’s disease (CD) is an inflammatory bowel disease characterized by immune-mediated flares affecting any region of the intestine alternating with remission periods. In CD, the ileum is frequently affected and about one third of patients presents with a pure ileal type. Moreover, the ileal type of CD presents epidemiological specificities like a younger age at onset and often a strong link with smoking and genetic susceptibility genes. Most of these genes are associated with Paneth cell dysfunction, a cell type found in the intestinal crypts of the ileum. Besides, a Western-type diet is associated in epidemiological studies with CD onset and increasing evidence shows that diet can modulate the composition of bile acids and gut microbiota, which in turn modulates the susceptibility of the ileum to inflammation. Thus, the interplay between environmental factors and the histological and anatomical features of the ileum is thought to explain the specific transcriptome profile observed in CD ileitis. Indeed, both immune response and cellular healing processes harbour differences between ileal and non-ileal CD. Taken together, these findings advocate for a dedicated therapeutic approach to managing ileal CD. Currently, interventional pharmacological studies have failed to clearly demonstrate distinct response profiles according to disease site. However, the high rate of stricturing disease in ileal CD requires the identification of new therapeutic targets to significantly change the natural history of this debilitating disease.
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Affiliation(s)
- Nicolas Richard
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- CHU Rouen, Department of Gastroenterology, Rouen University Hospital-Charles Nicolle, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Guillaume Savoye
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- CHU Rouen, Department of Gastroenterology, Rouen University Hospital-Charles Nicolle, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Mathilde Leboutte
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Asma Amamou
- APC Microbiome Ireland, Biosciences Building, University College Cork, Cork T12 YT20, Ireland
| | - Subrata Ghosh
- APC Microbiome Ireland, Biosciences Building, University College Cork, Cork T12 YT20, Ireland
| | - Rachel Marion-Letellier
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
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15
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A Chinese girl of Blau syndrome with renal arteritis and a literature review. Pediatr Rheumatol Online J 2023; 21:23. [PMID: 36915122 PMCID: PMC10010039 DOI: 10.1186/s12969-023-00804-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 02/26/2023] [Indexed: 03/16/2023] Open
Abstract
BACKGROUND Blau syndrome is a rare autoinflammatory disease caused by autosomal dominant mutations in the CARD15/NOD2 gene. Vascular involvement is a rare phenotype in Blau syndrome patients. In this study, we aimed to describe a 20-year- old Chinese girl with Blau syndrome complicated by renal arteritis. In addition, we summarized a literature review of published cases of vascular involvement in patients with Blau syndrome. CASE PRESENTATION We describe a 20-year-old girl who was initially misdiagnosed with juvenile idiopathic arthritis (JIA) almost 15 years prior. In October 2019, she developed renal arteritis at the age of 17 years and was eventually diagnosed with Blau syndrome. A de-novo M513T mutation was found in her gene testing. A review of the literature on patients with Blau syndrome and vasculitis showed that a total of 18 cases were reported in the past 40 years. The vast majority of them were predominantly involved medium and large vessel arteritis. Of the 18 patients included in our literature review, 14 patients had aorto-arteritis, and 4 of them had renal artery involvement. Two patients presented with renal artery stenosis, 1with a sinus of Valsalva aneurysm, and 1 with retinal vasculitis. CONCLUSION A detailed medical history inquiry and a careful physical examination are helpful for the early identification of Blau syndrome, especially for infant onset refractory JIA. Medium-and large-vessel arteritis is a rare clinical manifestation in Blau syndrome patients. Careful examination of the peripheral pulse and measurement of blood pressure at every regular visit may be helpful in the early identification of Blau syndrome-arteritis. Early diagnosis and appropriate treatment may prevent or delay the occurrence of severe symptoms in patients to improve the patient's quality of life.
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16
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Olędzka AJ, Czerwińska ME. Role of Plant-Derived Compounds in the Molecular Pathways Related to Inflammation. Int J Mol Sci 2023; 24:ijms24054666. [PMID: 36902097 PMCID: PMC10003729 DOI: 10.3390/ijms24054666] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/21/2023] [Accepted: 02/23/2023] [Indexed: 03/04/2023] Open
Abstract
Inflammation is the primary response to infection and injury. Its beneficial effect is an immediate resolution of the pathophysiological event. However, sustained production of inflammatory mediators such as reactive oxygen species and cytokines may cause alterations in DNA integrity and lead to malignant cell transformation and cancer. More attention has recently been paid to pyroptosis, which is an inflammatory necrosis that activates inflammasomes and the secretion of cytokines. Taking into consideration that phenolic compounds are widely available in diet and medicinal plants, their role in the prevention and support of the treatment of chronic diseases is apparent. Recently, much attention has been paid to explaining the significance of isolated compounds in the molecular pathways related to inflammation. Therefore, this review aimed to screen reports concerning the molecular mode of action assigned to phenolic compounds. The most representative compounds from the classes of flavonoids, tannins, phenolic acids, and phenolic glycosides were selected for this review. Our attention was focused mainly on nuclear factor-κB (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), and mitogen-activated protein kinase (MAPK) signaling pathways. Literature searching was performed using Scopus, PubMed, and Medline databases. In conclusion, based on the available literature, phenolic compounds regulate NF-κB, Nrf2, and MAPK signaling, which supports their potential role in chronic inflammatory disorders, including osteoarthritis, neurodegenerative diseases, cardiovascular, and pulmonary disorders.
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Affiliation(s)
- Agata J. Olędzka
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Str., 02-097 Warsaw, Poland
- Centre for Preclinical Research, Medical University of Warsaw, 1B Banacha Str., 02-097 Warsaw, Poland
| | - Monika E. Czerwińska
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Str., 02-097 Warsaw, Poland
- Centre for Preclinical Research, Medical University of Warsaw, 1B Banacha Str., 02-097 Warsaw, Poland
- Correspondence: ; Tel.: +48-22-116-61-85
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17
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Secher T, Couturier A, Huot L, Bouscayrol H, Grandjean T, Boulard O, Hot D, Ryffel B, Chamaillard M. A Protective Role of NOD2 on Oxazolone-induced Intestinal Inflammation Through IL-1β-mediated Signalling Pathway. J Crohns Colitis 2023; 17:111-122. [PMID: 35917251 DOI: 10.1093/ecco-jcc/jjac106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND AND AIMS NOD2 has emerged as a critical player in the induction of both Th1 and Th2 responses for potentiation and polarisation of antigen-dependent immunity. Loss-of-function mutations in the NOD2-encoding gene and deregulation of its downstream signalling pathway have been linked to Crohn's disease. Although it is well documented that NOD2 is capable of sensing bacterial muramyl dipeptide, it remains counter-intuitive to link development of overt intestinal inflammation to a loss of bacterial-induced inflammatory response. We hypothesised that a T helper bias could also contribute to an autoimmune-like colitis different from inflammation that is fully fledged by Th1 type cells. METHODS An oedematous bowel wall with a mixed Th1/Th2 response was induced in mice by intrarectal instillation of the haptenating agent oxazolone. Survival and clinical scoring were evaluated. At several time points after instillation, colonic damage was assessed by macroscopic and microscopic observations. To evaluate the involvement of NOD2 in immunochemical phenomena, quantitative polymerase chain reaction [PCR] and flow cytometry analysis were performed. Bone marrow chimera experimentation allowed us to evaluate the role of haematopoietic/non-hematopoietic NOD2-expressing cells. RESULTS Herein, we identified a key regulatory circuit whereby NOD2-mediated sensing of a muramyl dipeptide [MDP] by radio-resistant cells improves colitis with a mixed Th1/Th2 response that is induced by oxazolone. Genetic ablation of either Nod2 or Ripk2 precipitated oxazolone colitis that is predominantly linked to a lack of interferon-gamma. Bone marrow chimera experiments revealed that inactivation of Nod2 signalling in non-haematopoietic cells is causing a biased M1-M2 polarisation of macrophages and a decreased frequency of splenic regulatory T cells that correlates with an impaired activation of CD4 + T cells within mesenteric lymph nodes. Mechanistically, mice were protected from oxazolone-induced colitis upon administration of MDP in an interleukin-1- and interleukin-23-dependent manner. CONCLUSIONS These findings indicate that Nod2 signalling may prevent pathological conversion of T helper cells for maintenance of tissue homeostasis.
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Affiliation(s)
- Thomas Secher
- INEM, Orléans University, CNRS UMR 7355, F-45071, Orléans, France.,CEPR, Tours University, INSERM U1100, F-37000, Tours, France
| | | | - Ludovic Huot
- Centre d'Infection et d'Immunité de Lille, Université de Lille, CNRS, Inserm, CHRU Lille, Institut Pasteur de Lille, U1019-UMR 9017, F-59000, Lille, France
| | - Helene Bouscayrol
- Service d'oncologie-radiothérapie, CHR d'Orléans-La Source, Orléans, France
| | - Teddy Grandjean
- Centre d'Infection et d'Immunité de Lille, Université de Lille, CNRS, Inserm, CHRU Lille, Institut Pasteur de Lille, U1019-UMR 9017, F-59000, Lille, France
| | - Olivier Boulard
- Laboratory of Cell Physiology, Inserm U1003, University of Lille, Lille, France
| | - David Hot
- CEPR, Tours University, INSERM U1100, F-37000, Tours, France.,University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41-UAR 2014-PLBS, F-59000 Lille, France
| | - Bernhard Ryffel
- INEM, Orléans University, CNRS UMR 7355, F-45071, Orléans, France
| | - Mathias Chamaillard
- Laboratory of Cell Physiology, Inserm U1003, University of Lille, Lille, France
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18
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Johnson TO, Akinsanmi AO, Ejembi SA, Adeyemi OE, Oche JR, Johnson GI, Adegboyega AE. Modern drug discovery for inflammatory bowel disease: The role of computational methods. World J Gastroenterol 2023; 29:310-331. [PMID: 36687123 PMCID: PMC9846937 DOI: 10.3748/wjg.v29.i2.310] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 11/02/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) comprising ulcerative colitis, Crohn’s disease and microscopic colitis are characterized by chronic inflammation of the gastrointestinal tract. IBD has spread around the world and is becoming more prevalent at an alarming rate in developing countries whose societies have become more westernized. Cell therapy, intestinal microecology, apheresis therapy, exosome therapy and small molecules are emerging therapeutic options for IBD. Currently, it is thought that low-molecular-mass substances with good oral bio-availability and the ability to permeate the cell membrane to regulate the action of elements of the inflammatory signaling pathway are effective therapeutic options for the treatment of IBD. Several small molecule inhibitors are being developed as a promising alternative for IBD therapy. The use of highly efficient and time-saving techniques, such as computational methods, is still a viable option for the development of these small molecule drugs. The computer-aided (in silico) discovery approach is one drug development technique that has mostly proven efficacy. Computational approaches when combined with traditional drug development methodology dramatically boost the likelihood of drug discovery in a sustainable and cost-effective manner. This review focuses on the modern drug discovery approaches for the design of novel IBD drugs with an emphasis on the role of computational methods. Some computational approaches to IBD genomic studies, target identification, and virtual screening for the discovery of new drugs and in the repurposing of existing drugs are discussed.
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Affiliation(s)
| | | | | | | | - Jane-Rose Oche
- Department of Biochemistry, University of Jos, Jos 930222, Plateau, Nigeria
| | - Grace Inioluwa Johnson
- Faculty of Clinical Sciences, College of Health Sciences, University of Jos, Jos 930222, Plateau, Nigeria
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19
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Dowdell AS, Cartwright IM, Kitzenberg DA, Kostelecky RE, Mahjoob O, Saeedi BJ, Welch N, Glover LE, Colgan SP. Essential role for epithelial HIF-mediated xenophagy in control of Salmonella infection and dissemination. Cell Rep 2022; 40:111409. [PMID: 36170839 PMCID: PMC9553003 DOI: 10.1016/j.celrep.2022.111409] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 06/21/2022] [Accepted: 09/02/2022] [Indexed: 01/18/2023] Open
Abstract
The intestinal mucosa exists in a state of “physiologic hypoxia,” where oxygen tensions are markedly lower than those in other tissues. Intestinal epithelial cells (IECs) have evolved to maintain homeostasis in this austere environment through oxygen-sensitive transcription factors, including hypoxia-inducible factors (HIFs). Using an unbiased chromatin immunoprecipitation (ChIP) screen for HIF-1 targets, we identify autophagy as a major pathway induced by hypoxia in IECs. One important function of autophagy is to defend against intracellular pathogens, termed “xenophagy.” Analysis reveals that HIF is a central regulator of autophagy and that in vitro infection of IECs with Salmonella Typhimurium results in induction of HIF transcriptional activity that tracks with the clearance of intracellular Salmonella. Work in vivo demonstrates that IEC-specific deletion of HIF compromises xenophagy and exacerbates bacterial dissemination. These results reveal that the interaction between hypoxia, HIF, and xenophagy is an essential innate immune component for the control of intracellular pathogens. Dowdell et al. show that hypoxia, through stabilization of HIF-1α, activates autophagy in intestinal epithelial cells (IECs). Further, the model invasive bacterium Salmonella Typhimurium stabilizes HIF in IECs to trigger anti-bacterial autophagy (xenophagy). This mechanism demonstrates an essential mucosal innate immune response for control of invasive pathogens.
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Affiliation(s)
- Alexander S Dowdell
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA; Rocky Mountain Veterans Hospital, Aurora, CO, USA
| | - Ian M Cartwright
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA; Rocky Mountain Veterans Hospital, Aurora, CO, USA
| | - David A Kitzenberg
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Rachael E Kostelecky
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Omemh Mahjoob
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Bejan J Saeedi
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Nichole Welch
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Louise E Glover
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA; School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Sean P Colgan
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA; Rocky Mountain Veterans Hospital, Aurora, CO, USA.
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20
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Spivak I, Fluhr L, Elinav E. Local and systemic effects of microbiome‐derived metabolites. EMBO Rep 2022; 23:e55664. [PMID: 36031866 PMCID: PMC9535759 DOI: 10.15252/embr.202255664] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/10/2022] [Accepted: 08/16/2022] [Indexed: 12/12/2022] Open
Abstract
Commensal microbes form distinct ecosystems within their mammalian hosts, collectively termed microbiomes. These indigenous microbial communities broadly expand the genomic and functional repertoire of their host and contribute to the formation of a “meta‐organism.” Importantly, microbiomes exert numerous biochemical reactions synthesizing or modifying multiple bioactive small molecules termed metabolites, which impact their host's physiology in a variety of contexts. Identifying and understanding molecular mechanisms of metabolite–host interactions, and how their disrupted signaling can contribute to diseases, may enable their therapeutic application, a modality termed “postbiotic” therapy. In this review, we highlight key examples of effects of bioactive microbe‐associated metabolites on local, systemic, and immune environments, and discuss how these may impact mammalian physiology and associated disorders. We outline the challenges and perspectives in understanding the potential activity and function of this plethora of microbially associated small molecules as well as possibilities to harness them toward the promotion of personalized precision therapeutic interventions.
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Affiliation(s)
- Igor Spivak
- Systems Immunology Department Weizmann Institute of Science Rehovot Israel
- Medical Clinic III University Hospital Aachen Aachen Germany
| | - Leviel Fluhr
- Systems Immunology Department Weizmann Institute of Science Rehovot Israel
| | - Eran Elinav
- Systems Immunology Department Weizmann Institute of Science Rehovot Israel
- Microbiome & Cancer Division, DKFZ Heidelberg Germany
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21
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Barreto E Barreto L, Rattes IC, da Costa AV, Gama P. Paneth cells and their multiple functions. Cell Biol Int 2022; 46:701-710. [PMID: 35032139 DOI: 10.1002/cbin.11764] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 12/30/2021] [Accepted: 01/08/2022] [Indexed: 01/08/2023]
Abstract
The small intestine mucosa is lined by specialized cells that form the crypt-villus axis, which expands its surface. Among the six intestinal epithelial cell types, the Paneth cell is located at the base of the crypt, and it contains numerous granules in its cytoplasm, composed of antimicrobial peptides, such as defensins and lysozyme, and growth factors, such as EGF, TGF-alpha, and Wnt ligands. Together, these elements act in the defense against microorganisms, regulation of intestinal microbiota, maintenance, and regulation of stem cell identity. Pathologies that target Paneth cells can disturb such defense activity, but they also affect the maintenance of stem cell niche. In that way, Crohn's disease, necrotizing enterocolitis, and graft-versus-host disease promote a reduction of Paneth cell population, and consequently of secretion of their products into the lumen of the crypts, making the affected organism predisposed to infections and dysbiosis. Additionally, the emergence of new intestinal cells is also decreased. This review aims to address the main characteristics of Paneth cells, highlighting their multiple functions and the importance of their preservation to ensure bowel homeostasis. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Laylla Barreto E Barreto
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Isadora Campos Rattes
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Aline Vasques da Costa
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Patrícia Gama
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil
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22
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Jensen SK, Pærregaard SI, Brandum EP, Jørgensen AS, Hjortø GM, Jensen BAH. OUP accepted manuscript. Gastroenterol Rep (Oxf) 2022; 10:goac008. [PMID: 35291443 PMCID: PMC8915887 DOI: 10.1093/gastro/goac008] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 01/07/2022] [Accepted: 02/16/2022] [Indexed: 11/24/2022] Open
Abstract
Organismal survival depends on a well-balanced immune system and maintenance of host–microbe mutualism. The fine-tuned relationship between the gut microbiota and host immunity is constantly challenged by opportunistic bacteria testing the integrity of gastrointestinal (GI) barrier defenses. Barrier dysfunction reduces immunological tolerance towards otherwise innocuous microbes; it is a process that may instigate chronic inflammation. Paradoxically, sustained inflammation further diminishes barrier function, enabling bacterial translocation to extra-intestinal tissues. Once translocated, these bacteria stimulate systemic inflammation, thereby compromising organ function. While genetic risk alleles associate with barrier dysfunction, environmental stressors are key triggers of GI inflammation and associated breakdown in immune tolerance towards resident gut microbes. As dietary components dictate substrate availability, they also orchestrate microbiota composition and function, including migratory and pro-inflammatory potential, thus holding the capacity to fuel both GI and extra-intestinal inflammation. Additionally, Western diet consumption may weaken barrier defenses via curbed Paneth cell function and diminished host-defense peptide secretion. This review focuses on intervenable niches of host–microbe interactions and mucosal immunity with the ambition to provide a framework of plausible strategies to improve barrier function and regain tolerance in the inflamed mucosa via nutritional intervention.
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Affiliation(s)
- Sune K Jensen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Simone I Pærregaard
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Emma P Brandum
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Astrid S Jørgensen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Gertrud M Hjortø
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Benjamin A H Jensen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Corresponding author. Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, Build. 22.5.39, Copenhagen N 2200, Denmark. Tel: +45-35330188;
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23
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Guo X, Yang X, Li Q, Shen X, Zhong H, Yang Y. The Microbiota in Systemic Lupus Erythematosus: An Update on the Potential Function of Probiotics. Front Pharmacol 2021; 12:759095. [PMID: 34887760 PMCID: PMC8650621 DOI: 10.3389/fphar.2021.759095] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 11/01/2021] [Indexed: 12/18/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a kind of chronic diffuse connective tissue illness characterized by multisystem and multiorgan involvement, repeated recurrence and remission, and the presence of a large pool of autoantibodies in the body. Although the exact cause of SLE is not thoroughly revealed, accumulating evidence has manifested that intake of probiotics alters the composition of the gut microbiome, regulating the immunomodulatory and inflammatory response, which may be linked to the disease pathogenesis. Particularly, documented experiments demonstrated that SLE patients have remarkable changes in gut microbiota compared to healthy controls, indicating that the alteration of microbiota may be implicated in different phases of SLE. In this review, the alteration of microbiota in the development of SLE is summarized, and the mechanism of intestinal microbiota on the progression of immune and inflammatory responses in SLE is also discussed. Due to limited reports on the effects of probiotics supplementation in SLE patients, we emphasize advancements made in the last few years on the function and mechanisms of probiotics in the development of SLE animal models. Besides, we follow through literature to survey whether probiotics supplements can be an adjuvant therapy for comprehensive treatment of SLE. Research has indicated that intake of probiotics alters the composition of the gut microbiome, contributing to prevent the progression of SLE. Adjustment of the gut microbiome through probiotics supplementation seems to alleviate SLE symptoms and their cardiovascular and renal complications in animal models, marking this treatment as a potentially novel approach.
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Affiliation(s)
- Xirui Guo
- Department of Pharmacy, Chengdu Second People's Hospital, Chengdu, China
| | - Xuerong Yang
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Qi Li
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaoyan Shen
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Huiyun Zhong
- Department of Pharmacy, Sichuan Vocational College of Health and Rehabilitation, Zigong, China.,Department of Pharmacy, The First People's Hospital of Zigong, Zigong, China
| | - Yong Yang
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
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24
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Han YM, Gao H, Hua RX, Liang C, Guo YX, Shang HW, Lu X, Xu JD. Paneth cells and intestinal health. Shijie Huaren Xiaohua Zazhi 2021; 29:1362-1372. [DOI: 10.11569/wcjd.v29.i23.1362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Paneth cells (PC) are a group of secretory cells derived from intestinal stem cells (ISC) and colonized in the bottom of the small intestinal crypt. As an important "guardian" of intestinal health, PC can not only secrete a variety of antibacterial peptides and cytokines to regulate intestinal homeostasis and participate in immune responses, but also release growth factors to support the stem cell niche and regulate their proliferation and differentiation. Of particular concern, as a static stem cell pool, PC can acquire a stem cell-like transcriptome after the injury of intestinal tissue so as to promote regeneration and repair the damaged intestinal tissue. Particularly, PC are closely related to a number of diseases that affect intestinal health, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). The research of biological functions of PC may provide ideas for the treatment of these diseases. In summary, the role of PC in maintaining intestinal health should not be underestimated.
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Affiliation(s)
- Yi-Min Han
- 2019 Oral Medicine, Capital Medical University, Beijing 100069, China
| | - Han Gao
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
| | - Rong-Xuan Hua
- 2020 Clinical Medicine of "5+3" Program, Capital Medical University, Beijing 100069, China
| | - Chen Liang
- Clinical Medicine, Capital Medical University, Beijing 100069, China
| | - Yue-Xin Guo
- 2019 Oral Medicine of "5+3" Program, Capital Medical University, Beijing 100069, China
| | - Hong-Wei Shang
- Experimental Teaching Center of Basic Medical Morphology, Capital Medical University, Beijing 100069, China
| | - Xin Lu
- Experimental Teaching Center of Basic Medical Morphology, Capital Medical University, Beijing 100069, China
| | - Jing-Dong Xu
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
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25
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Bastos PAD, Wheeler R, Boneca IG. Uptake, recognition and responses to peptidoglycan in the mammalian host. FEMS Microbiol Rev 2021; 45:5902851. [PMID: 32897324 PMCID: PMC7794044 DOI: 10.1093/femsre/fuaa044] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 09/03/2020] [Indexed: 12/13/2022] Open
Abstract
Microbiota, and the plethora of signalling molecules that they generate, are a major driving force that underlies a striking range of inter-individual physioanatomic and behavioural consequences for the host organism. Among the bacterial effectors, one finds peptidoglycan, the major constituent of the bacterial cell surface. In the steady-state, fragments of peptidoglycan are constitutively liberated from bacterial members of the gut microbiota, cross the gut epithelial barrier and enter the host system. The fate of these peptidoglycan fragments, and the outcome for the host, depends on the molecular nature of the peptidoglycan, as well the cellular profile of the recipient tissue, mechanism of cell entry, the expression of specific processing and recognition mechanisms by the cell, and the local immune context. At the target level, physiological processes modulated by peptidoglycan are extremely diverse, ranging from immune activation to small molecule metabolism, autophagy and apoptosis. In this review, we bring together a fragmented body of literature on the kinetics and dynamics of peptidoglycan interactions with the mammalian host, explaining how peptidoglycan functions as a signalling molecule in the host under physiological conditions, how it disseminates within the host, and the cellular responses to peptidoglycan.
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Affiliation(s)
- Paulo A D Bastos
- Institut Pasteur, Biology and genetics of the bacterial cell wall Unit, 25-28 rue du Docteur Roux, Paris 75724, France; CNRS, UMR 2001 "Microbiologie intégrative et moléculaire", Paris 75015, France.,Université de Paris, Sorbonne Paris Cité, 12 rue de l'Ecole de Médecine, 75006, Paris, France
| | - Richard Wheeler
- Institut Pasteur, Biology and genetics of the bacterial cell wall Unit, 25-28 rue du Docteur Roux, Paris 75724, France; CNRS, UMR 2001 "Microbiologie intégrative et moléculaire", Paris 75015, France.,Tumour Immunology and Immunotherapy, Institut Gustave Roussy, 114 rue Edouard-Vaillant, Villejuif 94800, France; INSERM UMR 1015, Villejuif 94800, France
| | - Ivo G Boneca
- Institut Pasteur, Biology and genetics of the bacterial cell wall Unit, 25-28 rue du Docteur Roux, Paris 75724, France; CNRS, UMR 2001 "Microbiologie intégrative et moléculaire", Paris 75015, France
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26
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Atreya R, Siegmund B. Location is important: differentiation between ileal and colonic Crohn's disease. Nat Rev Gastroenterol Hepatol 2021; 18:544-558. [PMID: 33712743 DOI: 10.1038/s41575-021-00424-6] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/29/2021] [Indexed: 01/31/2023]
Abstract
Crohn's disease can affect any part of the gastrointestinal tract; however, current European and national guidelines worldwide do not differentiate between small-intestinal and colonic Crohn's disease for medical treatment. Data from the past decade provide evidence that ileal Crohn's disease is distinct from colonic Crohn's disease in several intestinal layers. Remarkably, colonic Crohn's disease shows an overlap with regard to disease behaviour with ulcerative colitis, underlining the fact that there is more to inflammatory bowel disease than just Crohn's disease and ulcerative colitis, and that subtypes, possibly defined by location and shared pathophysiology, are also important. This Review provides a structured overview of the differentiation between ileal and colonic Crohn's disease using data in the context of epidemiology, genetics, macroscopic differences such as creeping fat and histological findings, as well as differences in regard to the intestinal barrier including gut microbiota, mucus layer, epithelial cells and infiltrating immune cell populations. We also discuss the translation of these basic findings to the clinic, emphasizing the important role of treatment decisions. Thus, this Review provides a conceptual outlook on a new mechanism-driven classification of Crohn's disease.
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Affiliation(s)
- Raja Atreya
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Britta Siegmund
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
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27
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Hardman CS, Chen YL, Salimi M, Nahler J, Corridoni D, Jagielowicz M, Fonseka CL, Johnson D, Repapi E, Cousins DJ, Barlow JL, McKenzie ANJ, Simmons A, Ogg G. IL-6 effector function of group 2 innate lymphoid cells (ILC2) is NOD2 dependent. Sci Immunol 2021; 6:eabe5084. [PMID: 34021026 PMCID: PMC7611333 DOI: 10.1126/sciimmunol.abe5084] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 02/26/2021] [Accepted: 04/21/2021] [Indexed: 01/24/2023]
Abstract
Cutaneous group 2 innate lymphoid cells (ILC2) are spatially and epigenetically poised to respond to barrier compromise and associated immunological threats. ILC2, lacking rearranged antigen-specific receptors, are primarily activated by damage-associated cytokines and respond with type 2 cytokine production. To investigate ILC2 potential for direct sensing of skin pathogens and allergens, we performed RNA sequencing of ILC2 derived from in vivo challenged human skin or blood. We detected expression of NOD2 and TLR2 by skin and blood ILC2. Stimulation of ILC2 with TLR2 agonist alone not only induced interleukin-5 (IL-5) and IL-13 expression but also elicited IL-6 expression in combination with Staphylococcus aureus muramyl dipeptide (MDP). Heat-killed skin-resident bacteria provoked an IL-6 profile in ILC2 in vitro that was notably impaired in ILC2 derived from patients with nucleotide-binding oligomerization domain-containing protein 2 (NOD2) mutations. In addition, we show that NOD2 signaling can stimulate autophagy in ILC2, which was also impaired in patients with NOD2 mutations. Here, we have identified a role for ILC2 NOD2 signaling in the differential regulation of ILC2-derived IL-6 and have reported a previously unrecognized pathway of direct ILC2 bacterial sensing.
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Affiliation(s)
- Clare S Hardman
- MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Yi-Ling Chen
- MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Maryam Salimi
- MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Janina Nahler
- MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Daniele Corridoni
- MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Marta Jagielowicz
- MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Chathuranga L Fonseka
- MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - David Johnson
- Department of Plastic and Reconstructive Surgery, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, UK
| | - Emmanouela Repapi
- MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, Oxford, UK
| | - David J Cousins
- Department of Infection, Immunity and Inflammation, NIHR Leicester Respiratory Biomedical Research Unit, University of Leicester, Leicester, UK
- MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, London, UK
| | | | | | - Alison Simmons
- MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Graham Ogg
- MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
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28
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Ferguson M, Foley E. Microbial recognition regulates intestinal epithelial growth in homeostasis and disease. FEBS J 2021; 289:3666-3691. [PMID: 33977656 DOI: 10.1111/febs.15910] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 04/06/2021] [Accepted: 04/30/2021] [Indexed: 12/13/2022]
Abstract
The intestine is constantly exposed to a dynamic community of microbes. Intestinal epithelial cells respond to microbes through evolutionarily conserved recognition pathways, such as the immune deficiency (IMD) pathway of Drosophila, the Toll-like receptor (TLR) response of flies and vertebrates, and the vertebrate nucleotide-binding oligomerization domain (NOD) pathway. Microbial recognition pathways are tightly controlled to respond effectively to pathogens, tolerate the microbiome, and limit intestinal disease. In this review, we focus on contributions of different model organisms to our understanding of how epithelial microbe recognition impacts intestinal proliferation and differentiation in homeostasis and disease. In particular, we compare how microbes and subsequent recognition by the intestine influences barrier integrity, intestinal repair and tumorigenesis in Drosophila, zebrafish, mice, and organoids. In addition, we discuss the importance of microbial recognition in homeostatic intestinal growth and discuss how immune pathways directly impact stem cell and crypt dynamics.
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Affiliation(s)
- Meghan Ferguson
- Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.,Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Edan Foley
- Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.,Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
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29
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Nelson A, Stewart CJ, Kennedy NA, Lodge JK, Tremelling M, Probert CS, Parkes M, Mansfield JC, Smith DL, Hold GL, Lees CW, Bridge SH, Lamb CA. The Impact of NOD2 Genetic Variants on the Gut Mycobiota in Crohn's Disease Patients in Remission and in Individuals Without Gastrointestinal Inflammation. J Crohns Colitis 2021; 15:800-812. [PMID: 33119074 PMCID: PMC8095387 DOI: 10.1093/ecco-jcc/jjaa220] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Historical and emerging data implicate fungi in Crohn's disease [CD] pathogenesis. However, a causal link between mycobiota, dysregulated immunity, and any impact of NOD2 variants remains elusive. This study aims to evaluate associations between NOD2 variants and faecal mycobiota in CD patients and non-CD subjects. METHODS Faecal samples were obtained from 34 CD patients [18 NOD2 mutant, 16 NOD2 wild-type] identified from the UK IBD Genetics Consortium. To avoid confounding influence of mucosal inflammation, CD patients were in clinical remission and had a faecal calprotectin <250 μg/g; 47 non-CD subjects were included as comparator groups, including 22 matched household [four NOD2 mutant] and 25 non-household subjects with known NOD2 genotype [14 NOD2 mutant] identified by the NIHR BioResource Cambridge. Faecal mycobiota composition was determined using internal transcribed spacer 1 [ITS1] sequencing and was compared with 16S rRNA gene sequences and volatile organic compounds. RESULTS CD was associated with higher numbers of fungal observed taxonomic units [OTUs] [p = 0.033]. Principal coordinates analysis using Jaccard index [p = 0.018] and weighted Bray-Curtis dissimilarities [p = 0.01] showed Candida spp. clustered closer to CD patients whereas Cryptococcus spp. clustered closer to non-CD. In CD, we found higher relative abundance of Ascomycota [p = 0.001] and lower relative abundance Basidiomycota [p = 0.019] phyla. An inverse relationship was found between bacterial and fungal Shannon diversity in NOD2 wild-type which was independent of CD [r = -0.349; p = 0.029]. CONCLUSIONS This study confirms compositional changes in the gut mycobiota in CD and provides evidence that fungi may play a role in CD pathogenesis. No NOD2 genotype-specific differences were observed in the faecal mycobiota.
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Affiliation(s)
- Andrew Nelson
- Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, UK
| | - Christopher J Stewart
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Nicholas A Kennedy
- IBD Pharmacogenetics Group, University of Exeter, Exeter, UK
- Department of Gastroenterology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
| | - John K Lodge
- Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, UK
| | - Mark Tremelling
- Department of Gastroenterology, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK
| | | | - Chris S Probert
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
- Department of Gastroenterology, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Miles Parkes
- Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - John C Mansfield
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
- Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Darren L Smith
- Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, UK
| | - Georgina L Hold
- Gastrointestinal Research Group, University of Aberdeen, Aberdeen, UK
- Microbiome Research Centre, St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Charlie W Lees
- Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
- Edinburgh IBD Unit, Western General Hospital, Edinburgh, UK
| | - Simon H Bridge
- Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Christopher A Lamb
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
- Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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30
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Mutational analyses of novel rat models with targeted modifications in inflammatory bowel disease susceptibility genes. Mamm Genome 2021; 32:173-182. [PMID: 33843019 PMCID: PMC8128796 DOI: 10.1007/s00335-021-09868-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 03/17/2021] [Indexed: 12/19/2022]
Abstract
Mutations and single base pair polymorphisms in various genes have been associated with increased susceptibility to inflammatory bowel disease (IBD). We have created a series of rat strains carrying targeted genetic alterations within three IBD susceptibility genes: Nod2, Atg16l1, and Il23r, using CRISPR/Cas9 genome editing technology. Knock-out alleles and alleles with known human susceptibility polymorphisms were generated on three different genetic backgrounds: Fischer, Lewis and Sprague Dawley. The availability of these rat models will contribute to our understanding of the basic biological roles of these three genes as well as provide new potential IBD animal models.
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31
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Kienes I, Weidl T, Mirza N, Chamaillard M, Kufer TA. Role of NLRs in the Regulation of Type I Interferon Signaling, Host Defense and Tolerance to Inflammation. Int J Mol Sci 2021; 22:1301. [PMID: 33525590 PMCID: PMC7865845 DOI: 10.3390/ijms22031301] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/22/2021] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Type I interferon signaling contributes to the development of innate and adaptive immune responses to either viruses, fungi, or bacteria. However, amplitude and timing of the interferon response is of utmost importance for preventing an underwhelming outcome, or tissue damage. While several pathogens evolved strategies for disturbing the quality of interferon signaling, there is growing evidence that this pathway can be regulated by several members of the Nod-like receptor (NLR) family, although the precise mechanism for most of these remains elusive. NLRs consist of a family of about 20 proteins in mammals, which are capable of sensing microbial products as well as endogenous signals related to tissue injury. Here we provide an overview of our current understanding of the function of those NLRs in type I interferon responses with a focus on viral infections. We discuss how NLR-mediated type I interferon regulation can influence the development of auto-immunity and the immune response to infection.
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Affiliation(s)
- Ioannis Kienes
- Department of Immunology, Institute for Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany; (I.K.); (T.W.); (N.M.)
| | - Tanja Weidl
- Department of Immunology, Institute for Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany; (I.K.); (T.W.); (N.M.)
| | - Nora Mirza
- Department of Immunology, Institute for Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany; (I.K.); (T.W.); (N.M.)
| | | | - Thomas A. Kufer
- Department of Immunology, Institute for Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany; (I.K.); (T.W.); (N.M.)
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32
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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.
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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
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33
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Mudde ACA, Booth C, Marsh RA. Evolution of Our Understanding of XIAP Deficiency. Front Pediatr 2021; 9:660520. [PMID: 34222142 PMCID: PMC8247594 DOI: 10.3389/fped.2021.660520] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 05/17/2021] [Indexed: 12/17/2022] Open
Abstract
X-linked inhibitor of apoptosis (XIAP) deficiency is a rare inborn error of immunity first described in 2006. XIAP deficiency is characterised by immune dysregulation and a broad spectrum of clinical manifestations, including haemophagocytic lymphohistiocytosis (HLH), inflammatory bowel disease (IBD), hypogammaglobulinemia, susceptibility to infections, splenomegaly, cytopaenias, and other less common autoinflammatory phenomena. Since the first description of the disease, many XIAP deficient patients have been identified and our understanding of the disease has grown. Over 90 disease causing mutations have been described and more inflammatory disease manifestations, such as hepatitis, arthritis, and uveitis, are now well-recognised. Recently, following the introduction of reduced intensity conditioning (RIC), outcomes of allogeneic haematopoietic stem cell transplantation (HSCT), the only curative treatment option for XIAP deficiency, have improved. The pathophysiology of XIAP deficiency is not fully understood, however it is known that XIAP plays a role in both the innate and adaptive immune response and in immune regulation, most notably through modulation of tumour necrosis factor (TNF)-receptor signalling and regulation of NLRP3 inflammasome activity. In this review we will provide an up to date overview of both the clinical aspects and pathophysiology of XIAP deficiency.
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Affiliation(s)
- Anne C A Mudde
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Claire Booth
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.,Department of Immunology and Gene Therapy, Great Ormond Street Hospital, London, United Kingdom
| | - Rebecca A Marsh
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Department of Pediatrics, University of Cincinnati, Cincinnati, OH, United States
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Genetic Deletion of NOD1 Prevents Cardiac Ca 2+ Mishandling Induced by Experimental Chronic Kidney Disease. Int J Mol Sci 2020; 21:ijms21228868. [PMID: 33238586 PMCID: PMC7700567 DOI: 10.3390/ijms21228868] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 11/16/2020] [Accepted: 11/19/2020] [Indexed: 12/23/2022] Open
Abstract
Risk of cardiovascular disease (CVD) increases considerably as renal function declines in chronic kidney disease (CKD). Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) has emerged as a novel innate immune receptor involved in both CVD and CKD. Following activation, NOD1 undergoes a conformational change that allows the activation of the receptor-interacting serine/threonine protein kinase 2 (RIP2), promoting an inflammatory response. We evaluated whether the genetic deficiency of Nod1 or Rip2 in mice could prevent cardiac Ca2+ mishandling induced by sixth nephrectomy (Nx), a model of CKD. We examined intracellular Ca2+ dynamics in cardiomyocytes from Wild-type (Wt), Nod1-/- and Rip2-/- sham-operated or nephrectomized mice. Compared with Wt cardiomyocytes, Wt-Nx cells showed an impairment in the properties and kinetics of the intracellular Ca2+ transients, a reduction in both cell shortening and sarcoplasmic reticulum Ca2+ load, together with an increase in diastolic Ca2+ leak. Cardiomyocytes from Nod1-/--Nx and Rip2-/--Nx mice showed a significant amelioration in Ca2+ mishandling without modifying the kidney impairment induced by Nx. In conclusion, Nod1 and Rip2 deficiency prevents the intracellular Ca2+ mishandling induced by experimental CKD, unveiling new innate immune targets for the development of innovative therapeutic strategies to reduce cardiac complications in patients with CKD.
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Yang E, Shen J. The roles and functions of Paneth cells in Crohn's disease: A critical review. Cell Prolif 2020; 54:e12958. [PMID: 33174662 PMCID: PMC7791172 DOI: 10.1111/cpr.12958] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 10/15/2020] [Accepted: 10/24/2020] [Indexed: 12/13/2022] Open
Abstract
Paneth cells (PCs) are located at the base of small intestinal crypts and secrete the α‐defensins, human α‐defensin 5 (HD‐5) and human α‐defensin 6 (HD‐6) in response to bacterial, cholinergic and other stimuli. The α‐defensins are broad‐spectrum microbicides that play critical roles in controlling gut microbiota and maintaining intestinal homeostasis. Inflammatory bowel disease, including ulcerative colitis and Crohn's disease (CD), is a complicated autoimmune disorder. The pathogenesis of CD involves genetic factors, environmental factors and microflora. Surprisingly, with regard to genetic factors, many susceptible genes and pathogenic pathways of CD, including nucleotide‐binding oligomerization domain 2 (NOD2), autophagy‐related 16‐like 1 (ATG16L1), immunity‐related guanosine triphosphatase family M (IRGM), wingless‐related integration site (Wnt), leucine‐rich repeat kinase 2 (LRRK2), histone deacetylases (HDACs), caspase‐8 (Casp8) and X‐box‐binding protein‐1 (XBP1), are relevant to PCs. As the underlying mechanisms are being unravelled, PCs are identified as the central element of CD pathogenesis, integrating factors among microbiota, intestinal epithelial barrier dysfunction and the immune system. In the present review, we demonstrate how these genes and pathways regulate CD pathogenesis via their action on PCs and what treatment modalities can be applied to deal with these PC‐mediated pathogenic processes.
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Affiliation(s)
- Erpeng Yang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Shen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
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36
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Liu F, Romantseva T, Park YJ, Golding H, Zaitseva M. Production of fever mediator PGE 2 in human monocytes activated with MDP adjuvant is controlled by signaling from MAPK and p300 HAT: Key role of T cell derived factor. Mol Immunol 2020; 128:139-149. [PMID: 33126082 DOI: 10.1016/j.molimm.2020.10.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 10/06/2020] [Accepted: 10/14/2020] [Indexed: 10/23/2022]
Abstract
Fever and inflammatory responses were observed in some subjects in early clinical trials of vaccines adjuvanted with muramyl dipeptide (MDP), a NOD2 agonist. Biosynthesis of Prostaglandin E2 (PGE2) that transmits febrile signals to the brain is controlled by an inducible enzyme, Cyclooxygenase 2 (COX-2). MDP alone was not sufficient to induce expression of COX-2 and PGE2 production in vitro. Conditioned medium prepared from Peripheral Blood Mononuclear Cells (PBMCs)-derived CD3-bead purified human T cells (TCM) dramatically increased COX2 gene transcription, COX-2 protein expression, and PGE2 production in MDP-treated monocytes. We explored epigenetic changes at the COX2 promoter using Chromatin Immunoprecipitation assay (ChIP). Increase in COX2 transcription correlated with increased recruitment of RNA polymerase II (Pol II) and p300 histone acetyl transferase (HAT) to the COX2 promoter in monocytes activated with MDP and TCM. The role of p300 HAT was confirmed by using C646, an inhibitor of p300, that reduced binding of acetylated H3 and H4 histones at the COX2 promoter, COX2 transcription, and PGE2 production in monocytes. Binding of p300, Nuclear Factor Kappa B (NF-κB), and Pol II to the COX2 promoter was also sensitive to inhibitors of Mitogen-Activated Protein Kinase (MAPK) pathway and to antibodies against Macrophage-1 (Mac-1) integrin in MDP/TCM-treated monocytes. Importantly, recombinant Glycoprotein Ib alfa (GPIbα), the recently identified factor in TCM, increased binding of NF-κB, p300, and of Pol II to the COX2 promoter and COX2 transcription in MDP-treated monocytes. Our findings suggest that a second signal through Mac-1 and MAPK is triggered by a T cell derived soluble GPIbα protein leading to the assembly of the transcription machinery at the COX2 promoter and production of PGE2 in human monocytes in response to MDP/NOD2 activation.
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Affiliation(s)
- Fengjie Liu
- Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Silver Spring, MD 20993, United States
| | - Tatiana Romantseva
- Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Silver Spring, MD 20993, United States
| | - Yun-Jong Park
- Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Silver Spring, MD 20993, United States
| | - Hana Golding
- Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Silver Spring, MD 20993, United States
| | - Marina Zaitseva
- Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Silver Spring, MD 20993, United States.
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37
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Raftery AL, Tsantikos E, Harris NL, Hibbs ML. Links Between Inflammatory Bowel Disease and Chronic Obstructive Pulmonary Disease. Front Immunol 2020; 11:2144. [PMID: 33042125 PMCID: PMC7517908 DOI: 10.3389/fimmu.2020.02144] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 08/07/2020] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the gastrointestinal and respiratory tracts, respectively. These mucosal tissues bear commonalities in embryology, structure and physiology. Inherent similarities in immune responses at the two sites, as well as overlapping environmental risk factors, help to explain the increase in prevalence of IBD amongst COPD patients. Over the past decade, a tremendous amount of research has been conducted to define the microbiological makeup of the intestine, known as the intestinal microbiota, and determine its contribution to health and disease. Intestinal microbial dysbiosis is now known to be associated with IBD where it impacts upon intestinal epithelial barrier integrity and leads to augmented immune responses and the perpetuation of chronic inflammation. While much less is known about the lung microbiota, like the intestine, it has its own distinct, diverse microflora, with dysbiosis being reported in respiratory disease settings such as COPD. Recent research has begun to delineate the interaction or crosstalk between the lung and the intestine and how this may influence, or be influenced by, the microbiota. It is now known that microbial products and metabolites can be transferred from the intestine to the lung via the bloodstream, providing a mechanism for communication. While recent studies indicate that intestinal microbiota can influence respiratory health, intestinal dysbiosis in COPD has not yet been described although it is anticipated since factors that lead to dysbiosis are similarly associated with COPD. This review will focus on the gut-lung axis in the context of IBD and COPD, highlighting the role of environmental and genetic factors and the impact of microbial dysbiosis on chronic inflammation in the intestinal tract and lung.
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Affiliation(s)
- April L Raftery
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Evelyn Tsantikos
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Nicola L Harris
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Margaret L Hibbs
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
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38
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Tuladhar S, Kanneganti TD. NLRP12 in innate immunity and inflammation. Mol Aspects Med 2020; 76:100887. [PMID: 32838963 DOI: 10.1016/j.mam.2020.100887] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 06/01/2020] [Accepted: 07/29/2020] [Indexed: 02/07/2023]
Abstract
Nucleotide-binding leucine-rich repeat-containing proteins, or NOD-like receptors (NLRs), are intracellular innate immune sensors that can regulate several signaling pathways, including MyD88- and TRIF-dependent pathways. In addition to these regulatory roles, some NLRs can assemble into multimeric protein complexes known as inflammasomes. NLRP12 is a member of the NLR family that contains an N-terminal pyrin domain, a central nucleotide-binding domain, and a C-terminal leucine-rich repeat. It has been shown to play a role in forming an inflammasome in response to specific infections, and it can also function as a regulator of inflammatory signaling. During Yersinia pestis or Plasmodium chabaudi infection, NLRP12 induces the release of the inflammasome-dependent cytokines IL-1β and IL-18. These NLRP12-dependent cytokines confer protection against severe infections caused by these pathogens. Conversely, during infection with Salmonella enterica serovar Typhimurium, vesicular stomatitis virus, Klebsiella pneumoniae, or Mycobacterium tuberculosis, and in colonic tumorigenesis, NLRP12 acts as a negative regulator of the NFκB and MAPK signaling pathways. NLRP12 also negatively regulates canonical and non-canonical signaling in T cells and causes exacerbated autoimmune diseases. Furthermore, NLRP12 acts as a central component in maintaining intestinal inflammation and gut homeostasis. Therefore, the ability of NLRP12 to function as an inflammasome or as a negative regulator is context-dependent. In this review, we provide an overview of the NLR family members and summarize recent insights into the roles of NLRP12 as an inflammasome and as a negative regulator.
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Affiliation(s)
- Shraddha Tuladhar
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
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Carlos D, Pérez MM, Leite JA, Rocha FA, Martins LMS, Pereira CA, Fraga-Silva TFC, Pucci TA, Ramos SG, Câmara NOS, Bonato VLD, Tostes RC, Silva JS. NOD2 Deficiency Promotes Intestinal CD4+ T Lymphocyte Imbalance, Metainflammation, and Aggravates Type 2 Diabetes in Murine Model. Front Immunol 2020; 11:1265. [PMID: 32774333 PMCID: PMC7381387 DOI: 10.3389/fimmu.2020.01265] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 05/19/2020] [Indexed: 12/21/2022] Open
Abstract
Type 2 diabetes (T2D) is a metabolic disease characterized by increased inflammation, NOD-like receptors (NLRs) activation and gut dysbiosis. Our research group has recently reported that intestinal Th17 response limits gut dysbiosis and LPS translocation to visceral adipose tissue (VAT), protecting against metabolic syndrome. However, whether NOD2 receptor contributes intestinal Th17 immunity, modulates dysbiosis-driven metabolic tissue inflammation, and obesity-induced T2D remain poorly understood. In this context, we observed that mice lacking NOD2 fed a high-fat diet (HFD) display severe obesity, exhibit greater adiposity, and more hepatic steatosis compared to HFD-fed wild-type (WT) mice. In addition, they develop increased hyperglycemia, worsening of glucose intolerance, and insulin resistance. Notably, the deficiency of NOD2 causes a deviation from M2 macrophage and regulatory T cells (Treg) to M1 macrophage and mast cells into VAT compared to WT mice fed HFD. An imbalance was also observed in Th17/Th1 cell populations, with reduced IL-17 and IL-22 gene expression in the mesenteric lymph nodes (MLNs) and ileum, respectively, of NOD2-deficient mice fed HFD. 16S rRNA sequencing indicates lower richness, alpha diversity, and a depletion of Allobaculum, Lactobacillus, and enrichment with Bacteroides genera in these mice compared to HFD-fed WT mice. These alterations were associated with disrupted tight-junctions expression, augmented serum LPS, and bacterial translocation into VAT. Overall, NOD2 activation is required for a protective Th17 over Th1 immunity in the gut, which seems to decrease gram-negative bacteria outgrowth in gut microbiota, attenuating the endotoxemia, metainflammation, and protecting against obesity-induced T2D.
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Affiliation(s)
- Daniela Carlos
- Departments of Biochemistry and Immunology, University of São Paulo, Ribeirão Preto, Brazil
| | - Malena M Pérez
- Departments of Biochemistry and Immunology, University of São Paulo, Ribeirão Preto, Brazil
| | - Jefferson A Leite
- Departments of Biochemistry and Immunology, University of São Paulo, Ribeirão Preto, Brazil
| | - Fernanda A Rocha
- Departments of Biochemistry and Immunology, University of São Paulo, Ribeirão Preto, Brazil
| | - Larissa M S Martins
- Departments of Biochemistry and Immunology, University of São Paulo, Ribeirão Preto, Brazil
| | | | - Thais F C Fraga-Silva
- Departments of Biochemistry and Immunology, University of São Paulo, Ribeirão Preto, Brazil
| | - Taís A Pucci
- Departments of Biochemistry and Immunology, University of São Paulo, Ribeirão Preto, Brazil
| | - Simone G Ramos
- Pathology and Legal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Niels O S Câmara
- Department of Immunology, Institute of Biomedical Science (ICB), University of São Paulo, Ribeirão Preto, Brazil
| | - Vânia L D Bonato
- Departments of Biochemistry and Immunology, University of São Paulo, Ribeirão Preto, Brazil
| | - Rita C Tostes
- Pharmacology, University of São Paulo, Ribeirão Preto, Brazil
| | - João S Silva
- Departments of Biochemistry and Immunology, University of São Paulo, Ribeirão Preto, Brazil.,Fiocruz-Bi-Institutional Translational Medicine Plataform, Ribeirão Preto, Brazil
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40
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Caruso R, Lo BC, Núñez G. Host-microbiota interactions in inflammatory bowel disease. Nat Rev Immunol 2020; 20:411-426. [PMID: 32005980 DOI: 10.1038/s41577-019-0268-7] [Citation(s) in RCA: 464] [Impact Index Per Article: 92.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/16/2019] [Indexed: 12/25/2022]
Abstract
The mammalian intestine is colonized by trillions of microorganisms that have co-evolved with the host in a symbiotic relationship. The presence of large numbers of symbionts near the epithelial surface of the intestine poses an enormous challenge to the host because it must avoid the activation of harmful inflammatory responses to the microorganisms while preserving its ability to mount robust immune responses to invading pathogens. In patients with inflammatory bowel disease, there is a breakdown of the multiple strategies that the immune system has evolved to promote the separation between symbiotic microorganisms and the intestinal epithelium and the effective killing of penetrant microorganisms, while suppressing the activation of inappropriate T cell responses to resident microorganisms. Understanding the complex interactions between intestinal microorganisms and the host may provide crucial insight into the pathogenesis of inflammatory bowel disease as well as new avenues to prevent and treat the disease.
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Affiliation(s)
- Roberta Caruso
- Department of Pathology and Rogel Cancer Center, the University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Bernard C Lo
- Department of Pathology and Rogel Cancer Center, the University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Gabriel Núñez
- Department of Pathology and Rogel Cancer Center, the University of Michigan Medical School, Ann Arbor, Michigan, USA.
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41
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Sanguisorba officinalis L. derived from herbal medicine prevents intestinal inflammation by inducing autophagy in macrophages. Sci Rep 2020; 10:9972. [PMID: 32561763 PMCID: PMC7305163 DOI: 10.1038/s41598-020-65306-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 05/04/2020] [Indexed: 01/05/2023] Open
Abstract
Disturbed activation of autophagy is implicated in the pathogenesis of inflammatory bowel disease. Accordingly, several autophagy-related genes have been identified as Crohn's disease susceptibility genes. We screened the autophagy activators from a library including 3,922 natural extracts using a high-throughput assay system. The extracts identified as autophagy activators were administered to mice with 2% dextran sodium sulfate (DSS). Among the autophagy inducers, Sanguisorba officinalis L. (SO) suppressed DSS-induced colitis. To identify the mechanism by which SO ameliorates colitis, epithelial cell and innate myeloid cells-specific Atg7-deficient mice (Villin-cre; Atg7f/f and LysM-cre; Atg7f/f mice, respectively) were analyzed. SO-mediated inhibition of colitis was observed in Villin-cre; Atg7f/f mice. However, SO and a mixture of its components including catechin acid, ellagic acid, gallic acid, and ziyuglycoside II (Mix4) did not suppressed colitis in LysM-cre; Atg7f/f mice. In large intestinal macrophages (Mφ) of Atg7f/f mice, SO and Mix4 upregulated the expression of marker genes of anti-inflammatory Mφ including Arg1, Cd206, and Relma. However, these alterations were not induced in LysM-cre; Atg7f/f mice. These findings indicate that SO and its active components ameliorate DSS-induced colitis by providing intestinal Mφ with anti-inflammatory profiles via promotion of Atg7-dependent autophagy.
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42
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Tikka C, Manthari RK, Ommati MM, Niu R, Sun Z, Zhang J, Wang J. Immune disruption occurs through altered gut microbiome and NOD2 in arsenic induced mice: Correlation with colon cancer markers. CHEMOSPHERE 2020; 246:125791. [PMID: 31927375 DOI: 10.1016/j.chemosphere.2019.125791] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 12/27/2019] [Accepted: 12/29/2019] [Indexed: 06/10/2023]
Abstract
The gut microbial compositions are easily affected by the environmental chemicals like arsenic (As) leading to dysbiosis. The dysbiosis of gut microbiome has associated with numerous diseases; among which cancer is one of the major diseases. The meticulous mechanism underlying As- altered gut microbiome, Nucleotide domine containing protein 2 (NOD2) and how altered gut microbiome disturbs the intestinal homeostasis to regulate colon cancer markers remains unclear. For this, one hundred twenty 8-week old age male mice were divided into two exposure periods (3 and 6 months), and each exposure group animals were further divided into four groups as control (received only distilled H2O), low (0.15 mg As2O3/L), medium (1.5 mg As2O3/L) and high (15 mg As2O3/L) dose (each group containing 15 mice) administrated for 3 and 6 months. The results showed that As exposure highly altered gut microbiome with a significant depletion in NOD2 in contrast to control groups. Moreover, the dendritic cells (CD11a, CD103, CX3CR1) and macrophages (F4/80) were significantly increased by As exposure. Interestingly, increased trend of inflammatory cytokines (TNF-α, IFN-γ, IL-17) and depleted anti-inflammatory cytokines (IL-10) was observed in As exposed mice. Furthermore, the colon cancer markers β-catenin has increased while APC was arrested by As both in 3 and 6 months treated animals. Many studies reported that As altered gut microbial compositions, in this study, our results suggested that altered gut microbiome indirectly regulates colon cancer marker through immune system destruction mediated by inflammatory cytokines.
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Affiliation(s)
- Chiranjeevi Tikka
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
| | - Ram Kumar Manthari
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
| | - Mohammad Mehdi Ommati
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China; Department of Life Science, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
| | - Ruiyan Niu
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
| | - Zilong Sun
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
| | - Jianhai Zhang
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
| | - Jundong Wang
- Shanxi Key Laboratory of Ecological Animal Science and Environmental Veterinary Medicine, College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China.
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Abstract
Crohn's disease is an inflammatory bowel disease that is characterized by chronic inflammation of any part of the gastrointestinal tract, has a progressive and destructive course and is increasing in incidence worldwide. Several factors have been implicated in the cause of Crohn's disease, including a dysregulated immune system, an altered microbiota, genetic susceptibility and environmental factors, but the cause of the disease remains unknown. The onset of the disease at a young age in most cases necessitates prompt but long-term treatment to prevent disease flares and disease progression with intestinal complications. Thus, earlier, more aggressive treatment with biologic therapies or novel small molecules could profoundly change the natural history of the disease and decrease complications and the need for hospitalization and surgery. Although less invasive biomarkers are in development, diagnosis still relies on endoscopy and histological assessment of biopsy specimens. Crohn's disease is a complex disease, and treatment should be personalized to address the underlying pathogenetic mechanism. In the future, disease management might rely on severity scores that incorporate prognostic factors, bowel damage assessment and non-invasive close monitoring of disease activity to reduce the severity of complications.
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44
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Griffin ME, Hespen CW, Wang Y, Hang HC. Translation of peptidoglycan metabolites into immunotherapeutics. Clin Transl Immunology 2019; 8:e1095. [PMID: 31798878 PMCID: PMC6883908 DOI: 10.1002/cti2.1095] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 11/15/2019] [Accepted: 11/17/2019] [Indexed: 12/16/2022] Open
Abstract
The discovery of defined peptidoglycan metabolites that activate host immunity and their specific receptors has revealed fundamental insights into host-microbe recognition and afforded new opportunities for therapeutic development against infection and cancer. In this review, we summarise the discovery of two key peptidoglycan metabolites, γ-d-glutamyl-meso-diaminopimelic acid (iE-DAP) and muramyl dipeptide and their respective receptors, Nod1 and Nod2, and review progress towards translating these findings into therapeutic agents. Notably, synthetic derivatives of peptidoglycan metabolites have already yielded approved drugs for chemotherapy-induced leukopenia and paediatric osteosarcoma; however, the broad effects of peptidoglycan metabolites on host immunity suggest additional translational opportunities for new therapeutics towards other cancers, microbial infections and inflammatory diseases.
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Affiliation(s)
- Matthew E Griffin
- Laboratory of Chemical Biology and Microbial PathogenesisThe Rockefeller UniversityNew YorkNYUSA
| | - Charles W Hespen
- Laboratory of Chemical Biology and Microbial PathogenesisThe Rockefeller UniversityNew YorkNYUSA
| | - Yen‐Chih Wang
- Laboratory of Chemical Biology and Microbial PathogenesisThe Rockefeller UniversityNew YorkNYUSA
| | - Howard C Hang
- Laboratory of Chemical Biology and Microbial PathogenesisThe Rockefeller UniversityNew YorkNYUSA
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45
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Pusceddu MM, Barboza M, Keogh CE, Schneider M, Stokes P, Sladek JA, Kim HJD, Torres-Fuentes C, Goldfild LR, Gillis SE, Brust-Mascher I, Rabasa G, Wong KA, Lebrilla C, Byndloss MX, Maisonneuve C, Bäumler AJ, Philpott DJ, Ferrero RL, Barrett KE, Reardon C, Gareau MG. Nod-like receptors are critical for gut-brain axis signalling in mice. J Physiol 2019; 597:5777-5797. [PMID: 31652348 DOI: 10.1113/jp278640] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 10/24/2019] [Indexed: 12/12/2022] Open
Abstract
KEY POINTS •Nucleotide binding oligomerization domain (Nod)-like receptors regulate cognition, anxiety and hypothalamic-pituitary-adrenal axis activation. •Nod-like receptors regulate central and peripheral serotonergic biology. •Nod-like receptors are important for maintenance of gastrointestinal physiology. •Intestinal epithelial cell expression of Nod1 receptors regulate behaviour. ABSTRACT Gut-brain axis signalling is critical for maintaining health and homeostasis. Stressful life events can impact gut-brain signalling, leading to altered mood, cognition and intestinal dysfunction. In the present study, we identified nucleotide binding oligomerization domain (Nod)-like receptors (NLR), Nod1 and Nod2, as novel regulators for gut-brain signalling. NLR are innate immune pattern recognition receptors expressed in the gut and brain, and are important in the regulation of gastrointestinal physiology. We found that mice deficient in both Nod1 and Nod2 (NodDKO) demonstrate signs of stress-induced anxiety, cognitive impairment and depression in the context of a hyperactive hypothalamic-pituitary-adrenal axis. These deficits were coupled with impairments in the serotonergic pathway in the brain, decreased hippocampal cell proliferation and immature neurons, as well as reduced neural activation. In addition, NodDKO mice had increased gastrointestinal permeability and altered serotonin signalling in the gut following exposure to acute stress. Administration of the selective serotonin reuptake inhibitor, fluoxetine, abrogated behavioural impairments and restored serotonin signalling. We also identified that intestinal epithelial cell-specific deletion of Nod1 (VilCre+ Nod1f/f ), but not Nod2, increased susceptibility to stress-induced anxiety-like behaviour and cognitive impairment following exposure to stress. Together, these data suggest that intestinal epithelial NLR are novel modulators of gut-brain communication and may serve as potential novel therapeutic targets for the treatment of gut-brain disorders.
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Affiliation(s)
- Matteo M Pusceddu
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Mariana Barboza
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Ciara E Keogh
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Melinda Schneider
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Patricia Stokes
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Jessica A Sladek
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Hyun Jung D Kim
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Cristina Torres-Fuentes
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA.,Department of Food Science & Technology, University of California Davis, Davis, CA, USA
| | - Lily R Goldfild
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Shane E Gillis
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Ingrid Brust-Mascher
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Gonzalo Rabasa
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Kyle A Wong
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Carlito Lebrilla
- Department of Chemistry, University of California Davis, Davis, CA, USA
| | - Mariana X Byndloss
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, USA
| | | | - Andreas J Bäumler
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, USA
| | - Dana J Philpott
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Richard L Ferrero
- Hudson Institute of Medical Research, Department of Molecular and Translational Science and Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Melbourne, VIC, Australia
| | - Kim E Barrett
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Colin Reardon
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Mélanie G Gareau
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
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McKernan DP. Pattern recognition receptors as potential drug targets in inflammatory disorders. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2019; 119:65-109. [PMID: 31997773 DOI: 10.1016/bs.apcsb.2019.09.001] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Pattern recognition receptors (PRRs) are a key part of the innate immune system, the body's first line of defense against infection and tissue damage. This superfamily of receptors including Toll-like receptors (TLRs), NOD-like receptors (NLRs), C-type lectin-like receptors (CLRs) and RIG-like receptors (RLRs) are responsible for initiation of the inflammatory response by their recognition of molecular patterns present in invading microorganisms (such as bacteria, viruses or fungi) during infection or in molecules released following tissue damage during acute or chronic disease states (such as sepsis or arthritis). These receptors are widely expressed and located on the cell surface, in intracellular compartments or in the cytoplasm can detect a single or subset of molecules including lipoproteins, carbohydrates or nucleic acids. In response, they initiate an intracellular signaling cascade that culminates in the synthesis and release of cytokines, chemokines and vasoactive molecules. These steps are necessary to maintain tissue homeostasis and remove potentially dangerous pathogens. However, during extreme or acute responses or during chronic disease, this can be damaging and even lead to death. Therefore, it is thought that targeting such receptors may offer a therapeutic approach in chronic inflammatory diseases or in cases of acute infection leading to sepsis. Herein, the current knowledge on the molecular biology of PRRs is reviewed along with their association with inflammatory and infectious diseases. Finally, the testing of therapeutic compounds and their future merit as targets is discussed.
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Liu P, Lu Z, Liu L, Li R, Liang Z, Shen M, Xu H, Ren D, Ji M, Yuan S, Shang D, Zhang Y, Liu H, Tu Z. NOD-like receptor signaling in inflammation-associated cancers: From functions to targeted therapies. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 64:152925. [PMID: 31465982 DOI: 10.1016/j.phymed.2019.152925] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 04/06/2019] [Accepted: 04/08/2019] [Indexed: 05/22/2023]
Abstract
BACKGROUND Recently, many studies have reported that some botanicals and natural products were able to regulate NOD-like receptor signaling. NOD-like receptors (NLRs) have been established as crucial regulators in inflammation-associated tumorigenesis, angiogenesis, cancer cell stemness and chemoresistance. NLRs specifically sense pathogen-associated molecular patterns and respond by activating other signaling regulators, including Rip2 kinase, NF-κB, MAPK and ASC/caspase-1, leading to the secretion of various cytokines. PURPOSE The aim of this article is to review the molecular mechanisms of NOD-like receptor signaling in inflammation-associated cancers and the NLRs-targeted botanicals and synthetic small molecules in cancer intervention. RESULTS Aberrant activation of NLRs occurs in various cancers, orchestrating the tissue microenvironment and potentiating neoplastic risk. Blocking NLR inflammasome activation by botanicals or synthetic small molecules may be a valuable way to prevent cancer progression. Moreover, due to the roles of NLRs in regulating cytokine production, NLR signaling may be correlated with senescence-associated secretory phenotype. CONCLUSION In this review, we discuss how NLR signaling is involved in inflammation-associated cancers, and highlight the NLR-targeted botanicals and synthetic small molecules in cancer intervention.
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Affiliation(s)
- Peng Liu
- Institute of Life Sciences, Jiangsu University, 301 Xuefu Road, Jingkou District, Zhenjiang, Jiangsu 212013, China
| | - Ziwen Lu
- School of Pharmacy, Jiangsu University, 301 Xuefu Road, Jingkou District, Zhenjiang, Jiangsu 212013, China
| | - Lanlan Liu
- Institute of Life Sciences, Jiangsu University, 301 Xuefu Road, Jingkou District, Zhenjiang, Jiangsu 212013, China
| | - Ruyan Li
- Institute of Life Sciences, Jiangsu University, 301 Xuefu Road, Jingkou District, Zhenjiang, Jiangsu 212013, China
| | - Zhiquan Liang
- School of Pharmacy, Jiangsu University, 301 Xuefu Road, Jingkou District, Zhenjiang, Jiangsu 212013, China
| | - Mingxiang Shen
- Institute of Life Sciences, Jiangsu University, 301 Xuefu Road, Jingkou District, Zhenjiang, Jiangsu 212013, China
| | - Han Xu
- School of Pharmacy, Jiangsu University, 301 Xuefu Road, Jingkou District, Zhenjiang, Jiangsu 212013, China
| | - Dewan Ren
- School of Pharmacy, Jiangsu University, 301 Xuefu Road, Jingkou District, Zhenjiang, Jiangsu 212013, China
| | - Mengchen Ji
- Institute of Life Sciences, Jiangsu University, 301 Xuefu Road, Jingkou District, Zhenjiang, Jiangsu 212013, China
| | - Sirui Yuan
- School of Pharmacy, Jiangsu University, 301 Xuefu Road, Jingkou District, Zhenjiang, Jiangsu 212013, China
| | - Dongsheng Shang
- School of Pharmacy, Jiangsu University, 301 Xuefu Road, Jingkou District, Zhenjiang, Jiangsu 212013, China
| | - Yibang Zhang
- School of Pharmacy, Jiangsu University, 301 Xuefu Road, Jingkou District, Zhenjiang, Jiangsu 212013, China
| | - Hanqing Liu
- School of Pharmacy, Jiangsu University, 301 Xuefu Road, Jingkou District, Zhenjiang, Jiangsu 212013, China.
| | - Zhigang Tu
- Institute of Life Sciences, Jiangsu University, 301 Xuefu Road, Jingkou District, Zhenjiang, Jiangsu 212013, China.
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Abstract
Introduction: Inflammatory bowel diseases (IBD) are on the rise worldwide. This review covers the current concepts of the etiology of Crohn´s disease and ulcerative colitis by focusing on an unbalanced interaction between the intestinal microbiota and the mucosal barrier. Understanding these issues is of paramount importance for the development of targeted therapies aiming at the disease cause.Area covered: Gut microbiota alterations and a dysfunctional intestinal mucosa are associated with IBD. Here we focus on specific defense structures of the mucosal barrier, namely antimicrobial peptides and the mucus layer, which keep the gut microbiota at a distance under healthy conditions and are defective in IBD.Expert commentary: The microbiology of both forms of IBD is different but characterized by a reduced bacterial diversity and richness. Abundance of certain bacterial species is altered, and the compositional changes are related to disease activity. In IBD the mucus layer above the epithelium is contaminated by bacteria and the immune reaction is dominated by the antibacterial response. Human genetics suggest that many of the basic deficiencies in the mucosal response, due to Paneth cell, defensin and mucus defects, are primary. Nutrition may also be important but so far there is no therapy targeting the mucosal barrier.
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Affiliation(s)
- Eduard F Stange
- Innere Medizin I, Medizinische Universitätsklinik, Tübingen, Germany
| | - Bjoern O Schroeder
- Laboratory for Molecular Infection Medicine Sweden (MIMS) -The Nordic EMBL Partnership for Molecular Medicine, and Department of Molecular Biology, Umeå University, Umeå, Sweden
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Segal AW. Studies on patients establish Crohn's disease as a manifestation of impaired innate immunity. J Intern Med 2019; 286:373-388. [PMID: 31136040 DOI: 10.1111/joim.12945] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The fruitless search for the cause of Crohn's disease has been conducted for more than a century. Various theories, including autoimmunity, mycobacterial infection and aberrant response to food and other ingested materials, have been abandoned for lack of robust proof. This review will provide the evidence, obtained from patients with this condition, that the common predisposition to Crohn's is a failure of the acute inflammatory response to tissue damage. This acute inflammation normally attracts large numbers of neutrophil leucocytes which engulf and clear bacteria and autologous debris from the inflamed site. The underlying predisposition in Crohn's disease is unmasked by damage to the bowel mucosa, predominantly through infection, which allows faecal bowel contents access to the vulnerable tissues within. Consequent upon failure of the clearance of these infectious and antigenic intestinal contents, it becomes contained, leading to a chronic granulomatous inflammation, producing cytokine release, local tissue damage and systemic symptoms. Multiple molecular pathologies extending across the whole spectrum of the acute inflammatory and innate immune response lead to the common predisposition in which defective monocyte and macrophage function plays a central role. Family linkage and exome sequencing together with GWAS have identified some of the molecules involved, including receptors, molecules involved in vesicle trafficking, and effector cells. Current therapy is immunosuppressant, which controls the symptoms but accentuates the underlying problem, which can only logically be tackled by correcting the primary lesion/s by gene therapy or genome editing, or through the development of drugs that stimulate innate immunity.
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Affiliation(s)
- A W Segal
- From the, Division of Medicine, University College London, London, UK
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50
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Maeda K, Caldez MJ, Akira S. Innate immunity in allergy. Allergy 2019; 74:1660-1674. [PMID: 30891811 PMCID: PMC6790574 DOI: 10.1111/all.13788] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 02/26/2019] [Accepted: 03/10/2019] [Indexed: 12/13/2022]
Abstract
Innate immune system quickly responds to invasion of microbes and foreign substances through the extracellular and intracellular sensing receptors, which recognize distinctive molecular and structural patterns. The recognition of innate immune receptors leads to the induction of inflammatory and adaptive immune responses by activating downstream signaling pathways. Allergy is an immune-related disease and results from a hypersensitive immune response to harmless substances in the environment. However, less is known about the activation of innate immunity during exposure to allergens. New insights into the innate immune system by sensors and their signaling cascades provide us with more important clues and a framework for understanding allergy disorders. In this review, we will focus on recent advances in the innate immune sensing system.
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Affiliation(s)
- Kazuhiko Maeda
- Laboratory of Host Defense, The World Premier International Research Center Initiative (WPI) Immunology Frontier Research Center (IFReC)Osaka UniversityOsakaJapan
| | - Matias J. Caldez
- Laboratory of Host Defense, The World Premier International Research Center Initiative (WPI) Immunology Frontier Research Center (IFReC)Osaka UniversityOsakaJapan
| | - Shizuo Akira
- Laboratory of Host Defense, The World Premier International Research Center Initiative (WPI) Immunology Frontier Research Center (IFReC)Osaka UniversityOsakaJapan
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