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Chang Y, Chen J, Peng Y, Zhang K, Zhang Y, Zhao X, Wang D, Li L, Zhu J, Liu K, Li Z, Pan S, Huang K. Gut-derived macrophages link intestinal damage to brain injury after cardiac arrest through TREM1 signaling. Cell Mol Immunol 2025; 22:437-455. [PMID: 39984674 PMCID: PMC11955566 DOI: 10.1038/s41423-025-01263-0] [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: 08/28/2024] [Revised: 12/19/2024] [Accepted: 01/20/2025] [Indexed: 02/23/2025] Open
Abstract
Brain injury is the leading cause of death and disability in survivors of cardiac arrest, where neuroinflammation triggered by infiltrating macrophages plays a pivotal role. Here, we seek to elucidate the origin of macrophages infiltrating the brain and their mechanism of action after cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Wild-type or photoconvertible Cd68-Cre:R26-LSL-KikGR mice were subjected to 10-min CA/CPR, and the migration of gut-derived macrophages into brain was assessed. Transcriptome sequencing was performed to identify the key proinflammatory signal of macrophages infiltrating the brain, triggering receptor expressed on myeloid cells 1 (TREM1). Upon drug intervention, the effects of TREM1 on post-CA/CPR brain injury were further evaluated. 16S rRNA sequencing was used to detect gut dysbiosis after CA/CPR. Through photoconversion experiments, we found that small intestine-derived macrophages infiltrated the brain and played a crucial role in triggering secondary brain injury after CA/CPR. The infiltrating peripheral macrophages showed upregulated TREM1 levels, and we further revealed the crucial role of gut-derived TREM1+ macrophages in post-CA/CPR brain injury through a drug intervention targeting TREM1. Moreover, a close correlation between upregulated TREM1 expression and poor neurological outcomes was observed in CA survivors. Mechanistically, CA/CPR caused a substantial expansion of Enterobacter at the early stage, which ignited intestinal TREM1 signaling via the activation of Toll-like receptor 4 on macrophages through the release of lipopolysaccharide. Our findings reveal essential crosstalk between the gut and brain after CA/CPR and underscore the potential of targeting TREM1+ small intestine-derived macrophages as a novel therapeutic strategy for mitigating post-CA/CPR brain injury.
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Affiliation(s)
- Yuan Chang
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiancong Chen
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuqin Peng
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Kunxue Zhang
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuzhen Zhang
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaolin Zhao
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Di Wang
- Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Lei Li
- Clinical Laboratory, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Juan Zhu
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Kewei Liu
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhentong Li
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Suyue Pan
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Kaibin Huang
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
- Department of Neurology, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, China.
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Vinolo E, Maillefer M, Jolly L, Colné N, Meiffren G, Carrasco K, Derive M. The potential of targeting TREM-1 in IBD. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2024; 101:301-330. [PMID: 39521605 DOI: 10.1016/bs.apha.2024.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
Innate immune dysfunction is a hallmark of the pathogenesis of Inflammatory Bowel Disease, both in Crohn's disease and ulcerative colitis. Despite considerable efforts in research to better understand the pathophysiology of IBD and for the development of new therapeutic modalities for IBD patients, there is no therapy specifically targeting the dysregulations of the innate immune response available today in that field. TREM-1 is exclusively expressed by innate immune cells and is an immune amplifier. Its engagement following the primary activation of Pattern Recognition Receptors, including Toll-Like Receptors, triggers the development of a dysregulated and sustained innate immune response, promoting the perpetuation of the inflammatory response in the mucosa of IBD patients, microscopic mucosal tissue alterations, impaired autophagy, impaired epithelial barrier integrity and function, ulcerations, and mucosal damages. In patients, TREM-1 activation is associated with the active status of the disease as well as with severity. Blocking TREM-1 in experimental colitis attenuates the dysregulated innate immune response leading to improved clinical signs. Anti-TREM-1 approaches have the potential of controlling the pathogenic dysregulation of the immune response in IBD by targeting an upstream amplification loop of the activation of innate immunity.
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Lai W, Xian C, Chen M, Luo D, Zheng J, Zhao S, Li XG. Single-cell and bulk transcriptomics reveals M2d macrophages as a potential therapeutic strategy for mucosal healing in ulcerative colitis. Int Immunopharmacol 2023; 121:110509. [PMID: 37369160 DOI: 10.1016/j.intimp.2023.110509] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/31/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023]
Abstract
Mucosal healing is essential for treating ulcerative colitis (UC), which results from imbalanced macrophage polarization and dysregulated inflammatory responses. However, the mechanisms of cellular communication and signal transduction that regulate mucosal healing among macrophage subtypes require further investigation. We use bulk and single-cell RNA sequencing analysis to reveal that macrophage subtypes vary in different UC states. At the same time, chemokine and angiogenesis signaling is strongly associated with M2 macrophage's infiltrated proportion. To get more insight into subtypes of macrophages in mucosal healing, we divided macrophages into M1, M2b, and M2d macrophages. Based on the differentially expressed genes (DEGs) between M2d and M1 macrophages, KEGG and GO analysis highlights M2d macrophages' ability to alleviate inflammation and promote epithelial healing. Trajectory analysis revealed opposite differentiation of macrophage subsets between UC and healthy groups, with M1 and M2d macrophages coexisting in the same differentiation branch under UC conditions. Along the pseudotime axis, CCL3 and VEGFA expression increased in UC, while IL10RA remained stable in UC but increased in healthy controls. CellChat identified CCL3-CCR1 has strong communication between M1 and M2d macrophages, while the IL10 signaling pathway is activated explicitly in M2d macrophages to mitigate inflammation and promote epithelial healing. We also speculate that high levels of VEGFA activate endothelial cells expressing VEGFR and worsen inflammation. To conclude, we suggested IL10 and VEGF signaling in M2d macrophages as potential therapeutic targets for mucosal healing. However, it is necessary to establish reliable methods for isolating and purifying M2d macrophages before these targets can be effectively utilized.
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Affiliation(s)
- Weiming Lai
- Department of Pharmaceutical Engineering, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Changxiu Xian
- Department of Pharmaceutical Engineering, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Mingxia Chen
- College of Animal Science and Technology, Guangdong Polytechnic of Science and Trade, 510640 Guangzhou, China
| | - Ding Luo
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China
| | - Junxia Zheng
- Department of Pharmaceutical Engineering, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Suqing Zhao
- Department of Pharmaceutical Engineering, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Xiang-Guang Li
- Department of Pharmaceutical Engineering, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China.
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Filardy AA, Ferreira JRM, Rezende RM, Kelsall BL, Oliveira RP. The intestinal microenvironment shapes macrophage and dendritic cell identity and function. Immunol Lett 2023; 253:41-53. [PMID: 36623708 PMCID: PMC9907447 DOI: 10.1016/j.imlet.2023.01.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 12/12/2022] [Accepted: 01/04/2023] [Indexed: 01/09/2023]
Abstract
The gut comprises the largest body interface with the environment and is continuously exposed to nutrients, food antigens, and commensal microbes, as well as to harmful pathogens. Subsets of both macrophages and dendritic cells (DCs) are present throughout the intestinal tract, where they primarily inhabit the gut-associate lymphoid tissue (GALT), such as Peyer's patches and isolated lymphoid follicles. In addition to their role in taking up and presenting antigens, macrophages and DCs possess extensive functional plasticity and these cells play complementary roles in maintaining immune homeostasis in the gut by preventing aberrant immune responses to harmless antigens and microbes and by promoting host defense against pathogens. The ability of macrophages and DCs to induce either inflammation or tolerance is partially lineage imprinted, but can also be dictated by their activation state, which in turn is determined by their specific microenvironment. These cells express several surface and intracellular receptors that detect danger signals, nutrients, and hormones, which can affect their activation state. DCs and macrophages play a fundamental role in regulating T cells and their effector functions. Thus, modulation of intestinal mucosa immunity by targeting antigen presenting cells can provide a promising approach for controlling pathological inflammation. In this review, we provide an overview on the characteristics, functions, and origins of intestinal macrophages and DCs, highlighting the intestinal microenvironmental factors that influence their functions during homeostasis. Unraveling the mechanisms by which macrophages and DCs regulate intestinal immunity will deepen our understanding on how the immune system integrates endogenous and exogenous signals in order to maintain the host's homeostasis.
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Affiliation(s)
- Alessandra A Filardy
- Laboratório de Imunologia Celular, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Brazil.
| | - Jesuino R M Ferreira
- Laboratório de Imunologia Celular, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Brazil
| | - Rafael M Rezende
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, USA
| | - Brian L Kelsall
- Laboratory of Molecular Immunology, NIAID, National Institutes of Health, USA
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Zhang C, Kan X, Zhang B, Ni H, Shao J. The role of triggering receptor expressed on myeloid cells-1 (TREM-1) in central nervous system diseases. Mol Brain 2022; 15:84. [PMID: 36273145 PMCID: PMC9588203 DOI: 10.1186/s13041-022-00969-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 10/07/2022] [Indexed: 12/29/2022] Open
Abstract
Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily and is mainly expressed on the surface of myeloid cells such as monocytes, macrophages, and neutrophils. It plays an important role in the triggering and amplification of inflammatory responses, and it is involved in the development of various infectious and non-infectious diseases, autoimmune diseases, and cancers. In recent years, TREM-1 has also been found to participate in the pathological processes of several central nervous system (CNS) diseases. Targeting TREM-1 may be a promising strategy for treating these diseases. This paper aims to characterize TREM-1 in terms of its structure, signaling pathway, expression, regulation, ligands and pathophysiological role in CNS diseases.
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Affiliation(s)
- Chunyan Zhang
- Department of Neurology, The Third People’s Hospital of Zhangjiagang City, Suzhou, 215600 Jiangsu China
| | - Xugang Kan
- grid.417303.20000 0000 9927 0537Department of Neurobiology and Anatomy, XuzhouKeyLaboratoryofNeurobiology, Xuzhou Medical University, Xuzhou, 221004 Jiangsu China
| | - Baole Zhang
- grid.417303.20000 0000 9927 0537Department of Neurobiology and Anatomy, XuzhouKeyLaboratoryofNeurobiology, Xuzhou Medical University, Xuzhou, 221004 Jiangsu China
| | - Haibo Ni
- Department of Neurosurgery, The First People’s Hospital of Zhangjiagang City, Suzhou, 215600 Jiangsu China
| | - Jianfeng Shao
- Department of Neurology, The Third People’s Hospital of Zhangjiagang City, Suzhou, 215600 Jiangsu China
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Ma S, Zhang J, Liu H, Li S, Wang Q. The Role of Tissue-Resident Macrophages in the Development and Treatment of Inflammatory Bowel Disease. Front Cell Dev Biol 2022; 10:896591. [PMID: 35721513 PMCID: PMC9199005 DOI: 10.3389/fcell.2022.896591] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/09/2022] [Indexed: 11/13/2022] Open
Abstract
Inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis, is a refractory disease with many immune abnormalities and pathologies in the gastrointestinal tract. Because macrophages can distinguish innocuous antigens from potential pathogens to maintain mucosa barrier functions, they are essential cells in the intestinal immune system. With numerous numbers in the intestinal tract, tissue-resident macrophages have a significant effect on the constant regeneration of intestinal epithelial cells and maintaining the immune homeostasis of the intestinal mucosa. They also have a significant influence on IBD through regulating pro-(M1) or anti-inflammatory (M2) phenotype polarization according to different environmental cues. The disequilibrium of the phenotypes and functions of macrophages, disturbed by intracellular or extracellular stimuli, influences the progression of disease. Further investigation of macrophages’ role in the progression of IBD will facilitate deciphering the pathogenesis of disease and exploring novel targets to develop novel medications. In this review, we shed light on the origin and maintenance of intestinal macrophages, as well as the role of macrophages in the occurrence and development of IBD. In addition, we summarize the interaction between gut microbiota and intestinal macrophages, and the role of the macrophage-derived exosome. Furthermore, we discuss the molecular and cellular mechanisms participating in the polarization and functions of gut macrophages, the potential targeted strategies, and current clinical trials for IBD.
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Affiliation(s)
- Shengjie Ma
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Chang Chun, China
| | - Jiaxin Zhang
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Chang Chun, China
| | - Heshi Liu
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Chang Chun, China
| | - Shuang Li
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Chang Chun, China
| | - Quan Wang
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Chang Chun, China
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Lu L, Liu YJ, Cheng PQ, Hu D, Xu HC, Ji G. Macrophages play a role in inflammatory transformation of colorectal cancer. World J Gastrointest Oncol 2021; 13:2013-2028. [PMID: 35070038 PMCID: PMC8713318 DOI: 10.4251/wjgo.v13.i12.2013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/21/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide, and it is also a typical inflammatory cancer. The function of macrophages is very important in the tissue immune microenvironment during inflammatory and carcinogenic transformation. Here, we evaluated the function and mechanism of macrophages in intestinal physiology and in different pathological stages. Furthermore, the role of macrophages in the immune microenvironment of CRC and the influence of the intestinal population and hypoxic environment on macrophage function are summarized. In addition, in the era of tumor immunotherapy, CRC currently has a limited response rate to immune checkpoint inhibitors, and we summarize potential therapeutic strategies for targeting tumor-associated macrophages.
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Affiliation(s)
- Lu Lu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yu-Jing Liu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Pei-Qiu Cheng
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Dan Hu
- Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai 200120, China
| | - Han-Chen Xu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, Shanghai 200120, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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Harriman R, Lewis JS. Bioderived materials that disarm the gut mucosal immune system: Potential lessons from commensal microbiota. Acta Biomater 2021; 133:187-207. [PMID: 34098091 DOI: 10.1016/j.actbio.2021.05.045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/25/2021] [Accepted: 05/20/2021] [Indexed: 12/12/2022]
Abstract
Over the course of evolution, mammals and gut commensal microbes have adapted to coexist with each other. This homeostatic coexistence is dependent on an intricate balance between tolerogenic and inflammatory responses directed towards beneficial, commensal microbes and pathogenic intruders, respectively. Immune tolerance towards the gut microflora is largely sustained by immunomodulatory molecules produced by the commensals, which protect the bacteria from immune advances and maintain the gut's unique tolerogenic microenvironment, as well as systemic homeostasis. The identification and characterization of commensal-derived, tolerogenic molecules could lead to their utilization in biomaterials-inspired delivery schemes involving nano/microparticles or hydrogels, and potentially lead to the next generation of commensal-derived therapeutics. Moreover, gut-on-chip technologies could augment the discovery and characterization of influential commensals by providing realistic in vitro models conducive to finicky microbes. In this review, we provide an overview of the gut immune system, describe its intricate relationships with the microflora and identify major genera involved in maintaining tolerogenic responses and peripheral homeostasis. More relevant to biomaterials, we discuss commensal-derived molecules that are known to interface with immune cells and discuss potential strategies for their incorporation into biomaterial-based strategies aimed at culling inflammatory diseases. We hope this review will bridge the current findings in gut immunology, microbiology and biomaterials and spark further investigation into this emerging field. STATEMENT OF SIGNIFICANCE: Despite its tremendous potential to culminate into revolutionary therapeutics, the synergy between immunology, microbiology, and biomaterials has only been explored at a superficial level. Strategic incorporation of biomaterial-based technologies may be necessary to fully characterize and capitalize on the rapidly growing repertoire of immunomodulatory molecules derived from commensal microbes. Bioengineers may be able to combine state-of-the-art delivery platforms with immunomodulatory cues from commensals to provide a more holistic approach to combating inflammatory disease. This interdisciplinary approach could potentiate a neoteric field of research - "commensal-inspired" therapeutics with the promise of revolutionizing the treatment of inflammatory disease.
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Affiliation(s)
- Rian Harriman
- University of California Davis, Department of Biomedical Engineering, Davis, CA 95616, USA
| | - Jamal S Lewis
- University of California Davis, Department of Biomedical Engineering, Davis, CA 95616, USA.
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Soluble Triggering Receptor on Myeloid Cell-1 and its Predictive Factors in Patients With End-Stage Kidney Disease on Hemodialysis. ASAIO J 2021; 68:605-609. [PMID: 34352818 DOI: 10.1097/mat.0000000000001541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Triggering receptor expressed on myeloid cells (TREM)-1 is a potent and early amplifier of the inflammatory response expressed on neutrophils and monocytes/macrophages. TREM-1, and its soluble form (sTREM-1), are increased in sepsis and other noninfectious inflammatory conditions. However, virtually no data are available in kidney disease. To determine serum sTREM-1 and its associated variables in patients on hemodialysis (HD), cross-sectional study including 264 HD patients and 148 controls. sTREM-1 was measured by quantitative sandwich enzyme immunoassay; soluble tumor necrosis factor receptor-1 (sTNF-R1), interleukin-6 (IL-6), and C-reactive protein (CRP) were also measured. All inflammation markers were significantly higher in HD patients than controls. Median (IQR) sTREM-1 was 1,006 (613-1,650) pg/mL but undetectable in controls. Considering only HD patients, sTREM-1 was positively correlated with IL-6 (r = 0.19, p = 0.008), and its levels were significantly higher in patients with arteriovenous fistula than in those with temporary catheter (1,226 vs. 743 pg/mL), in patients with 3 HD sessions/week than in those with 2 sessions/week (1,150 vs. 646 pg/mL), and in patients with >1 year on HD than in those with ≤1 year (1,100 vs. 948 pg/mL), whereas they were not different regarding age or presence of infection. Serum sTREM-1, sTNF-R1, IL-6, and CRP were higher in HD patients compared to controls. In HD patients, sTREM-1 displayed higher levels in individuals with arteriovenous fistula, 3 sessions/week and longer vintage, but not in those with infection or older age; in multivariate analysis, only the first two variables significantly predicted higher sTREM-1 levels.
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Alshehri D, Saadah O, Mosli M, Edris S, Alhindi R, Bahieldin A. Dysbiosis of gut microbiota in inflammatory bowel disease: Current therapies and potential for microbiota-modulating therapeutic approaches. Bosn J Basic Med Sci 2021; 21:270-283. [PMID: 33052081 PMCID: PMC8112554 DOI: 10.17305/bjbms.2020.5016] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 09/17/2020] [Indexed: 12/16/2022] Open
Abstract
There is a growing body of evidence reinforcing the unique connections between the host microbiome, health, and diseases. Due to the extreme importance of the symbiotic relationship between the intestinal microbiome and the host, it is not surprising that any alteration in the gut microbiota would result in various diseases, including inflammatory bowel disease (IBD), Crohn's disease, (CD) and ulcerative colitis (UC). IBD is a chronic, relapsing-remitting condition that is associated with significant morbidity, mortality, compromised quality of life, and costly medical care. Dysbiosis is believed to exacerbate the progression of IBD. One of the currently used treatments for IBD are anti-tumor necrosis factor (TNF) drugs, representing a biologic therapy that is reported to have an impact on the gut microbiota composition. The efficacy of anti-TNF agents is hindered by the possibility of non-response, which occurs in 10-20% of treated patients, and secondary loss of response, which occurs in up to 30% of treated patients. This underscores the need for novel therapies and studies that evaluate the role of the gut microbiota in these conditions. The success of any therapeutic strategy for IBD depends on our understanding of the interactions that occur between the gut microbiota and the host. In this review, the health and disease IBD-associated microbiota patterns will be discussed, in addition to the effect of currently used therapies for IBD on the gut microbiota composition, as well as new therapeutic approaches that can be used to overcome the current treatment constraints.
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Affiliation(s)
- Dikhnah Alshehri
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Biology, Faculty of Science, Tabuk University, Tabuk, Saudi Arabia
| | - Omar Saadah
- Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; Inflammatory Bowel Disease Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mahmoud Mosli
- Inflammatory Bowel Disease Research Group, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sherif Edris
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Genetics, Faculty of Agriculture, Ain Shams University, Cairo, Egypt; Princess Al Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders (PACER-HD), Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Rashad Alhindi
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ahmed Bahieldin
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Genetics, Faculty of Agriculture, Ain Shams University, Cairo, Egypt
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Caër C, Gorreja F, Forsskåhl SK, Brynjolfsson SF, Szeponik L, Magnusson MK, Börjesson LG, Block M, Bexe-Lindskog E, Wick MJ. TREM-1+ Macrophages Define a Pathogenic Cell Subset in the Intestine of Crohn's Disease Patients. J Crohns Colitis 2021; 15:1346-1361. [PMID: 33537747 PMCID: PMC8328300 DOI: 10.1093/ecco-jcc/jjab022] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS Uncontrolled activation of intestinal mononuclear phagocytes [MNPs] drives chronic inflammation in inflammatory bowel disease [IBD]. Triggering receptor expressed on myeloid cells 1 [TREM-1] has been implicated in the pathogenesis of IBD. However, the role of TREM-1+ cell subsets in driving IBD pathology and the link with clinical parameters are not understood. We investigated TREM-1 expression in human intestinal MNP subsets and examined blocking TREM-1 as a potential IBD therapy. METHODS TREM-1 gene expression was analysed in intestinal mucosa, enriched epithelial and lamina propria [LP] layers, and purified cells from controls and IBD patients. TREM-1 protein on immune cells was assessed by flow cytometry and immunofluorescence microscopy. Blood monocyte activation was examined by large-scale gene expression using a TREM-1 agonist or LP conditioned media [LP-CM] from patients in the presence or absence of TREM-1 and tumour necrosis factor [TNF] antagonist antibodies. RESULTS TREM-1 gene expression increases in intestinal mucosa from IBD patients and correlates with disease score. TREM-1+ cells, which are mainly immature macrophages and CD11b+ granulocytes, increase among LP cells from Crohn's disease patients and their frequency correlates with inflammatory molecules in LP-CM. LP-CM from Crohn's disease patients induces an inflammatory transcriptome in blood monocytes, including increased IL-6 expression, which is reduced by simultaneous blocking of TREM-1 and TNF. CONCLUSIONS High intestinal TREM-1 expression, reflecting a high frequency of TREM-1+ immature macrophages and TREM-1+CD11b+ granulocytes, is linked to the deleterious inflammatory microenvironment in IBD patients. Therefore, blocking the TREM-1 pathway, especially simultaneously with anti-TNF therapy, has potential as a new IBD therapy.
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Affiliation(s)
- Charles Caër
- Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Frida Gorreja
- Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Sophia K Forsskåhl
- Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Siggeir F Brynjolfsson
- Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden,Department of Immunology, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland,Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Louis Szeponik
- Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maria K Magnusson
- Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lars G Börjesson
- Colorectal Unit, Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Mattias Block
- Colorectal Unit, Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Elinor Bexe-Lindskog
- Colorectal Unit, Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Mary Jo Wick
- Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden,Corresponding author: Mary Jo Wick, Department of Microbiology and Immunology, Institute for Biomedicine, University of Gothenburg, Box 435, 405 30 Gothenburg, Sweden. Tel.: +46 786 6325;
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Feng JY, Su WJ, Chuang FY, Pan SW, Yeh YC, Lin YY, Chen NJ. TREM-1 enhances Mycobacterium tuberculosis-induced inflammatory responses in macrophages. Microbes Infect 2020; 23:104765. [PMID: 33049389 DOI: 10.1016/j.micinf.2020.10.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 08/09/2020] [Accepted: 10/05/2020] [Indexed: 01/06/2023]
Abstract
Triggering receptor expressed on myeloid cells 1 (TREM-1) extensively interacts with toll-like receptors and amplifies pro-inflammatory responses. The effect of TREM-1 on Mycobacterium tuberculosis (MTB)-related immune responses remains to be elucidated. We isolated bone marrow-derived macrophages (BMDMs) from wild-type mice and Trem-1 KO mice and treated them with MTB whole cell lysate and EsxA (ESAT-6). Cytokine production and mRNA expression, including Trem-1, following stimulation were evaluated. Intratracheal instillation of heat-killed MTB (HKMTB) in mice was performed and the presence of TREM-1-positive macrophages was investigated by immunohistochemistry analysis. In our study, BMDMs isolated from wild-type mice produced more pro-inflammatory cytokines and demonstrated higher inflammatory gene expression levels compared with those isolated from Trem-1 KO mice when stimulated with MTB whole cell lysate. EsxA had a synergistic effect with MTB whole cell lysate on the induction of pro-inflammatory responses. The gene expression of Trem-1 was upregulated when treated with MTB-related proteins. TREM-1-positive macrophages were identified in the lung tissues from patients with active TB and from wild-type mice treated with intratracheal instillation of HKMTB. In conclusion, in mouse macrophages, TREM-1 could enhance pro-inflammatory immune responses when stimulated with MTB-related proteins. The gene expression of Trem-1 could also be induced by MTB-related stimulation.
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Affiliation(s)
- Jia-Yih Feng
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Wei-Juin Su
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Fan-Yi Chuang
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Sheng-Wei Pan
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan; Institute of Public Health, National Yang-Ming University, Taipei, Taiwan
| | - Yi-Chen Yeh
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yung-Yang Lin
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cerebrovascular Diseases, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
| | - Nien-Jung Chen
- Institute of Microbiology and Immunology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan.
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13
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Ruder B, Becker C. At the Forefront of the Mucosal Barrier: The Role of Macrophages in the Intestine. Cells 2020; 9:E2162. [PMID: 32987848 PMCID: PMC7601053 DOI: 10.3390/cells9102162] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 09/17/2020] [Accepted: 09/22/2020] [Indexed: 12/14/2022] Open
Abstract
Macrophages are part of the innate immunity and are key players for the maintenance of intestinal homeostasis. They belong to the group of mononuclear phagocytes, which exert bactericidal functions and help to clear apoptotic cells. Moreover, they play essential roles for the maintenance of epithelial integrity and tissue remodeling during wound healing processes and might be implicated in intestinal tumor development. Macrophages are antigen-presenting cells and secrete immune-modulatory factors, like chemokines and cytokines, which are necessary to activate other intestinal immune cells and therefore to shape immune responses in the gut. However, overwhelming activation or increased secretion of pro-inflammatory cytokines might also contribute to the pathogenesis of inflammatory bowel disease. Presently, intestinal macrophages are in the center of intense studies, which might help to develop new therapeutic strategies to counteract the development or treat already existing inflammatory diseases in the gut. In this review, we focus on the origin of intestinal macrophages and, based on current knowledge, discuss their role in the gut during homeostasis and inflammation, as well as during intestinal wound healing and tumor development.
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Affiliation(s)
| | - Christoph Becker
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Hartmannstr. 14, 91052 Erlangen, Germany;
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14
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Intestinal Macrophages at the Crossroad between Diet, Inflammation, and Cancer. Int J Mol Sci 2020; 21:ijms21144825. [PMID: 32650452 PMCID: PMC7404402 DOI: 10.3390/ijms21144825] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/03/2020] [Accepted: 07/04/2020] [Indexed: 12/11/2022] Open
Abstract
Intestinal macrophages are key players in the regulation of the oral tolerance, controlling gut homeostasis by discriminating innocuous antigens from harmful pathogens. Diet exerts a significant impact on human health, influencing the composition of gut microbiota and the developing of several non-communicable diseases, including cancer. Nutrients and microbiota are able to modify the profile of intestinal macrophages, shaping their key function in the maintenance of the gut homeostasis. Intestinal disease often occurs as a breakdown of this balance: defects in monocyte-macrophage differentiation, wrong dietary habits, alteration of microbiota composition, and impairment in the resolution of inflammation may contribute to the development of intestinal chronic inflammation and colorectal cancer. Accordingly, dietary interventions and macrophage-targeted therapies are emerging as innovative tools for the treatment of several intestinal pathologies. In this review, we will describe the delicate balance between diet, microbiota and intestinal macrophages in homeostasis and how the perturbation of this equilibrium may lead to the occurrence of inflammatory conditions in the gut. The understanding of the molecular pathways and dietary factors regulating the activity of intestinal macrophages might result in the identification of innovative targets for the treatments of intestinal pathologies.
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15
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Raggi F, Bosco MC. Targeting Mononuclear Phagocyte Receptors in Cancer Immunotherapy: New Perspectives of the Triggering Receptor Expressed on Myeloid Cells (TREM-1). Cancers (Basel) 2020; 12:cancers12051337. [PMID: 32456204 PMCID: PMC7281211 DOI: 10.3390/cancers12051337] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 05/18/2020] [Accepted: 05/22/2020] [Indexed: 12/14/2022] Open
Abstract
Inflammatory cells are major players in the onset of cancer. The degree of inflammation and type of inflammatory cells in the tumor microenvironment (TME) are responsible for tilting the balance between tumor progression and regression. Cancer-related inflammation has also been shown to influence the efficacy of conventional therapy. Mononuclear phagocytes (MPs) represent a major component of the inflammatory circuit that promotes tumor progression. Despite their potential to activate immunosurveillance and exert anti-tumor responses, MPs are subverted by the tumor to support its growth, immune evasion, and spread. MP responses in the TME are dictated by a network of stimuli integrated through the cross-talk between activatory and inhibitory receptors. Alterations in receptor expression/signaling can create excessive inflammation and, when chronic, promote tumorigenesis. Research advances have led to the development of new therapeutic strategies aimed at receptor targeting to induce a tumor-infiltrating MP switch from a cancer-supportive toward an anti-tumor phenotype, demonstrating efficacy in different human cancers. This review provides an overview of the role of MP receptors in inflammation-mediated carcinogenesis and discusses the most recent updates regarding their targeting for immunotherapeutic purposes. We focus in particular on the TREM-1 receptor, a major amplifier of MP inflammatory responses, highlighting its relevance in the development and progression of several types of inflammation-associated malignancies and the promises of its inhibition for cancer immunotherapy.
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16
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Dantas PHDS, Matos ADO, da Silva Filho E, Silva-Sales M, Sales-Campos H. Triggering receptor expressed on myeloid cells-1 (TREM-1) as a therapeutic target in infectious and noninfectious disease: a critical review. Int Rev Immunol 2020; 39:188-202. [PMID: 32379561 DOI: 10.1080/08830185.2020.1762597] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The triggering receptor expressed on myeloid cells-1 (TREM-1) is an innate immune receptor found in the surface of several immune and non-immune cells. Since its first description in 2000, this molecule and its soluble form (sTREM-1) have been implicated in many diseases with infectious and noninfectious origins. As an amplifier of inflammation, the membrane-associated TREM-1 (mTREM-1) isoform induces the production of pro-inflammatory mediators, thus contributing to the pathogenesis of diseases such as sepsis, arthritis, colitis and infections. In this context, many studies have used molecules capable of inhibiting TREM-1 activity as anti-inflammatory drugs. In this regard, a few peptides have been showing promising results in the amelioration of detrimental immune responses. Some commercially available drugs, including corticosteroids and antibiotics, with known anti-inflammatory effects, have also shown activity in TREM-1 signaling. Therefore, considering the potential of this receptor as a therapeutic target, the present review encompasses the main compounds explored so far in TREM-1 modulation, highlighting and critically discussing its effects and major drawbacks of such approaches.
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Affiliation(s)
| | - Amanda de Oliveira Matos
- Institute of Tropical Pathology and Public Health, Federal University of Goias, Goiânia, Goiás, Brazil
| | - Ernandes da Silva Filho
- Institute of Tropical Pathology and Public Health, Federal University of Goias, Goiânia, Goiás, Brazil
| | - Marcelle Silva-Sales
- Institute of Tropical Pathology and Public Health, Federal University of Goias, Goiânia, Goiás, Brazil
| | - Helioswilton Sales-Campos
- Institute of Tropical Pathology and Public Health, Federal University of Goias, Goiânia, Goiás, Brazil
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17
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Caër C, Wick MJ. Human Intestinal Mononuclear Phagocytes in Health and Inflammatory Bowel Disease. Front Immunol 2020; 11:410. [PMID: 32256490 PMCID: PMC7093381 DOI: 10.3389/fimmu.2020.00410] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 02/21/2020] [Indexed: 12/18/2022] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a complex immune-mediated disease of the gastrointestinal tract that increases morbidity and negatively influences the quality of life. Intestinal mononuclear phagocytes (MNPs) have a crucial role in maintaining epithelial barrier integrity while controlling pathogen invasion by activating an appropriate immune response. However, in genetically predisposed individuals, uncontrolled immune activation to intestinal flora is thought to underlie the chronic mucosal inflammation that can ultimately result in IBD. Thus, MNPs are involved in fine-tuning mucosal immune system responsiveness and have a critical role in maintaining homeostasis or, potentially, the emergence of IBD. MNPs include monocytes, macrophages and dendritic cells, which are functionally diverse but highly complementary. Despite their crucial role in maintaining intestinal homeostasis, specific functions of human MNP subsets are poorly understood, especially during diseases such as IBD. Here we review the current understanding of MNP ontogeny, as well as the recently identified human intestinal MNP subsets, and discuss their role in health and IBD.
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Affiliation(s)
- Charles Caër
- Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Mary Jo Wick
- Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
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18
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TREM Receptors Connecting Bowel Inflammation to Neurodegenerative Disorders. Cells 2019; 8:cells8101124. [PMID: 31546668 PMCID: PMC6829526 DOI: 10.3390/cells8101124] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 09/16/2019] [Accepted: 09/21/2019] [Indexed: 02/07/2023] Open
Abstract
Alterations in Triggering Receptors Expressed on Myeloid cells (TREM-1/2) are bound to a variety of infectious, sterile inflammatory, and degenerative conditions, ranging from inflammatory bowel disease (IBD) to neurodegenerative disorders. TREMs are emerging as key players in pivotal mechanisms often concurring in IBD and neurodegeneration, namely microbiota dysbiosis, leaky gut, and inflammation. In conditions of dysbiosis, compounds released by intestinal bacteria activate TREMs on macrophages, leading to an exuberant pro-inflammatory reaction up to damage in the gut barrier. In turn, TREM-positive activated macrophages along with inflammatory mediators may reach the brain through the blood, glymphatic system, circumventricular organs, or the vagus nerve via the microbiota-gut-brain axis. This leads to a systemic inflammatory response which, in turn, impairs the blood-brain barrier, while promoting further TREM-dependent neuroinflammation and, ultimately, neural injury. Nonetheless, controversial results still exist on the role of TREM-2 compared with TREM-1, depending on disease specificity, stage, and degree of inflammation. Therefore, the present review aimed to provide an update on the role of TREMs in the pathophysiology of IBD and neurodegeneration. The evidence here discussed the highlights of the potential role of TREMs, especially TREM-1, in bridging inflammatory processes in intestinal and neurodegenerative disorders.
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19
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Zhang X, Yang Y, Zhao Y. Macrophage phenotype and its relationship with renal function in human diabetic nephropathy. PLoS One 2019; 14:e0221991. [PMID: 31509552 PMCID: PMC6738594 DOI: 10.1371/journal.pone.0221991] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 05/30/2019] [Indexed: 12/30/2022] Open
Abstract
This study aimed to examine the macrophage phenotype and its relationship to renal function and histological changes in human DN and the effect of TREM-1 on high-glucose-induced macrophage activation. We observed that in renal tissue biopsies, the expression of CD68 and M1 was apparent in the glomeruli and interstitium, while accumulation of M2 and TREM-1 was primarily observed in the interstitium. The numbers of CD68, M1, and M2 macrophages infiltrating in the DN group were increased in a process-dependent manner compared with the control group, and the intensities of the infiltrates were proportional to the rate of subsequent decline in renal function. M1 macrophages were recruited into the kidney at an early stage (I+IIa) of DN. The M1-to-M2 macrophage ratio peaked at this time, whereas M2 macrophages predominated at later time points (III) when the percentage of M1/M2 macrophages was at its lowest level. In an in vitro study, we showed that under high glucose conditions, macrophages began to up-regulate their expression of TREM-1, M1, and marker iNOS and decreased the M2 marker MR. However, the above effects of high-glucose were abolished when TREM-1 expression was inhibited by TREM-1 siRNA. In conclusion, our study demonstrated that there was a positive correlation between the M1/M2 activation state and the progress of DN, and TREM-1 played an important role in high-glucose-induced macrophage phenotype transformation.
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Affiliation(s)
- Xiaoliang Zhang
- Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, Jiangsu, China
- * E-mail:
| | - Ying Yang
- Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, Jiangsu, China
| | - Yu Zhao
- Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, Jiangsu, China
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20
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Na YR, Stakenborg M, Seok SH, Matteoli G. Macrophages in intestinal inflammation and resolution: a potential therapeutic target in IBD. Nat Rev Gastroenterol Hepatol 2019; 16:531-543. [PMID: 31312042 DOI: 10.1038/s41575-019-0172-4] [Citation(s) in RCA: 573] [Impact Index Per Article: 95.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/13/2019] [Indexed: 02/07/2023]
Abstract
Macrophages are the gatekeepers of intestinal immune homeostasis as they discriminate between innocuous antigens and potential pathogens to maintain oral tolerance. However, in individuals with a genetic and environmental predisposition, regulation of intestinal immunity is impaired, leading to chronic relapsing immune activation and pathologies of the gastrointestinal tract, such as IBD. As evidence suggests a causal link between defects in the resolution of intestinal inflammation and altered monocyte-macrophage differentiation in patients with IBD, macrophages have been considered as a novel potential target to develop new treatment approaches. This Review discusses the molecular and cellular mechanisms involved in the differentiation and function of intestinal macrophages in homeostasis and inflammation, and their role in resolving the inflammatory process. Understanding the molecular pathways involved in the specification of intestinal macrophages might lead to a new class of targets that promote remission in patients with IBD.
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Affiliation(s)
- Yi Rang Na
- Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University Medical College, Seoul, South Korea
| | - Michelle Stakenborg
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Seung Hyeok Seok
- Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University Medical College, Seoul, South Korea.
| | - Gianluca Matteoli
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium.
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21
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Liu Q, Johnson EM, Lam RK, Wang Q, Bo Ye H, Wilson EN, Minhas PS, Liu L, Swarovski MS, Tran S, Wang J, Mehta SS, Yang X, Rabinowitz JD, Yang SS, Shamloo M, Mueller C, James ML, Andreasson KI. Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity. Nat Immunol 2019; 20:1023-1034. [PMID: 31263278 PMCID: PMC6778967 DOI: 10.1038/s41590-019-0421-2] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Accepted: 05/10/2019] [Indexed: 12/14/2022]
Abstract
Stroke is a multiphasic process in which initial cerebral ischemia is followed by secondary injury from immune responses to ischemic brain components. Here we demonstrate that peripheral CD11b+CD45+ myeloid cells magnify stroke injury via activation of triggering receptor expressed on myeloid cells 1 (TREM1), an amplifier of proinflammatory innate immune responses. TREM1 was induced within hours after stroke peripherally in CD11b+CD45+ cells trafficking to ischemic brain. TREM1 inhibition genetically or pharmacologically improved outcome via protective antioxidant and anti-inflammatory mechanisms. Positron electron tomography imaging using radiolabeled antibody recognizing TREM1 revealed elevated TREM1 expression in spleen and, unexpectedly, in intestine. In the lamina propria, noradrenergic-dependent increases in gut permeability induced TREM1 on inflammatory Ly6C+MHCII+ macrophages, further increasing epithelial permeability and facilitating bacterial translocation across the gut barrier. Thus, following stroke, peripheral TREM1 induction amplifies proinflammatory responses to both brain-derived and intestinal-derived immunogenic components. Critically, targeting this specific innate immune pathway reduces cerebral injury.
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Affiliation(s)
- Qingkun Liu
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Emily M Johnson
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Rachel K Lam
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Qian Wang
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Hong Bo Ye
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Edward N Wilson
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Paras S Minhas
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Ling Liu
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA
- Department of Chemistry, Princeton University, Princeton, NJ, USA
| | - Michelle S Swarovski
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Stephanie Tran
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Jing Wang
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Swapnil S Mehta
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Xi Yang
- Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Joshua D Rabinowitz
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA
- Department of Chemistry, Princeton University, Princeton, NJ, USA
| | - Samuel S Yang
- Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Mehrdad Shamloo
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
| | | | - Michelle L James
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
- Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Neuroscience Institute, Stanford University, Stanford, CA, USA
| | - Katrin I Andreasson
- Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
- Stanford Neuroscience Institute, Stanford University, Stanford, CA, USA.
- Stanford Immunology Program, Stanford University, Stanford, CA, USA.
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22
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Gaujoux R, Starosvetsky E, Maimon N, Vallania F, Bar-Yoseph H, Pressman S, Weisshof R, Goren I, Rabinowitz K, Waterman M, Yanai H, Dotan I, Sabo E, Chowers Y, Khatri P, Shen-Orr SS. Cell-centred meta-analysis reveals baseline predictors of anti-TNFα non-response in biopsy and blood of patients with IBD. Gut 2019; 68:604-614. [PMID: 29618496 PMCID: PMC6580771 DOI: 10.1136/gutjnl-2017-315494] [Citation(s) in RCA: 150] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 12/19/2017] [Accepted: 01/16/2018] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Although anti-tumour necrosis factor alpha (anti-TNFα) therapies represent a major breakthrough in IBD therapy, their cost-benefit ratio is hampered by an overall 30% non-response rate, adverse side effects and high costs. Thus, finding predictive biomarkers of non-response prior to commencing anti-TNFα therapy is of high value. DESIGN We analysed publicly available whole-genome expression profiles of colon biopsies obtained from multiple cohorts of patients with IBD using a combined computational deconvolution-meta-analysis paradigm which allows to estimate immune cell contribution to the measured expression and capture differential regulatory programmes otherwise masked due to variation in cellular composition. Insights from this in silico approach were experimentally validated in biopsies and blood samples of three independent test cohorts. RESULTS We found the proportion of plasma cells as a robust pretreatment biomarker of non-response to therapy, which we validated in two independent cohorts of immune-stained colon biopsies, where a plasma cellular score from inflamed biopsies was predictive of non-response with an area under the curve (AUC) of 82%. Meta-analysis of the cell proportion-adjusted gene expression data suggested that an increase in inflammatory macrophages in anti-TNFα non-responding individuals is associated with the upregulation of the triggering receptor expressed on myeloid cells 1 (TREM-1) and chemokine receptor type 2 (CCR2)-chemokine ligand 7 (CCL7) -axes. Blood gene expression analysis of an independent cohort, identified TREM-1 downregulation in non-responders at baseline, which was predictive of response with an AUC of 94%. CONCLUSIONS Our study proposes two clinically feasible assays, one in biopsy and one in blood, for predicting non-response to anti-TNFα therapy prior to initiation of treatment. Moreover, it suggests that mechanism-driven novel drugs for non-responders should be developed.
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Affiliation(s)
- Renaud Gaujoux
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel,CytoReason
| | - Elina Starosvetsky
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Naama Maimon
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel,Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Francesco Vallania
- Division of Biomedical Informatics Research, Department of Medicine, Stanford University, Palo Alto, California, USA,Stanford Institute for Immunity Transplantation and Infection, Department of Medicine, Stanford University, Palo Alto, California, USA
| | - Haggai Bar-Yoseph
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Sigal Pressman
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Roni Weisshof
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Idan Goren
- Department of Gastroenterology and Liver Diseases, IBD Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Keren Rabinowitz
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel,Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel
| | - Matti Waterman
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Henit Yanai
- Department of Gastroenterology and Liver Diseases, IBD Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel,Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel
| | - Iris Dotan
- Department of Gastroenterology and Liver Diseases, IBD Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel,Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel
| | - Edmond Sabo
- Department of Pathology, Rambam Health Care Campus, Haifa, Israel
| | - Yehuda Chowers
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel,Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Purvesh Khatri
- Division of Biomedical Informatics Research, Department of Medicine, Stanford University, Palo Alto, California, USA,Stanford Institute for Immunity Transplantation and Infection, Department of Medicine, Stanford University, Palo Alto, California, USA
| | - Shai S Shen-Orr
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
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23
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Functions of Macrophages in the Maintenance of Intestinal Homeostasis. J Immunol Res 2019; 2019:1512969. [PMID: 31011585 PMCID: PMC6442305 DOI: 10.1155/2019/1512969] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Revised: 12/03/2018] [Accepted: 12/16/2018] [Indexed: 02/07/2023] Open
Abstract
Intestinal macrophages constitute the largest pool of macrophages in the body and have emerged as crucial sentinels for pathogen recognition and elimination. The source and development of intestinal macrophages, as well as their distinct properties have been well documented. Intestinal macrophages exert their functions in the maintenance of intestinal homeostasis by shaping host-microbiota symbiosis, managing gut inflammation, crosstalking with T cells, and facilitating wound repair. Recently, nutritional regulation of intestinal macrophages has attracted substantial attention and is becoming a promising approach to disease prevention and control. Understanding the mechanisms employed by intestinal macrophages in mediating intestinal immune homeostasis and inflammation, as well as the mode of action of dietary nutrients in the modulating functions of intestinal macrophages, represents an opportunity to prevent and control inflammatory bowel diseases.
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24
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Fontana R, Raccosta L, Rovati L, Steffensen KR, Paniccia A, Jakobsson T, Melloni G, Bandiera A, Mangili G, Bergamini A, Maggioni D, Doglioni C, Crocchiolo R, Cella M, Mattioli M, Battaglia C, Colonna M, Russo V. Nuclear receptor ligands induce TREM-1 expression on dendritic cells: analysis of their role in tumors. Oncoimmunology 2018; 8:1554967. [PMID: 30723587 DOI: 10.1080/2162402x.2018.1554967] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 11/02/2018] [Accepted: 11/26/2018] [Indexed: 12/13/2022] Open
Abstract
Dendritic cells (DCs) initiate adaptive immune responses after their migration to secondary lymphoid organs. The LXR ligands/oxysterols and the RXR ligand 9-cis Retinoic Acid (9-cis RA) were shown to dampen DC migration to lymphoid organs through the inhibition of CCR7 expression. We performed transcriptomics of DCs undergoing maturation in the presence of the LXR ligand 22R-Hydroxycholesterol (22R-HC). The analysis highlighted more than 1500 genes modulated by 22R-HC treatment, including the triggering receptor expressed on myeloid cells (TREM)-1, which was found markedly up-regulated. We tested the effect of other nuclear receptor ligands (NRL) and we reported the induction of TREM-1 following RXR, RAR and VDR activation. From a functional point of view, triggering of TREM-1 induced by retinoids increased TNFα and IL-1β release, suggesting an active role of NRL-activated TREM-1+ DCs in inflammation-driven diseases, including cancer. Consistently with this hypothesis we detected DCs expressing TREM-1 in pleural effusions and ascites of cancer patients, an observation validated by the induction of TREM-1, LXR and RAR target genes when monocyte-DCs were activated in the presence of tumor-conditioned fluids. Finally, we observed a better control of LLC tumor growth in Trem-1-/- bone marrow chimera mice as compared to wild type chimera mice. Future studies will be necessary to shed light on the mechanism of TREM-1 induction by distinct NRL, and to characterize the role of TREM-1+ DCs in tumor growth.
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Affiliation(s)
- Raffaella Fontana
- Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Milan, Italy
| | - Laura Raccosta
- Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Milan, Italy
| | - Lucrezia Rovati
- Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Milan, Italy
| | - Knut R Steffensen
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
| | - Aida Paniccia
- Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Milan, Italy
| | - Tomas Jakobsson
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
| | - Giulio Melloni
- Thoracic Surgery Unit, IRCCS Scientific Institute San Raffaele, Milan, Italy
| | - Alessandro Bandiera
- Thoracic Surgery Unit, IRCCS Scientific Institute San Raffaele, Milan, Italy
| | - Giorgia Mangili
- Gynecologic Unit, IRCCS Scientific Institute San Raffaele, Milan, Italy
| | - Alice Bergamini
- Gynecologic Unit, IRCCS Scientific Institute San Raffaele, Milan, Italy
| | - Daniela Maggioni
- Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Milan, Italy
| | - Claudio Doglioni
- Department of Pathology, IRCCS Scientific Institute San Raffaele, Milan, Italy.,Department of Pathology, Università Vita-Salute San Raffaele, Milan, Italy
| | | | - Marina Cella
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
| | - Michela Mattioli
- Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, Segrate, Italy
| | - Cristina Battaglia
- Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, Segrate, Italy
| | - Marco Colonna
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
| | - Vincenzo Russo
- Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Milan, Italy
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Bain CC, Schridde A. Origin, Differentiation, and Function of Intestinal Macrophages. Front Immunol 2018; 9:2733. [PMID: 30538701 PMCID: PMC6277706 DOI: 10.3389/fimmu.2018.02733] [Citation(s) in RCA: 221] [Impact Index Per Article: 31.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Accepted: 11/06/2018] [Indexed: 12/12/2022] Open
Abstract
Macrophages are increasingly recognized as essential players in the maintenance of intestinal homeostasis and as key sentinels of the intestinal immune system. However, somewhat paradoxically, they are also implicated in chronic pathologies of the gastrointestinal tract, such as inflammatory bowel disease (IBD) and are therefore considered potential targets for novel therapies. In this review, we will discuss recent advances in our understanding of intestinal macrophage heterogeneity, their ontogeny and the potential factors that regulate their origin. We will describe how the local environment of the intestine imprints the phenotypic and functional identity of the macrophage compartment, and how this changes during intestinal inflammation and infection. Finally, we highlight key outstanding questions that should be the focus of future research.
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Affiliation(s)
- Calum C Bain
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Anika Schridde
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
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Gao S, Yi Y, Xia G, Yu C, Ye C, Tu F, Shen L, Wang W, Hua C. The characteristics and pivotal roles of triggering receptor expressed on myeloid cells-1 in autoimmune diseases. Autoimmun Rev 2018; 18:25-35. [PMID: 30408584 DOI: 10.1016/j.autrev.2018.07.008] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 07/09/2018] [Indexed: 01/13/2023]
Abstract
Triggering receptor expressed on myeloid cells-1 (TREM-1) engagement can directly trigger inflammation or amplify an inflammatory response by synergizing with TLRs or NLRs. Autoimmune diseases are a family of chronic systemic inflammatory disorders. The pivotal role of TREM-1 in inflammation makes it important to explore its immunological effects in autoimmune diseases. In this review, we summarize the structural and functional characteristics of TREM-1. Particularly, we discuss recent findings on TREM-1 pathway regulation in various autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), type 1 diabetes (T1D), and psoriasis. This receptor may potentially be manipulated to alter the inflammatory response to chronic inflammation and possible therapies are explored in this review.
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Affiliation(s)
- Sheng Gao
- Laboratory Animal Center, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
| | - Yongdong Yi
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Guojun Xia
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Chengyang Yu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Chenmin Ye
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Fuyang Tu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Leibin Shen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
| | - Wenqian Wang
- Department of Breast Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China.
| | - Chunyan Hua
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China.
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Che X, Park KC, Park SJ, Kang YH, Jin HA, Kim JW, Seo DH, Kim DK, Kim TI, Kim WH, Kim SW, Cheon JH. Protective effects of guggulsterone against colitis are associated with the suppression of TREM-1 and modulation of macrophages. Am J Physiol Gastrointest Liver Physiol 2018; 315:G128-G139. [PMID: 29543509 DOI: 10.1152/ajpgi.00027.2018] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Triggering receptor expressed on myeloid cells 1 (TREM-1)-expressing intestinal macrophages are significantly increased in the colons of patients with inflammatory bowel disease (IBD). We focused here on the effects of guggulsterone on macrophage modulation in colitis as a potential therapeutic molecule in human IBD and explore the underlying mechanisms. Gene expression in macrophages was examined and wound-healing assay using HT-29 cells was performed. Colitis in wild-type and IL-10-, Toll-like receptor 4 (TLR4)-, and myeloid differentiation primary response 88 (MyD88)-deficient mice was induced via the administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the colon. In both in vitro and in vivo experiments, guggulsterone suppressed intestinal inflammation amplified by TREM-1 stimulation, in which the suppression of NF-κB, activating protein-1, and proteasome pathways was involved. In the TNBS-induced colitis model, guggulsterone reduced disease activity index scores and TREM-1 expression, stimulated IL-10 production, and improved survival in wild-type mice. These effects were not observed in IL-10-, TLR4-, and MyD88-deficient mice. Guggulsterone also suppressed M1 polarization, yet induced the M2 phenotype in macrophages from IBD patients as well as from mice. These findings indicate that guggulsterone blocks the hyperactivation of macrophages via TREM-1 suppression and induces M2 polarization via IL-10 mediated by the TLR4 signaling pathway. Furthermore, this study provides a new rationale for the therapeutic potential of guggulsterone in the treatment of IBD. NEW & NOTEWORTHY We found that guggulsterone attenuates triggering receptor expressed on myeloid cells 1 (TREM-1)-mediated hyperactivation of macrophages and polarizes macrophages toward the M2 phenotype. This was mediated by IL-10 and partly Toll-like receptor 4 signaling pathways. Overall, these data support that guggulsterone as a natural plant sterol modulates macrophage phenotypes in colitis, which may be of novel therapeutic importance in inflammatory bowel disease treatment.
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Affiliation(s)
- Xiumei Che
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine , Seoul , Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine , Seoul , Korea
| | - Ki Cheong Park
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine , Seoul , Korea
- Department of Surgery, Yonsei University College of Medicine , Seoul , Korea
| | - Soo Jung Park
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine , Seoul , Korea
| | - You Hyun Kang
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine , Seoul , Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine , Seoul , Korea
| | - Hyun A Jin
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine , Seoul , Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine , Seoul , Korea
| | - Joo Wan Kim
- University of Toronto, Toronto, Ontario, Canada
| | - Dong Hyuk Seo
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine , Seoul , Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine , Seoul , Korea
| | - Dae Kyu Kim
- Chadwick International School , Seoul , Korea
| | - Tae Il Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine , Seoul , Korea
| | - Won Ho Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine , Seoul , Korea
| | - Seung Won Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine , Seoul , Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine , Seoul , Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine , Seoul , Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine , Seoul , Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine , Seoul , Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine , Seoul , Korea
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Han L, Fu L, Peng Y, Zhang A. Triggering Receptor Expressed on Myeloid Cells-1 Signaling: Protective and Pathogenic Roles on Streptococcal Toxic-Shock-Like Syndrome Caused by Streptococcus suis. Front Immunol 2018; 9:577. [PMID: 29619033 PMCID: PMC5871666 DOI: 10.3389/fimmu.2018.00577] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 03/07/2018] [Indexed: 12/15/2022] Open
Abstract
Streptococcus suis infections can cause septic shock, which is referred to as streptococcal toxic-shock-like syndrome (STSLS). The disease is characterized by a severe inflammatory response, multiple organ failure, and high mortality. However, no superantigen that is responsible for toxic shock syndrome was detected in S. suis, indicating that the mechanism underlying STSLS is different and remains to be elucidated. Triggering receptor expressed on myeloid cells-1 (TREM-1), belonging to the Ig superfamily, is an activating receptor expressed on myeloid cells, and has been recognized as a critical immunomodulator in several inflammatory diseases of both infectious and non-infectious etiologies. In this review, we discuss the current understanding of the immunoregulatory functions of TREM-1 on acute infectious diseases and then highlight the crucial roles of TREM-1 on the development of STSLS.
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Affiliation(s)
- Li Han
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Lei Fu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.,Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, China.,Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture, Wuhan, China.,International Research Center for Animal Disease, Ministry of Science and Technology, Wuhan, China
| | - Yongbo Peng
- Institute for Medical Biology, Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Anding Zhang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.,Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, China.,Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture, Wuhan, China.,International Research Center for Animal Disease, Ministry of Science and Technology, Wuhan, China
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Shi R, Zhang J, Peng Z, Yuan S, Gao S, Chen L, Yuan Y. Expression level of 12-amino acid triggering receptor on myeloid cells-like transcript 1 derived peptide alleviates lipopolysaccharide-induced acute lung injury in mice. Int J Mol Med 2018; 41:2159-2168. [PMID: 29393375 DOI: 10.3892/ijmm.2018.3443] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Accepted: 11/23/2017] [Indexed: 11/06/2022] Open
Abstract
Acute lung injury (ALI) is a critical illness with a high morbidity and mortality rate due to severe inflammation in the lungs. The effects and underlying mechanism of the triggering receptor expressed on myeloid cells‑1 (TREM‑1)‑like transcript‑1‑derived peptide (LR12) on ALI remain unclear. The aim of the present study was to determine whether LR12 attenuates lipopolysaccharide (LPS)‑induced ALI and elucidate the mechanism underlying it. Male C57BL/6 mice were randomly assigned to three groups as follows: Sham group, LPS + scramble group and LPS + LR12 group. Normal saline (NS) or LPS was administrated by intratracheal instillation, and NS, LR12 or LR12 scramble was administered intraperitoneally 30 min later. The treatment was repeated every 3 h three times. Mice were sacrificed 24 h later. Pulmonary pathological changes, the lung wet/dry weight ratio, the macrophage and neutrophil counts in bronchoalveolar lavage fluid and myeloperoxidase (MPO) activity in the lung tissues were observed. The inflammatory cytokines were evaluated by enzyme‑linked immunosorbent assay and lung neutrophil infiltration was detected by immunohistochemistry. Nuclear factor (NF)‑κB p65 and TREM‑1 were analyzed by western blotting, and the activation of NF‑κB was detected by electrophoretic mobility shift assay. LPS‑induced pathohistological injury, edema and neutrophil infiltration were significantly alleviated by TREM‑1 inhibitor, LR12. The proinflammatory cytokines [interleukin (IL)‑6, IL‑1β, tumor necrosis factor‑α] and chemokines (keratinocyte chemokine and monocyte chemoattractant protein‑1) were significantly reduced, whereas the anti‑inflammatory cytokines, IL‑10 were significantly increased by LR12. LR12 was identified to significantly decrease p65 expression levels in the nucleus and inhibit the activity of NF‑κB. Furthermore, LR12 alleviated LPS‑induced ALI by reducing the expression of TREM‑1, increasing the release of soluble TREM‑1 and inhibiting activation of the NF-κB signaling pathway.
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Affiliation(s)
- Ruili Shi
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Jiancheng Zhang
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Zhang Peng
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Shiying Yuan
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Sumin Gao
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Lin Chen
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yin Yuan
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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Kökten T, Gibot S, Lepage P, D'Alessio S, Hablot J, Ndiaye NC, Busby-Venner H, Monot C, Garnier B, Moulin D, Jouzeau JY, Hansmannel F, Danese S, Guéant JL, Muller S, Peyrin-Biroulet L. TREM-1 Inhibition Restores Impaired Autophagy Activity and Reduces Colitis in Mice. J Crohns Colitis 2018; 12:230-244. [PMID: 28961797 DOI: 10.1093/ecco-jcc/jjx129] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 09/15/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Triggering receptor expressed on myeloid cells-1 [TREM-1] is known to amplify inflammation in several diseases. Autophagy and endoplasmic reticulum [ER] stress, which activate the unfolded protein response [UPR], are closely linked and defects in these pathways contribute to the pathogenesis of inflammatory bowel disease [IBD]. Both autophagy and UPR are deeply involved in host-microbiota interactions for the clearance of intracellular pathogens, thus contributing to dysbiosis. We investigated whether inhibition of TREM-1 would prevent aberrant inflammation by modulating autophagy and ER stress and preventing dysbiosis. METHODS An experimental mouse model of colitis was established by dextran sulphate sodium treatment. TREM-1 was inhibited, either pharmacologically by LR12 peptide or genetically with Trem-1 knock-out [KO] mice. Colon tissues and faecal pellets of control and colitic mice were used. Levels of macroautophagy, chaperone-mediated autophagy [CMA], and UPR proteins were evaluated by western blotting. The composition of the intestinal microbiota was assessed by MiSeq sequencing in both LR12-treated and KO animals. RESULTS We confirmed that inhibition of TREM-1 attenuates the severity of colitis clinically, endoscopically and histologically. We observed an increase in macroautophagy [ATG1/ULK-1, ATG13, ATG5, ATG16L1, and MAP1LC3-I/II] and in CMA [HSPA8 and HSP90AA1], whereas there was a decrease in the UPR [PERK, IRE-1α, and ATF-6α] protein expression levels in TREM-1 inhibited colitic mice. TREM-1 inhibition prevented dysbiosis. CONCLUSIONS TREM-1 may represent a novel drug target for the treatment of IBD, by modulating autophagy activity and ER stress.
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Affiliation(s)
- Tunay Kökten
- Faculté de Médecine, Université de Lorraine, Vandœuvre-Lès-Nancy, France
| | - Sébastien Gibot
- Faculté de Médecine, Université de Lorraine, Vandœuvre-Lès-Nancy, France.,Service de Réanimation Médicale, Hôpital Central, Nancy, France
| | - Patricia Lepage
- Micalis Institute, Université Paris-Saclay, Jouy-en-Josas, France
| | - Silvia D'Alessio
- Department of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center and Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Julie Hablot
- Ingénierie Moléculaire et Physiopathologie Articulaire [IMoPA], Université de Lorraine, Vandœuvre-Lès-Nancy, France
| | | | - Hélène Busby-Venner
- Département d'Anatomie et Cytologie Pathologiques, Centre Hospitalier Universitaire Nancy-Brabois, Vandœuvre-Lès-Nancy, France
| | - Céline Monot
- Micalis Institute, Université Paris-Saclay, Jouy-en-Josas, France
| | - Benjamin Garnier
- Immunopathologie et Chimie Thérapeutique, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France
| | - David Moulin
- Ingénierie Moléculaire et Physiopathologie Articulaire [IMoPA], Université de Lorraine, Vandœuvre-Lès-Nancy, France
| | - Jean-Yves Jouzeau
- Ingénierie Moléculaire et Physiopathologie Articulaire [IMoPA], Université de Lorraine, Vandœuvre-Lès-Nancy, France
| | - Franck Hansmannel
- Faculté de Médecine, Université de Lorraine, Vandœuvre-Lès-Nancy, France
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Humanitas Clinical and Research Center, Milan, Italy
| | - Jean-Louis Guéant
- Faculté de Médecine, Université de Lorraine, Vandœuvre-Lès-Nancy, France
| | - Sylviane Muller
- Immunopathologie et Chimie Thérapeutique, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France
| | - Laurent Peyrin-Biroulet
- Faculté de Médecine, Université de Lorraine, Vandœuvre-Lès-Nancy, France.,Département d'Hépatogastroentérologie, Centre Hospitalier Universitaire Nancy-Brabois, Vandœuvre-Lès-Nancy, France
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Piroozmand A, Soltani B, Razavizadeh M, Matini AH, Moosavi GA, Salehi M, Soltani S. Comparison of gastric juice soluble triggering receptor expressed on myeloid cells and C-reactive protein for detection of Helicobacter pylori infection. Electron Physician 2017; 9:6111-6119. [PMID: 29560167 PMCID: PMC5843441 DOI: 10.19082/6111] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 10/20/2017] [Indexed: 12/11/2022] Open
Abstract
Background and aim Triggering receptor expressed on myeloid cells (TREM-1) is a receptor on phagocytes that is triggered by infectious agents. The soluble form of it (sTREM-1) can be elevated in gastric juice by Helicobacter pylori (H. pylori) infection of gastric mucosa. The aim of this study was to compare the diagnostic values of sTREM-1 and C-reactive protein (CRP) for detection of H. pylori infection in gastric mucosa. Methods In this diagnostic accuracy study on cases who underwent endoscopy from March 2015 to July 2016 in Shahid Beheshti Hospital, Kashan, Iran, gastric juice sTREM-1 and CRP concentrations were measured by enzyme-linked immunosorbent assays (ELISA) and their diagnostic values were compared to detect H. pylori infection. Gold standard test was histopathology. Data were entered into SPSS software version 16. Statistical analysis was made by Kolmogorov-Smirnov, Chi-square, Independent-samples t-test, Kruskal-Wallis, Mann-Whitney U, Pearson product-moment correlation, Receiver operating characteristic curve (ROC), Brier score, Nagelkerke R square and scaled reliability test. Results Of a total of 160 cases, 81 (50.6%) were H. pylori-positive based on pathology. The level of sTREM-1 in H. pylori-positive patients was significantly higher than H. pylori-negative patients (p=0.000), but no significant difference between CRP concentrations was shown between groups (p=0.7). Sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and accuracy of sTREM-1 were 82%, 75%, 3.3, 0.25, 78% and for CRP were 62%, 40%, 1.02, 0.98, 51% respectively for diagnosis of H. pylori infection. True positive and negative rates were 66 (81.5%) and 59 (74.7%) for sTREM-1 and 50 (61.7%) and 31 (39.2%) for CRP. The levels of sTREM-1 and CRP were not significantly different between endoscopic finding groups (p=0.97, p=0.2 respectively). Conclusion Despite CRP, sTREM-1 was a relatively acceptable indicator of H. pylori infection of gastric mucosa.
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Affiliation(s)
- Ahmad Piroozmand
- Ph.D. of Virology, Associate Professor, Department of Microbiology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran.,Autoimmune Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Babak Soltani
- M.D., Pediatric Infectious Diseases Specialist, Associate Professor, Department of Pediatrics, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran.,Infectious Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohsen Razavizadeh
- M.D., Gastroenterologist, Assistant Professor, Department of Internal Medicine, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Amir Hasan Matini
- M.D., Pathologist, Assistant Professor, Department of Pathology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Gholam Abbas Moosavi
- M.Sc. of Biostatistics, Lecturer, Department of Public Health, Faculty of Health, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Salehi
- M.D., Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Siamak Soltani
- M.D., Forensic Medicine Specialist, Associate Professor, Department of Forensic Medicine, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Abstract
Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune responses. Increasing evidence suggests a role for TREM-1 not only in acute pathogen-induced reactions but also in chronic and non-infectious inflammatory disorders, including various types of cancer. Here, we demonstrate that genetic deficiency in Trem1 protects from colorectal cancer. In particular, Trem1−/− mice exhibited reduced tumor numbers and load in an experimental model of inflammation-driven tumorigenesis. Gene expression analysis of Trem1−/− versus Trem1+/+ tumor tissue demonstrated distinct immune signatures. Whereas Trem1−/− tumors showed an increased abundance of transcripts linked to adaptive immunity, Trem1+/+ tumors were characterized by overexpression of innate pro-inflammatory genes associated with tumorigenesis. Compared to adjacent tumor-free colonic mucosa, expression of Trem1 was increased in murine and human colorectal tumors. Unexpectedly, TREM-1 was not detected on tumor-associated Ly6C− MHC class II+ macrophages. In contrast, TREM-1 was highly expressed by tumor-infiltrating neutrophils which represented the predominant myeloid population in Trem1+/+ but not in Trem1−/− tumors. Collectively, our findings demonstrate a clear role of TREM-1 for intestinal tumorigenesis and indicate TREM-1-expressing neutrophils as critical players in colorectal tumor development.
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Dennis EA, Robinson TO, Smythies LE, Smith PD. Characterization of Human Blood Monocytes and Intestinal Macrophages. ACTA ACUST UNITED AC 2017; 118:14.3.1-14.3.14. [PMID: 28762485 DOI: 10.1002/cpim.30] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Monocytes and macrophages play fundamental roles in defense against microbes, clearance of senescent and dead cells, and immunoregulation. Although blood monocytes are the source of intestinal macrophages in the developed mucosal immune system, blood monocytes and intestinal macrophages from healthy human subjects display distinct phenotypic and functional differences. Blood monocytes can be induced to polarize into M1 and M2 macrophages, whereas intestinal macrophages appear to be terminally differentiated and are unable to undergo such inducible polarization. Nevertheless, in response to local conditions, monocytes differentiated into intestinal macrophages display phenotypic and functional characteristics that enhance their capacity to provide non-inflammatory host defense and participate in local immunoregulation. Using the protocols described here, this unit presents the key phenotypic and functional differences between human blood monocytes and intestinal macrophages, as well as between mouse and human intestinal macrophages. © 2017 by John Wiley & Sons, Inc.
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Affiliation(s)
- Evida A Dennis
- Department of Medicine (Gastroenterology), VA Medical Center, Birmingham, Alabama
| | - Tanya O Robinson
- Department of Pediatrics (Rheumatology), VA Medical Center, Birmingham, Alabama
| | - Lesley E Smythies
- Department of Medicine (Gastroenterology), VA Medical Center, Birmingham, Alabama
| | - Phillip D Smith
- Department of Medicine (Gastroenterology), VA Medical Center, Birmingham, Alabama.,VA Medical Center, Birmingham, Alabama
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Sanders TJ, Yrlid U, Maloy KJ. Intestinal Mononuclear Phagocytes in Health and Disease. Microbiol Spectr 2017; 5:10.1128/microbiolspec.mchd-0047-2016. [PMID: 28102120 PMCID: PMC11687448 DOI: 10.1128/microbiolspec.mchd-0047-2016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Indexed: 12/20/2022] Open
Abstract
The intestine is the tissue of the body with the highest constitutive exposure to foreign antigen and is also a common entry portal for many local and systemic pathogens. Therefore, the local immune system has the unenviable task of balancing efficient responses to dangerous pathogens with tolerance toward beneficial microbiota and food antigens. As in most tissues, the decision between tolerance and immunity is critically governed by the activity of local myeloid cells. However, the unique challenges posed by the intestinal environment have necessitated the development of several specialized mononuclear phagocyte populations with distinct phenotypic and functional characteristics that have vital roles in maintaining barrier function and immune homeostasis in the intestine. Intestinal mononuclear phagocyte populations, comprising dendritic cells and macrophages, are crucial for raising appropriate active immune responses against ingested pathogens. Recent technical advances, including microsurgical approaches allowing collection of cells migrating in intestinal lymph, intravital microscopy, and novel gene-targeting approaches, have led to clearer distinctions between mononuclear phagocyte populations in intestinal tissue. In this review, we present an overview of the various subpopulations of intestinal mononuclear phagocytes and discuss their phenotypic and functional characteristics. We also outline their roles in host protection from infection and their regulatory functions in maintaining immune tolerance toward beneficial intestinal antigens.
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Affiliation(s)
| | - Ulf Yrlid
- Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, S-405 30 Gothenburg, Sweden
| | - Kevin J Maloy
- Sir William Dunn School of Pathology, Oxford, OX1 3RE, United Kingdom
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An Antibody Against Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) Dampens Proinflammatory Cytokine Secretion by Lamina Propria Cells from Patients with IBD. Inflamm Bowel Dis 2016; 22:1803-11. [PMID: 27243593 DOI: 10.1097/mib.0000000000000822] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Triggering receptor expressed on myeloid cells 1 (TREM-1) is a potent amplifier of inflammation. Recently, the antimicrobial peptide PGLYRP-1 was shown to be the ligand of TREM-1. Here, the ability of an anti-TREM-1 antibody to dampen the release of proinflammatory cytokines by colon lamina propria cells (LPCs) from patients with IBD was investigated and correlated with PGLYRP-1 levels. METHODS Biopsies from patients with ulcerative colitis (UC, n = 45) or Crohn's disease (CD, n = 26) were compared with those from individuals undergoing colonoscopy for other reasons (n = 17). TREM-1 expression was analyzed on myeloid cells by flow cytometry. Cell culture experiments with LPCs were used to analyze PGLYRP-1 and inflammatory cytokine levels and assess the effect of anti-TREM-1 on cytokine secretion. RESULTS The frequency of TREM-1-expressing neutrophils and recruited macrophages was higher in inflamed than in noninflamed biopsies. The PGLYRP-1 level in inflamed tissue was higher than in noninflamed tissue; it was produced primarily by neutrophils, and its level correlated with the secretion of proinflammatory cytokines. Secretion of myeloperoxidase, tumor necrosis factor-α, interleukin-1β, and interleukin-8 by LPCs stimulated with the potent TREM-1 agonist consisting of PGLYRP-1 complexed with peptidoglycan was reduced in the presence of anti-TREM-1. Moreover, a blocking effect of anti-TREM-1 was apparent when LPCs from a subset of inflamed individuals with elevated PGLYRP-1 were stimulated with killed bacteria. CONCLUSIONS An anti-TREM-1 antibody can dampen secretion of proinflammatory cytokines in inflamed patients with elevated PGLYRP-1. Moreover, PGLYRP-1 + myeloperoxidase is a potential biomarker for predicting the effect of anti-TREM-1 therapy.
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Kühl AA, Erben U, Kredel LI, Siegmund B. Diversity of Intestinal Macrophages in Inflammatory Bowel Diseases. Front Immunol 2015; 6:613. [PMID: 26697009 PMCID: PMC4670857 DOI: 10.3389/fimmu.2015.00613] [Citation(s) in RCA: 140] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Accepted: 11/22/2015] [Indexed: 12/23/2022] Open
Abstract
Macrophages as innate immune cells and fast responders to antigens play a central role in protecting the body from the luminal content at a huge interface. Chronic inflammation in inflammatory bowel diseases massively alters the number and the subset diversity of intestinal macrophages. We here address the diversity within the human intestinal macrophage compartment at the level of similarities and differences between homeostasis and chronic intestinal inflammation as well as between UC and CD, including the potential role of macrophage subsets for intestinal fibrosis. Hallmark of macrophages is their enormous plasticity, i.e., their capacity to integrate signals from their environment thereby changing their phenotype and functions. Tissue-resident macrophages located directly beneath the surface epithelium in gut homeostasis are mostly tolerogenic. The total number of macrophages increases with luminal contents entering the mucosa through a broken intestinal barrier in ulcerative colitis (UC) as well as in Crohn's disease (CD). Although not fully understood, the resulting mixtures of tissue-resident and tissue-infiltrating macrophages in both entities are diverse with respect to their phenotypes and their distribution. Macrophages in UC mainly act within the intestinal mucosa. In CD, macrophages can also be found in the muscularis and the mesenteric fat tissue compartment. Taken together, the present knowledge on human intestinal macrophages so far provides a good starting point to dig deeper into the similarities and differences of functional subsets and to finally use their phenotypical diversity as markers for complex local milieus in health and disease.
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Affiliation(s)
- Anja A Kühl
- Division of Gastroenterology, Infectious Diseases and Rheumatology, Medical Department, Charité - Universitätsmedizin Berlin , Berlin , Germany ; Research Center ImmunoSciences, Charité - Universitätsmedizin Berlin , Berlin , Germany
| | - Ulrike Erben
- Division of Gastroenterology, Infectious Diseases and Rheumatology, Medical Department, Charité - Universitätsmedizin Berlin , Berlin , Germany ; Research Center ImmunoSciences, Charité - Universitätsmedizin Berlin , Berlin , Germany
| | - Lea I Kredel
- Division of Gastroenterology, Infectious Diseases and Rheumatology, Medical Department, Charité - Universitätsmedizin Berlin , Berlin , Germany
| | - Britta Siegmund
- Division of Gastroenterology, Infectious Diseases and Rheumatology, Medical Department, Charité - Universitätsmedizin Berlin , Berlin , Germany ; Research Center ImmunoSciences, Charité - Universitätsmedizin Berlin , Berlin , Germany
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Li C, Luo X, Lin Y, Tang X, Ling L, Wang L, Jiang Y. A Higher Frequency of CD14+ CD169+ Monocytes/Macrophages in Patients with Colorectal Cancer. PLoS One 2015; 10:e0141817. [PMID: 26509874 PMCID: PMC4625021 DOI: 10.1371/journal.pone.0141817] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 10/13/2015] [Indexed: 12/31/2022] Open
Abstract
Objective Monocytes and macrophages can infiltrate into tumor microenvironment and regulate the progression of tumors. This study aimed at determining the frequency of different subsets of circulating monocytes and tumor infiltrating macrophages (TIMs) in patients with colorectal cancer (CRC). Methods The frequency of different subsets of circulating monocytes was characterized in 46 CRC patients and 22 healthy controls (HC) by flow cytometry. The frequency of different subsets of macrophages was analyzed in TIMs from 30 tumor tissues and in lamina propria mononuclear cells (LPMCs) from 12 non-tumor tissues. The concentrations of plasma cytokines and carcinoembryonic antigen (CEA) were determined. The potential association of these measures with the values of clinical parameters was analyzed. Results In comparison with that in the HC, the percentages of circulating CD14+CD169+, CD14+CD169+CD163+ and CD14+CD169+CD206+ monocytes and TIMs CD14+CD169+ as well as IL-10+CD14+CD169+, but not IL-12+ CD14+CD169+ macrophages were significantly increased, accompanied by higher levels of plasma IL-10 in the CRC patients. The percentages of CD14+CD169+ circulating monocytes and TIM macrophages were associated with the stage of disease and correlated positively with the levels of plasma IL-10 and CEA in CRC patients. Conclusion Our data suggest that an increase in the frequency of CD14+CD169+ cells may be associated with the development and progression of CRC and is concomitant rise of both, pro-tumor (M2-like, IL-10 producing) and anti-tumor (M1-like, IL-12 producing) monocytes and infiltrating macrophages. The frequency of CD14+CD169+ circulating monocytes and infiltrating macrophages may serve as a biomarker for evaluating the pathogenic degrees of CRC.
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Affiliation(s)
- Chenguang Li
- Department of Colorectal & Anal Surgery, The First Hospital of Jilin University, Changchun, China
| | - Xiaofan Luo
- Department of Colorectal & Anal Surgery, The First Hospital of Jilin University, Changchun, China
| | - Yuyang Lin
- Department of Colorectal & Anal Surgery, The First Hospital of Jilin University, Changchun, China
| | - Xiuqi Tang
- Department of Colorectal & Anal Surgery, The First Hospital of Jilin University, Changchun, China
| | - Limian Ling
- Department of Colorectal & Anal Surgery, The First Hospital of Jilin University, Changchun, China
| | - Lei Wang
- Department of Colorectal & Anal Surgery, The First Hospital of Jilin University, Changchun, China
- * E-mail: (YJ); (LW)
| | - Yanfang Jiang
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, China
- * E-mail: (YJ); (LW)
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Nguyen AH, Berim IG, Agrawal DK. Chronic inflammation and cancer: emerging roles of triggering receptors expressed on myeloid cells. Expert Rev Clin Immunol 2015; 11:849-57. [PMID: 25954917 DOI: 10.1586/1744666x.2015.1043893] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Inflammation is tightly regulated by a vast system that is intricately interconnected with innate immunity. Aberrations in expression or signaling, such as in innate immune receptors, can create excessive inflammation and, when chronic, often promote oncogenesis. The triggering receptor expressed on myeloid cells receptor family has been characterized as a major player in the amplification and signaling of the inflammatory response. In a number of chronic inflammatory conditions and malignancies, the triggering receptor expressed on myeloid cells has been implicated in disease severity and progression. In this article, the current understanding of triggering receptor expressed on myeloid cells function in pre-malignant, malignant and chronic inflammatory conditions is critically reviewed. The potential for therapeutic application is also discussed.
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Affiliation(s)
- Austin Huy Nguyen
- Center for Clinical and Translational Science, Creighton University School of Medicine, 2500 California Plaza Omaha, NE 68178, USA
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Schey R, Danzer C, Mattner J. Perturbations of mucosal homeostasis through interactions of intestinal microbes with myeloid cells. Immunobiology 2015; 220:227-235. [PMID: 25466587 PMCID: PMC4273735 DOI: 10.1016/j.imbio.2014.11.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 11/20/2014] [Accepted: 11/21/2014] [Indexed: 12/28/2022]
Abstract
Mucosal surfaces represent the largest areas of interactions of the host with its environment. Subsequently, the mucosal immune system has evolved complex strategies to maintain the integrity of the host by inducing protective immune responses against pathogenic and tolerance against dietary and commensal microbial antigens within the broad range of molecules the intestinal epithelium is exposed to. Among many other specialized cell subsets, myeloid cell populations - due to their strategic location in the subepithelial lamina propria - are the first ones to scavenge and process these intestinal antigens and to send consecutive signals to other immune and non-immune cell subsets. Thus, myeloid cell populations represent attractive targets for clinical intervention in chronic inflammatory bowel diseases (IBDs) such as ulcerative colitis (UC) and Crohn's disease (CD) as they initiate and modulate inflammatory or regulatory immune response and shape the intestinal T cell pool. Here, we discuss the interactions of the intestinal microbiota with dendritic cell and macrophage populations and review in this context the literature on four promising candidate molecules that are critical for the induction and maintenance of intestinal homeostasis on the one hand, but also for the initiation and propagation of chronic intestinal inflammation on the other.
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Affiliation(s)
- Regina Schey
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany.
| | - Claudia Danzer
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany
| | - Jochen Mattner
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany; Division of Immunobiology, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.
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Lemarié J, Barraud D, Gibot S. Host response biomarkers in sepsis: overview on sTREM-1 detection. Methods Mol Biol 2015; 1237:225-239. [PMID: 25319790 DOI: 10.1007/978-1-4939-1776-1_17] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
The diagnosis of sepsis, and especially its differentiation from sterile inflammation, may be challenging. TREM-1, the triggering receptor expressed on myeloid cells-1, is an amplifier of the innate immune response. Its soluble form acts as a decoy for the natural TREM-1 ligand and dampens its activation. In this chapter, we review the numerous studies that have evaluated the usefulness of sTREM-1 concentration determination for the diagnosis and the prognosis evaluation of sepsis or localized infection. Nowadays, sandwich ELISA kits are available and the assay is described.
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Affiliation(s)
- Jérémie Lemarié
- Department of Medical Intensive Care, Hôpital Central, 29 avenue du Maréchal de Lattre de Tassigny, 54035, Nancy Cedex, France
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Kim JY, Kim N, Yenari MA. Mechanisms and potential therapeutic applications of microglial activation after brain injury. CNS Neurosci Ther 2014; 21:309-19. [PMID: 25475659 DOI: 10.1111/cns.12360] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Revised: 10/24/2014] [Accepted: 10/26/2014] [Indexed: 12/14/2022] Open
Abstract
As the resident immune cells of the central nervous system, microglia rapidly respond to brain insults, including stroke and traumatic brain injury. Microglial activation plays a major role in neuronal cell damage and death by releasing a variety of inflammatory and neurotoxic mediators. Their activation is an early response that may exacerbate brain injury and many other stressors, especially in the acute stages, but are also essential to brain recovery and repair. The full range of microglial activities is still not completely understood, but there is accumulating knowledge about their role following brain injury. We review recent progress related to the deleterious and beneficial effects of microglia in the setting of acute neurological insults and the current literature surrounding pharmacological interventions for intervention.
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Affiliation(s)
- Jong-Youl Kim
- Department of Neurology, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, CA, USA
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Roe K, Gibot S, Verma S. Triggering receptor expressed on myeloid cells-1 (TREM-1): a new player in antiviral immunity? Front Microbiol 2014; 5:627. [PMID: 25505454 PMCID: PMC4244588 DOI: 10.3389/fmicb.2014.00627] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Accepted: 11/03/2014] [Indexed: 11/25/2022] Open
Abstract
The triggering receptor expressed on myeloid cells (TREM) family of protein receptors is rapidly emerging as a critical regulator of a diverse array of cellular functions, including amplification of inflammation. Although the ligand(s) for TREM have not yet been fully identified, circumstantial evidence indicates that danger- and pathogen-associated molecular patterns (DAMPs and PAMPs) can induce cytokine production via TREM-1 activation. The discovery of novel functions of TREM, such as regulation of T-cell proliferation and activation of antigen-presenting cells, suggests a larger role of TREM proteins in modulation of host immune responses to microbial pathogens, such as bacteria and fungi. However, the significance of TREM signaling in innate immunity to virus infections and the underlying mechanisms remain largely unclear. The nature and intensity of innate immune responses, specifically production of type I interferon and inflammatory cytokines is a crucial event in dictating recovery vs. adverse outcomes from virus infections. In this review, we highlight the emerging roles of TREM-1, including synergy with classical pathogen recognition receptors. Based on the literature using viral PAMPs and other infectious disease models, we further discuss how TREM-1 may influence host-virus interactions and viral pathogenesis. A deeper conceptual understanding of the mechanisms associated with pathogenic and/or protective functions of TREM-1 in antiviral immunity is essential to develop novel therapeutic strategies for the control of virus infection by modulating innate immune signaling.
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Affiliation(s)
- Kelsey Roe
- Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa Honolulu, HI, USA
| | - Sébastien Gibot
- Service de Réanimation Médicale, University Hospital of Nancy Nancy, France
| | - Saguna Verma
- Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa Honolulu, HI, USA
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Genua M, Rutella S, Correale C, Danese S. The triggering receptor expressed on myeloid cells (TREM) in inflammatory bowel disease pathogenesis. J Transl Med 2014; 12:293. [PMID: 25347935 PMCID: PMC4231187 DOI: 10.1186/s12967-014-0293-z] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Accepted: 10/09/2014] [Indexed: 01/29/2023] Open
Abstract
The Triggering Receptors Expressed on Myeloid cells (TREM) are a family of cell-surface molecules that control inflammation, bone homeostasis, neurological development and blood coagulation. TREM-1 and TREM-2, the best-characterized receptors so far, play divergent roles in several infectious diseases. In the intestine, TREM-1 is highly expressed by macrophages, contributing to inflammatory bowel disease (IBD) pathogenesis. Contrary to current understanding, TREM-2 also promotes inflammation in IBD by fueling dendritic cell functions. This review will focus specifically on recent insights into the role of TREM proteins in IBD development, and discuss opportunities for novel treatment approaches.
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Affiliation(s)
- Marco Genua
- IBD Center, Humanitas Clinical and Research Hospital, Rozzano, Italy.
| | - Sergio Rutella
- Division of Translational Medicine, Research Branch, Sidra Medical & Research Center, Doha, Qatar.
| | - Carmen Correale
- IBD Center, Humanitas Clinical and Research Hospital, Rozzano, Italy.
| | - Silvio Danese
- IBD Center, Humanitas Clinical and Research Hospital, Rozzano, Italy.
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Weber B, Schuster S, Zysset D, Rihs S, Dickgreber N, Schürch C, Riether C, Siegrist M, Schneider C, Pawelski H, Gurzeler U, Ziltener P, Genitsch V, Tacchini-Cottier F, Ochsenbein A, Hofstetter W, Kopf M, Kaufmann T, Oxenius A, Reith W, Saurer L, Mueller C. TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance. PLoS Pathog 2014; 10:e1003900. [PMID: 24453980 PMCID: PMC3894224 DOI: 10.1371/journal.ppat.1003900] [Citation(s) in RCA: 112] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Accepted: 12/10/2013] [Indexed: 12/02/2022] Open
Abstract
Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune reactions. While TREM-1-amplified responses likely aid an improved detection and elimination of pathogens, excessive production of cytokines and oxygen radicals can also severely harm the host. Studies addressing the pathogenic role of TREM-1 during endotoxin-induced shock or microbial sepsis have so far mostly relied on the administration of TREM-1 fusion proteins or peptides representing part of the extracellular domain of TREM-1. However, binding of these agents to the yet unidentified TREM-1 ligand could also impact signaling through alternative receptors. More importantly, controversial results have been obtained regarding the requirement of TREM-1 for microbial control. To unambiguously investigate the role of TREM-1 in homeostasis and disease, we have generated mice deficient in Trem1. Trem1−/− mice are viable, fertile and show no altered hematopoietic compartment. In CD4+ T cell- and dextran sodium sulfate-induced models of colitis, Trem1−/− mice displayed significantly attenuated disease that was associated with reduced inflammatory infiltrates and diminished expression of pro-inflammatory cytokines. Trem1−/− mice also exhibited reduced neutrophilic infiltration and decreased lesion size upon infection with Leishmania major. Furthermore, reduced morbidity was observed for influenza virus-infected Trem1−/− mice. Importantly, while immune-associated pathologies were significantly reduced, Trem1−/− mice were equally capable of controlling infections with L. major, influenza virus, but also Legionella pneumophila as Trem1+/+ controls. Our results not only demonstrate an unanticipated pathogenic impact of TREM-1 during a viral and parasitic infection, but also indicate that therapeutic blocking of TREM-1 in distinct inflammatory disorders holds considerable promise by blunting excessive inflammation while preserving the capacity for microbial control. Triggering receptor expressed on myeloid cells-1 (TREM-1) is an immune receptor expressed by myeloid cells that has the capacity to augment pro-inflammatory responses in the context of a microbial infection. While a TREM-1-amplified response likely serves the efficient clearance of pathogens, it also bears the potential to cause substantial tissue damage or even death. Hence, TREM-1 appears a possible therapeutic target for tempering deleterious host-pathogen interactions. However, in models of bacterial sepsis controversial findings have been obtained regarding the requirement of TREM-1 for bacterial control - depending on the overall degree of the TREM-1 blockade that was achieved. In order to conclusively investigate harmful versus essential functions of TREM-1 in vivo, we have generated mice deficient in Trem1. Trem1−/− mice were subjected to experimentally-induced intestinal inflammation (as a model of a non-infectious, yet microbial-driven disease) and also analysed following infections with Leishmania major, influenza virus and Legionella pneumophila. Across all models analysed, Trem1−/− mice showed substantially reduced immune-associated disease. We thus describe a previously unanticipated pathogenic role for TREM-1 also during a parasitic and viral infection. Importantly, our data suggest that in certain diseases microbial control can be achieved in the context of blunted inflammation in the absence of TREM-1.
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Affiliation(s)
- Benjamin Weber
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
| | - Steffen Schuster
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Daniel Zysset
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
| | - Silvia Rihs
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
| | - Nina Dickgreber
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
| | - Christian Schürch
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
- Department of Clinical Research, University of Bern, Bern, Switzerland
| | - Carsten Riether
- Department of Clinical Research, University of Bern, Bern, Switzerland
| | - Mark Siegrist
- Department of Clinical Research, University of Bern, Bern, Switzerland
| | | | - Helga Pawelski
- Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Ursina Gurzeler
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | | | - Vera Genitsch
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
| | | | - Adrian Ochsenbein
- Department of Clinical Research, University of Bern, Bern, Switzerland
- Department of Medical Oncology, University of Bern, Bern, Switzerland
| | - Willy Hofstetter
- Department of Clinical Research, University of Bern, Bern, Switzerland
| | - Manfred Kopf
- Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Thomas Kaufmann
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | | | - Walter Reith
- Department of Pathology and Immunology, Centre Medical Universitaire, Geneva, Switzerland
| | - Leslie Saurer
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
- * E-mail: (LS); (CM)
| | - Christoph Mueller
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
- * E-mail: (LS); (CM)
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Abstract
In the healthy gastrointestinal tract, homeostasis is an active process that requires a careful balance of host responses to the enteric luminal contents. Intestinal macrophages and dendritic cells (DCs) comprise a unique group of tissue immune cells that are ideally situated at the interface of the host and the enteric luminal environment to appropriately respond to microbes and ingested stimuli. However, intrinsic defects in macrophage and DC function contribute to the pathogenesis of inflammatory bowel diseases, as highlighted by recent genome-wide association studies. Gastrointestinal macrophages and DCs participate in inflammatory bowel disease development through inappropriate responses to enteric microbial stimuli, inefficient clearance of microbes from host tissues, and impaired transition from appropriate proinflammatory responses to anti-inflammatory responses that promote resolution. By understanding how intestinal macrophages and DCs initiate chronic inflammation, new pathogenesis-based therapeutic strategies to treat human inflammatory bowel diseases will be elucidated.
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TREM-1 inhibition attenuates inflammation and tumor within the colon. Int Immunopharmacol 2013; 17:155-61. [PMID: 23810411 DOI: 10.1016/j.intimp.2013.06.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Revised: 05/01/2013] [Accepted: 06/05/2013] [Indexed: 12/30/2022]
Abstract
The role of myeloid cell receptor TREM-1 as an amplifier of inflammation has been widely accepted and more interestingly, TREM-1 has been implicated in tumorigenesis. However, it is not clear whether TREM-1 links colon inflammation and tumor in vivo. This study aimed to investigate whether inhibition of proinflammatory TREM-1 would prevent aberrant inflammation and tumor development within the colon. In the present study, the mouse model of DSS-induced colitis and colitis-associated tumorigenesis was used. In vivo, the treatment with the TREM-1 antagonist LP17 or control peptide was initiated at the beginning of or after induction of experimental colitis or colitis-associated tumorigenesis. As a result, TREM-1 inhibition by LP17 treatment ameliorated the development of inflammation and tumor within the colon through exerting anti-inflammatory effects. In addition, LP17 decreased intestinal epithelial proliferation in DSS-induced colitis. Taken together, TREM-1 plays critical roles in colon inflammation and tumor and targeting TREM-1 may represent a novel therapeutic strategy for colon inflammation and associated cancer.
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Saurer L, Rihs S, Birrer M, Saxer-Seculic N, Radsak M, Mueller C. Elevated levels of serum-soluble triggering receptor expressed on myeloid cells-1 in patients with IBD do not correlate with intestinal TREM-1 mRNA expression and endoscopic disease activity. J Crohns Colitis 2012; 6:913-23. [PMID: 22410349 DOI: 10.1016/j.crohns.2012.02.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Revised: 02/09/2012] [Accepted: 02/11/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory responses. We have previously demonstrated a substantial increase in TREM-1-expressing macrophages in the inflamed intestinal mucosa of patients with inflammatory bowel diseases (IBD). TREM-1 is also produced as a soluble receptor (sTREM-1). Here, we aimed to determine whether serum sTREM-1 could be used as a surrogate marker of disease activity in patients with IBD. METHODS Intestinal biopsies and concurrently collected sera from patients with Crohn's disease (CD) and Ulcerative colitis (UC) enrolled in the Swiss IBD cohort study were analyzed for intestinal TREM-1 mRNA and serum sTREM-1 expression. TREM-1 mRNA and sTREM-1 were correlated with the endoscopically determined disease activity. Serum sTREM-1 and TREM-1 mRNA expression levels were further determined in sera and colonic tissues collected at various time-points post disease induction in an experimental mouse model of colitis and correlated with disease activity. RESULTS Expression of TREM-1 mRNA was upregulated in intestinal biopsies from patients with active disease but not in patients with quiescent disease. Serum sTREM-1 was elevated in IBD patients compared to normal controls. No substantial differences in sTREM-1 expression levels were found in patients with active versus quiescent disease. In colitic mice, colonic TREM-1 mRNA and serum sTREM-1 were also upregulated. While colonic TREM-1 mRNA expression levels correlated with disease activity, augmented serum sTREM-1 in fact associated with a milder course of disease. CONCLUSIONS Analysis of sTREM-1 as a surrogate marker of disease activity in patients with IBD warrants caution.
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Affiliation(s)
- Leslie Saurer
- Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
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Colonic epithelial response to injury requires Myd88 signaling in myeloid cells. Mucosal Immunol 2012; 5:194-206. [PMID: 22258450 PMCID: PMC3791628 DOI: 10.1038/mi.2011.65] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Proper colonic injury response requires myeloid-derived cells and Toll-like receptor/Myd88 signaling. However, the precise role of Myd88 signaling specifically in myeloid-derived cells that occurs during tissue damage is unclear. Therefore, we created a mouse line with Myd88 expression restricted to myeloid lineages (Myd88(-/-); LysM(Cre/+); ROSA26(Myd88/+); herein Mlcr). In these mice, Myd88 was appropriately expressed and mediated responses to bacterial ligand exposure in targeted cells. Importantly, the severe colonic epithelial phenotype observed in dextran sodium sulfate-injured Myd88(-/-) mice was rescued by the genetic modification of Mlcr mice. During injury, myeloid cell activation and enrichment of Ptsg2-expressing stromal cells occurred within the mesenchyme that surrounded the crypt bases of Mlcr and Myd88(+/-) mice but not Myd88(-/-) mice. Interestingly, these cellular changes to the crypt base mesenchyme also occurred, but to a lesser extent in uninjured Mlcr mice. These results show that Myd88 expression in myeloid cells was sufficient to rescue intestinal injury responses, and surprisingly, these cells appear to require an additional Myd88-dependent signal from a non-myeloid cell type during homeostasis.
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Bain CC, Mowat AM. Intestinal macrophages - specialised adaptation to a unique environment. Eur J Immunol 2011; 41:2494-8. [PMID: 21952804 DOI: 10.1002/eji.201141714] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Interest in intestinal mononuclear phagocytes (MPs), both DCs and macrophages (Mφs), has exploded in the recent years. In this Viewpoint we will detail how resident intestinal lamina propria (LP) Mφs possess distinctive properties that reflect adaptation to a unique microenvironment. They play quite different roles in the normal and inflamed mucosa and, as we will show, the existing paradigms of differentiated Mφ subsets and of 'resident' versus 'inflammatory' monocytes based on other tissues may not apply to the gut. Strategies for targeting Mφs as a means of dampening intestinal inflammation will need to take account of these unique characteristics.
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Affiliation(s)
- Calum C Bain
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK
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