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1
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Gao X, Yang C, Feng Z, Liu P, Liu Z. The signature of the small intestinal epithelial and immune cells in health and diseases. Chin Med J (Engl) 2025:00029330-990000000-01558. [PMID: 40394804 DOI: 10.1097/cm9.0000000000003615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Indexed: 05/22/2025] Open
Abstract
ABSTRACT The small intestine is essential for digestion, nutrient absorption, immune regulation, and microbial balance. Its epithelial lining, containing specialized cells like Paneth and tuft cells, is crucial for maintaining intestinal homeostasis. Paneth cells produce antimicrobial peptides and growth factors that support microbial regulation and intestinal stem cells, while tuft cells act as chemosensors, detecting environmental changes and modulating immune responses. Along with immune cells such as intraepithelial lymphocytes, innate lymphoid cells, T cells, and macrophages, they form a strong defense system that protects the epithelial barrier. Disruptions in this balance contribute to chronic inflammation, microbial dysbiosis, and compromised barrier function-key features of inflammatory bowel disease, celiac disease, and metabolic syndromes. Furthermore, dysfunctions in the small intestine and immune cells are linked to systemic diseases like obesity, diabetes, and autoimmune disorders. Recent research highlights promising therapeutic strategies, including modulation of epithelial and immune cell functions, probiotics, and gene editing to restore gut health and address systemic effects. This review emphasizes the pivotal roles of small intestinal epithelia and immune cells in maintaining intestinal homeostasis, their involvement in disease development, and emerging treatments for intestinal and systemic disorders.
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Affiliation(s)
- Xiang Gao
- Center for Inflammatory Bowel Disease Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Cuiping Yang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201801, China
| | - Zhongsheng Feng
- Center for Inflammatory Bowel Disease Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Ping Liu
- Department of Gastroenterology, Wuhu First People's Hospital, Wuhu, Anhui 241000, China
| | - Zhanju Liu
- Center for Inflammatory Bowel Disease Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
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He Y, Xiao D, Zhu H, Chen C, Liu Q, Xie J, Wei L, Dai Y, Ning Y, Li Y. Notch Signaling Aggravates Helicobacter pylori-Induced Inflammation by Promoting Macrophage Activation and Proinflammatory Th1/Th17 Responses. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00148-8. [PMID: 40316214 DOI: 10.1016/j.ajpath.2025.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 04/01/2025] [Accepted: 04/11/2025] [Indexed: 05/04/2025]
Abstract
The role of Notch signaling in regulating the immune response in infectious and inflammatory diseases has been extensively reported. However, its specific involvement in Helicobacter pylori infection is yet to be fully understood. In this study, in vitro analysis utilizing real-time quantitative PCR and Western blot revealed that H. pylori triggers the activation of Notch signaling in murine bone marrow-derived macrophages (BMDMs) and co-cultured CD4+ T cells, a process mediated by the Notch ligand protein jagged-1 (Jag1). There was a reciprocal enhancement between Jag1-Notch signaling and NF-κB pathway in H. pylori-infected macrophages. Pretreatment with a Notch signaling inhibitor, DAPT, reduced the expression of inflammatory mediators in macrophages, modulated their phenotype, and inhibited Th1 differentiation. In vivo, after treatment with DAPT in H. pylori-infected mice, the differentiation of Th1 and Th17 was decreased on flow cytometry analysis. Hematoxylin and eosin staining revealed reduced gastric mucosa inflammation, and enzyme-linked immunosorbent assay results demonstrated decreased levels of serum inflammatory cytokines. Furthermore, the terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) results showed that DAPT treatment improved the apoptosis of gastric mucosal cells. Collectively, the findings indicate that Notch signaling is implicated in exacerbating H. pylori-induced inflammation by promoting macrophage activation and Th1/Th17 responses, highlighting its potential as a therapeutic target for alleviating the progression of H. pylori-related diseases.
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Affiliation(s)
- Yunxuan He
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Danli Xiao
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Hongfei Zhu
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Chuxi Chen
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Qiaoyuan Liu
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Jinling Xie
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Lvying Wei
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yueqi Dai
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yunshan Ning
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.
| | - Yan Li
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.
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Denny JE, Flores JN, Mdluli NV, Abt MC. Standard mouse diets lead to differences in severity in infectious and non-infectious colitis. mBio 2025; 16:e0330224. [PMID: 40126017 PMCID: PMC11980566 DOI: 10.1128/mbio.03302-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 02/04/2025] [Indexed: 03/25/2025] Open
Abstract
Clostridioides difficile infects the large intestine and can result in debilitating and potentially fatal colitis. The intestinal microbiota is a major factor influencing the severity of disease following infection. Factors like diet that shape microbiota composition and function may modulate C. difficile colitis. Here, we report that mice fed two distinct standard mouse chows (LabDiet 5010 and LabDiet 5053) exhibited significantly different susceptibility to severe C. difficile infection. Both diets are grain-based with comparable profiles of macro and micronutrient composition. Diet 5010-fed mice had severe morbidity and mortality compared to Diet 5053-fed mice despite no differences in C. difficile colonization or toxin production. Furthermore, Diet 5053 protected mice from toxin-induced epithelial damage. This protection was microbiota-dependent as germ-free mice or mice harboring a reduced diversity microbiota fed Diet 5053 were not protected from severe infection. However, cohousing with mice harboring a complex microbiota restored the protective capacity of Diet 5053 but not Diet 5010. Metabolomic profiling revealed distinct metabolic capacities between Diet 5010- and Diet 5053-fed intestinal microbiotas. Diet 5053-mediated protection extended beyond C. difficile infection as Diet 5053-fed mice displayed less severe dextran sodium sulfate-induced colitis than Diet 5010-fed mice, highlighting a potentially broader capacity for Diet 5053 to limit colitis. These findings demonstrate that standard diet formulations in combination with the host microbiota can drive variability in severity of infectious and non-infectious murine colitis systems, and that diet holds therapeutic potential to limit the severity of C. difficile infection through modulating the functional capacity of the microbiota.IMPORTANCEDiet is a major modulator of the microbiota and intestinal health. This report finds that two different standard mouse diets starkly alter the severity of colitis observed in a pathogen-mediated (Clostridioides difficile) and non-infectious (dextran sodium sulfate) mouse colitis experimental systems. These findings in part explain study-to-study variability using these mouse systems to study disease. Since the gut microbiota plays a key role in intestinal homeostasis, diet-derived modulation of the microbiota is a promising avenue to control disease driven by intestinal inflammation and may represent a potential intervention strategy for at-risk patients.
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Affiliation(s)
- Joshua E. Denny
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Julia N. Flores
- Division of Infectious Disease, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Nontokozo V. Mdluli
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Michael C. Abt
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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4
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Sarrabayrouse G, Joulain C, Bessoles S, Chiron AS, Abina AM, Hacein-Bey-Abina S. Erythropoietin supplementation induces dysbiosis of the gut microbiota and impacts mucosal immunity in a non-diseased mouse model. Front Immunol 2025; 15:1465410. [PMID: 39916952 PMCID: PMC11798978 DOI: 10.3389/fimmu.2024.1465410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 12/20/2024] [Indexed: 02/09/2025] Open
Abstract
A number of drug treatments are known to alter the dialogue between the gut microbiota and the immune system components in the digestive mucosa. Alterations in intestinal homeostasis are now well known to affect peripheral immune responses and favor the occurrence of a number of pathologies such as allergies and cancers. Erythropoietin's known pleiotropic effects might explain the adverse events sometimes observed in anemic patients treated by erythropoiesis-stimulating agents (ESA). However, the impact of this therapeutic cytokine on the homeostasis of the intestinal tract has not previously been investigated in detail. By studying a mouse model of erythropoietin (EPO) supplementation for 28 days, we observed EPO-induced dysbiosis of the fecal microbiota characterized by a greater bacterial load, lower bacterial diversity and taxonomic changes. With regard to the mucosal immune system, an analysis of leukocyte populations in the small intestine and colon treatment revealed low proportions of ileal CD4 lymphocyte subpopulations (Treg, Tr17 and Th17 cells), IgA-secreting plasma cells, and a major macrophage subpopulation, involved in the control of lymphocyte responses. Our results provide for the first time a descriptive analysis of intestinal EPO's regulatory properties and raise questions about the involvement of EPO-induced alterations in the microbiota and the gut immune effectors in the control of intestinal and peripheral immune responses.
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Affiliation(s)
- Guillaume Sarrabayrouse
- Unité des technologies Chimiques et Biologiques pour la Santé, Université Paris Cité, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), UTCBS, Paris, France
| | - Corentin Joulain
- Unité des technologies Chimiques et Biologiques pour la Santé, Université Paris Cité, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), UTCBS, Paris, France
| | - Stéphanie Bessoles
- Unité des technologies Chimiques et Biologiques pour la Santé, Université Paris Cité, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), UTCBS, Paris, France
| | - Andrada S. Chiron
- Unité des technologies Chimiques et Biologiques pour la Santé, Université Paris Cité, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), UTCBS, Paris, France
- Clinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Saclay, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le-Kremlin-Bicêtre, France
| | - Amine M. Abina
- Unité des technologies Chimiques et Biologiques pour la Santé, Université Paris Cité, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), UTCBS, Paris, France
| | - Salima Hacein-Bey-Abina
- Unité des technologies Chimiques et Biologiques pour la Santé, Université Paris Cité, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), UTCBS, Paris, France
- Clinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Saclay, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le-Kremlin-Bicêtre, France
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Cerovic V, Pabst O, Mowat AM. The renaissance of oral tolerance: merging tradition and new insights. Nat Rev Immunol 2025; 25:42-56. [PMID: 39242920 DOI: 10.1038/s41577-024-01077-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/25/2024] [Indexed: 09/09/2024]
Abstract
Oral tolerance is the process by which feeding of soluble proteins induces antigen-specific systemic immune unresponsiveness. Oral tolerance is thought to have a central role in suppressing immune responses to 'harmless' food antigens, and its failure can lead to development of pathologies such as food allergies or coeliac disease. However, on the basis of long-standing experimental observations, the relevance of oral tolerance in human health has achieved new prominence recently following the discovery that oral administration of peanut proteins prevents the development of peanut allergy in at-risk human infants. In this Review, we summarize the new mechanistic insights into three key processes necessary for the induction of tolerance to oral antigens: antigen uptake and transport across the small intestinal epithelial barrier to the underlying immune cells; the processing, transport and presentation of fed antigen by different populations of antigen-presenting cells; and the development of immunosuppressive T cell populations that mediate antigen-specific tolerance. In addition, we consider how related but distinct processes maintain tolerance to bacterial antigens in the large intestine. Finally, we outline the molecular mechanisms and functional consequences of failure of oral tolerance and how these may be modulated to enhance clinical outcomes and prevent disease.
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Affiliation(s)
- Vuk Cerovic
- Institute of Molecular Medicine, RWTH Aachen University, Aachen, Germany.
| | - Oliver Pabst
- Institute of Molecular Medicine, RWTH Aachen University, Aachen, Germany
| | - Allan McI Mowat
- School of Infection and Immunity, College of Medicine, Veterinary Medicine and Life Sciences, University of Glasgow, Glasgow, UK.
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Yue N, Hu P, Tian C, Kong C, Zhao H, Zhang Y, Yao J, Wei Y, Li D, Wang L. Dissecting Innate and Adaptive Immunity in Inflammatory Bowel Disease: Immune Compartmentalization, Microbiota Crosstalk, and Emerging Therapies. J Inflamm Res 2024; 17:9987-10014. [PMID: 39634289 PMCID: PMC11615095 DOI: 10.2147/jir.s492079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 11/12/2024] [Indexed: 12/07/2024] Open
Abstract
The intestinal immune system is the largest immune organ in the human body. Excessive immune response to intestinal cavity induced by harmful stimuli including pathogens, foreign substances and food antigens is an important cause of inflammatory diseases such as celiac disease and inflammatory bowel disease (IBD). Although great progress has been made in the treatment of IBD by some immune-related biotherapeutic products, yet a considerable proportion of IBD patients remain unresponsive or immune tolerant to immunotherapeutic strategy. Therefore, it is necessary to further understand the mechanism of immune cell populations involved in enteritis, including dendritic cells, macrophages and natural lymphocytes, in the steady-state immune tolerance of IBD, in order to find effective IBD therapy. In this review, we discussed the important role of innate and adaptive immunity in the development of IBD. And the relationship between intestinal immune system disorders and microflora crosstalk were also presented. We also focus on the new findings in the field of T cell immunity, which might identify novel cytokines, chemokines or anti-cytokine antibodies as new approaches for the treatment of IBD.
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Affiliation(s)
- Ningning Yue
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Peng Hu
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, People’s Republic of China
| | - Chengmei Tian
- Department of Emergency, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Chen Kong
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Hailan Zhao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Yuan Zhang
- Department of Medical Administration, Huizhou Institute of Occupational Diseases Control and Prevention, Huizhou, People’s Republic of China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Yuqi Wei
- Department of Rehabilitation, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Defeng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Lisheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
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Raya Tonetti F, Eguileor A, Llorente C. Goblet cells: guardians of gut immunity and their role in gastrointestinal diseases. EGASTROENTEROLOGY 2024; 2:e100098. [PMID: 39524932 PMCID: PMC11542612 DOI: 10.1136/egastro-2024-100098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Accepted: 08/08/2024] [Indexed: 11/16/2024]
Abstract
Goblet cells (GCs) are specialised guardians lining the intestine. They play a critical role in gut defence and immune regulation. GCs continuously secrete mucus creating a physical barrier to protect from pathogens while harbouring symbiotic gut bacteria adapted to live within the mucus. GCs also form specialised GC-associated passages in a dynamic and regulated manner to deliver luminal antigens to immune cells, promoting gut tolerance and preventing inflammation. The composition of gut bacteria directly influences GC function, highlighting the intricate interplay between these components of a healthy gut. Indeed, imbalances in the gut microbiome can disrupt GC function, contributing to various gastrointestinal diseases like colorectal cancer, inflammatory bowel disease, cystic fibrosis, pathogen infections and liver diseases. This review explores the interplay between GCs and the immune system. We delve into the underlying mechanisms by which GC dysfunction contributes to the development and progression of gastrointestinal diseases. Finally, we examine current and potential treatments that target GCs and represent promising avenues for further investigation.
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Affiliation(s)
- Fernanda Raya Tonetti
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Alvaro Eguileor
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, California, USA
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Zhang X, Chen X, Yang F, Shao H, Bai T, Meng X, Wu Y, Yang A, Chen H, Li X. Extracellular adenosine triphosphate skews the T helper cell balance and enhances neutrophil activation in mice with food allergies. Food Funct 2024; 15:5641-5654. [PMID: 38726659 DOI: 10.1039/d4fo01135j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/21/2024]
Abstract
Exposure to food allergens elicits fast changes in the intestinal microenvironment, which guides the development of allergic reactions. Investigating the key information about these changes may help in better understanding food allergies. In this research, we explored the relationship between a food allergy and extracellular adenosine triphosphate (ATP), a danger molecule that has been proved to regulate the onset of allergic asthma and dermatitis but has not been studied in food allergies, by developing a unique animal model through allergen-containing diet feeding. After consuming an allergen-containing diet for 7 days, the allergic mice exhibited severe enteritis with elevated luminal ATP levels. The dysregulated luminal ATP worsened food-induced enteritis by enhancing Th17 cell responses and increasing mucosal neutrophil accumulation. In vitro experiments demonstrated that ATP intervention facilitated Th17 cell differentiation and neutrophil activation. In addition, the diet-induced allergy showed noticeable gut dysbiosis, characterized by decreased microbial diversity and increased diet-specific microbiota signatures. As the first, we show that food-induced enteritis is associated with an elevated concentration of luminal ATP. The dysregulated extracellular ATP exacerbated the enteritis of mice to a food challenge by manipulating intestinal Th17 cells and neutrophils.
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Affiliation(s)
- Xing Zhang
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, P.R. China.
- School of Food Science and Technology, Nanchang University, Nanchang 330047, P.R. China
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, P.R. China
| | - Xiao Chen
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, P.R. China.
- School of Food Science and Technology, Nanchang University, Nanchang 330047, P.R. China
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, P.R. China
| | - Fan Yang
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, P.R. China.
- School of Food Science and Technology, Nanchang University, Nanchang 330047, P.R. China
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, P.R. China
| | - Huming Shao
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, P.R. China.
- School of Food Science and Technology, Nanchang University, Nanchang 330047, P.R. China
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, P.R. China
| | - Tianliang Bai
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, P.R. China.
- School of Food Science and Technology, Nanchang University, Nanchang 330047, P.R. China
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, P.R. China
| | - Xuanyi Meng
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, P.R. China
- Jiangxi Province Key Laboratory of Food Allergy, Nanchang University, Nanchang 330047, China
| | - Yong Wu
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, P.R. China
- Jiangxi Province Key Laboratory of Food Allergy, Nanchang University, Nanchang 330047, China
| | - Anshu Yang
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, P.R. China
- Jiangxi Province Key Laboratory of Food Allergy, Nanchang University, Nanchang 330047, China
| | - Hongbing Chen
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, P.R. China.
- School of Food Science and Technology, Nanchang University, Nanchang 330047, P.R. China
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, P.R. China
- Jiangxi Province Key Laboratory of Food Allergy, Nanchang University, Nanchang 330047, China
| | - Xin Li
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, P.R. China.
- School of Food Science and Technology, Nanchang University, Nanchang 330047, P.R. China
- Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, P.R. China
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Baillou A, Tomal F, Chaumeil T, Barc C, Levern Y, Sausset A, Pezier T, Schulthess J, Peltier-Pain P, Laurent F, Lacroix-Lamandé S. Characterization of intestinal mononuclear phagocyte subsets in young ruminants at homeostasis and during Cryptosporidium parvum infection. Front Immunol 2024; 15:1379798. [PMID: 38756777 PMCID: PMC11096452 DOI: 10.3389/fimmu.2024.1379798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 04/03/2024] [Indexed: 05/18/2024] Open
Abstract
Introduction Cryptosporidiosis is a poorly controlled zoonosis caused by an intestinal parasite, Cryptosporidium parvum, with a high prevalence in livestock (cattle, sheep, and goats). Young animals are particularly susceptible to this infection due to the immaturity of their intestinal immune system. In a neonatal mouse model, we previously demonstrated the importance of the innate immunity and particularly of type 1 conventional dendritic cells (cDC1) among mononuclear phagocytes (MPs) in controlling the acute phase of C. parvum infection. These immune populations are well described in mice and humans, but their fine characterization in the intestine of young ruminants remained to be further explored. Methods Immune cells of the small intestinal Peyer's patches and of the distal jejunum were isolated from naive lambs and calves at different ages. This was followed by their fine characterization by flow cytometry and transcriptomic analyses (q-RT-PCR and single cell RNAseq (lamb cells)). Newborn animals were infected with C. parvum, clinical signs and parasite burden were quantified, and isolated MP cells were characterized by flow cytometry in comparison with age matched control animals. Results Here, we identified one population of macrophages and three subsets of cDC (cDC1, cDC2, and a minor cDC subset with migratory properties) in the intestine of lamb and calf by phenotypic and targeted gene expression analyses. Unsupervised single-cell transcriptomic analysis confirmed the identification of these four intestinal MP subpopulations in lamb, while highlighting a deeper diversity of cell subsets among monocytic and dendritic cells. We demonstrated a weak proportion of cDC1 in the intestine of highly susceptible newborn lambs together with an increase of these cells within the first days of life and in response to the infection. Discussion Considering cDC1 importance for efficient parasite control in the mouse model, one may speculate that the cDC1/cDC2 ratio plays also a key role for the efficient control of C. parvum in young ruminants. In this study, we established the first fine characterization of intestinal MP subsets in young lambs and calves providing new insights for comparative immunology of the intestinal MP system across species and for future investigations on host-Cryptosporidium interactions in target species.
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Affiliation(s)
- Ambre Baillou
- Unité Mixte de Recherches (UMR)1282 Infectiologie et Santé Publique, INRAE Centre Val de Loire, Université François Rabelais de Tours, Nouzilly, France
- Phileo by Lesaffre, Marcq-en-Barœul, France
| | - Florian Tomal
- Unité Mixte de Recherches (UMR)1282 Infectiologie et Santé Publique, INRAE Centre Val de Loire, Université François Rabelais de Tours, Nouzilly, France
| | - Thierry Chaumeil
- Unité Expérimentale (UE)1277 Plateforme d’Infectiologie Expérimentale (PFIE), INRAE Centre Val de Loire, Nouzilly, France
| | - Céline Barc
- Unité Expérimentale (UE)1277 Plateforme d’Infectiologie Expérimentale (PFIE), INRAE Centre Val de Loire, Nouzilly, France
| | - Yves Levern
- Unité Mixte de Recherches (UMR)1282 Infectiologie et Santé Publique, INRAE Centre Val de Loire, Université François Rabelais de Tours, Nouzilly, France
| | - Alix Sausset
- Unité Mixte de Recherches (UMR)1282 Infectiologie et Santé Publique, INRAE Centre Val de Loire, Université François Rabelais de Tours, Nouzilly, France
| | - Tiffany Pezier
- Unité Mixte de Recherches (UMR)1282 Infectiologie et Santé Publique, INRAE Centre Val de Loire, Université François Rabelais de Tours, Nouzilly, France
| | | | | | - Fabrice Laurent
- Unité Mixte de Recherches (UMR)1282 Infectiologie et Santé Publique, INRAE Centre Val de Loire, Université François Rabelais de Tours, Nouzilly, France
| | - Sonia Lacroix-Lamandé
- Unité Mixte de Recherches (UMR)1282 Infectiologie et Santé Publique, INRAE Centre Val de Loire, Université François Rabelais de Tours, Nouzilly, France
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10
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Murase S, Mantani Y, Ohno N, Shimada A, Nakanishi S, Morishita R, Yokoyama T, Hoshi N. Regional differences in the ultrastructure of mucosal macrophages in the rat large intestine. Cell Tissue Res 2024; 396:245-253. [PMID: 38485763 DOI: 10.1007/s00441-024-03883-w] [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: 09/06/2023] [Accepted: 02/25/2024] [Indexed: 04/28/2024]
Abstract
We previously clarified the histological characteristics of macrophages in the rat small intestine using serial block-face scanning electron microscopy (SBF-SEM). However, the regional differences in the characteristics of macrophages throughout the large intestine remain unknown. Here, we performed a pilot study to explore the regional differences in the ultrastructure of mucosal macrophages in the large intestine by using SBF-SEM analysis. SBF-SEM analysis conducted on the luminal side of the cecum and descending colon revealed macrophages as amorphous cells possessing abundant lysosomes and vacuoles. Macrophages in the cecum exhibited a higher abundance of lysosomes and a lower abundance of vacuoles than those in the descending colon. Macrophages with many intraepithelial cellular processes were observed beneath the intestinal superficial epithelium in the descending colon. Moreover, macrophages in contact with nerve fibers were more prevalent in the cecum than in the descending colon, and a subset of them surrounded a nerve bundle only in the cecum. In conclusion, the present pilot study suggested that the quantity of some organelles (lysosomes and vacuoles) in macrophages differed between the cecum and the descending colon and that there were some region-specific subsets of macrophages like nerve-associated macrophages in the cecum.
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Affiliation(s)
- Shota Murase
- Laboratory of Histophysiology, Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-Cho, Nada-Ku, Kobe, Hyogo, 657-8501, Japan
| | - Youhei Mantani
- Laboratory of Histophysiology, Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-Cho, Nada-Ku, Kobe, Hyogo, 657-8501, Japan.
| | - Nobuhiko Ohno
- Department of Anatomy, Division of Histology and Cell Biology, Jichi Medical University, School of Medicine, Shimotsuke, Tochigi, 329-0498, Japan
- Division of Ultrastructural Research, National Institute for Physiological Sciences, Okazaki, Aichi, 444-8787, Japan
| | - Asaka Shimada
- Laboratory of Histophysiology, Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-Cho, Nada-Ku, Kobe, Hyogo, 657-8501, Japan
| | - Satoki Nakanishi
- Laboratory of Histophysiology, Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-Cho, Nada-Ku, Kobe, Hyogo, 657-8501, Japan
| | - Rinako Morishita
- Laboratory of Histophysiology, Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-Cho, Nada-Ku, Kobe, Hyogo, 657-8501, Japan
| | - Toshifumi Yokoyama
- Laboratory of Animal Molecular Morphology, Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-Cho, Nada-Ku, Kobe, Hyogo, 657-8501, Japan
| | - Nobuhiko Hoshi
- Laboratory of Animal Molecular Morphology, Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-Cho, Nada-Ku, Kobe, Hyogo, 657-8501, Japan
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11
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Kim HJ, Jang J, Na K, Lee EH, Gu HJ, Lim YH, Joo SA, Baek SE, Roh JY, Maeng HJ, Kim YH, Lee YJ, Oh BC, Jung Y. TLR7-dependent eosinophil degranulation links psoriatic skin inflammation to small intestinal inflammatory changes in mice. Exp Mol Med 2024; 56:1164-1177. [PMID: 38689088 PMCID: PMC11148187 DOI: 10.1038/s12276-024-01225-y] [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: 10/02/2023] [Revised: 01/26/2024] [Accepted: 02/13/2024] [Indexed: 05/02/2024] Open
Abstract
Recent evidence of gut microbiota dysbiosis in the context of psoriasis and the increased cooccurrence of inflammatory bowel disease and psoriasis suggest a close relationship between skin and gut immune responses. Using a mouse model of psoriasis induced by the Toll-like receptor (TLR) 7 ligand imiquimod, we found that psoriatic dermatitis was accompanied by inflammatory changes in the small intestine associated with eosinophil degranulation, which impaired intestinal barrier integrity. Inflammatory responses in the skin and small intestine were increased in mice prone to eosinophil degranulation. Caco-2 human intestinal epithelial cells were treated with media containing eosinophil granule proteins and exhibited signs of inflammation and damage. Imiquimod-induced skin and intestinal changes were attenuated in eosinophil-deficient mice, and this attenuation was counteracted by the transfer of eosinophils. Imiquimod levels and the distribution of eosinophils were positively correlated in the intestine. TLR7-deficient mice did not exhibit intestinal eosinophil degranulation but did exhibit attenuated inflammation in the skin and small intestine following imiquimod administration. These results suggest that TLR7-dependent bidirectional skin-to-gut communication occurs in psoriatic inflammation and that inflammatory changes in the intestine can accelerate psoriasis.
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Affiliation(s)
- Hee Joo Kim
- Department of Dermatology, Gachon Gil Medical Center, College of Medicine, Gachon University, Incheon, 21565, Korea
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, Korea
| | - Jinsun Jang
- Department of Health Science and Technology, Gachon Advanced Institute for Health Science & Technology, Gachon University, Incheon, 21999, Korea
| | - Kunhee Na
- Department of Health Science and Technology, Gachon Advanced Institute for Health Science & Technology, Gachon University, Incheon, 21999, Korea
| | - Eun-Hui Lee
- Department of Microbiology, College of Medicine, Gachon University, Incheon, 21999, Korea
| | - Hyeon-Jung Gu
- Department of Health Science and Technology, Gachon Advanced Institute for Health Science & Technology, Gachon University, Incheon, 21999, Korea
| | - Yoon Hee Lim
- Department of Microbiology, College of Medicine, Gachon University, Incheon, 21999, Korea
| | - Seul-A Joo
- College of Pharmacy, Gachon University, Incheon, 21936, Korea
| | - Seung Eun Baek
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, 50612, Korea
| | - Joo-Young Roh
- Department of Dermatology, Gachon Gil Medical Center, College of Medicine, Gachon University, Incheon, 21565, Korea
- Department of Dermatology, Ewha Womans University Medical Center, College of Medicine, Ewha Womans University, Seoul, 07804, Korea
| | - Han-Joo Maeng
- College of Pharmacy, Gachon University, Incheon, 21936, Korea
| | - Yun Hak Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, 50612, Korea
- Department of Biomedical Informatics, School of Medicine, Pusan National University, Yangsan, 50612, Korea
| | - Young-Jae Lee
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, Korea
- Department of Health Science and Technology, Gachon Advanced Institute for Health Science & Technology, Gachon University, Incheon, 21999, Korea
- Department of Biochemistry, College of Medicine, Gachon University, Incheon, 21999, Korea
| | - Byung-Chul Oh
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, Korea
- Department of Health Science and Technology, Gachon Advanced Institute for Health Science & Technology, Gachon University, Incheon, 21999, Korea
- Department of Physiology, College of Medicine, Gachon University, Incheon, 21999, Korea
| | - YunJae Jung
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, Korea.
- Department of Health Science and Technology, Gachon Advanced Institute for Health Science & Technology, Gachon University, Incheon, 21999, Korea.
- Department of Microbiology, College of Medicine, Gachon University, Incheon, 21999, Korea.
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12
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Ilomäki MA, Polari L, Stenvall CGA, Tayyab M, Kähärä K, Ridge KM, Toivola DM. Defining a timeline of colon pathologies after keratin 8 loss: rapid crypt elongation and diarrhea are followed by epithelial erosion and cell exfoliation. Am J Physiol Gastrointest Liver Physiol 2024; 326:G67-G77. [PMID: 37962942 PMCID: PMC11208023 DOI: 10.1152/ajpgi.00140.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 10/27/2023] [Accepted: 10/28/2023] [Indexed: 11/15/2023]
Abstract
Keratins are epithelial intermediate filament proteins that play a crucial role in cellular stress protection, with K8 being the most abundant in the colon. The intestinal epithelial-specific K8-deficient mouse model (K8flox/flox;Villin-Cre) exhibits characteristics of inflammatory bowel disease, including diarrhea, crypt erosion, hyperproliferation, and decreased barrier function. Nevertheless, the order in which these events occur and whether they are a direct cause of K8 loss or a consequence of one event inducing another remains unexplored. Increased knowledge about early events in the disruption of colon epithelial integrity would help to understand the early pathology of inflammatory and functional colon disorders and develop preclinical models and diagnostics of colonic diseases. Here, we aimed to characterize the order of physiological events after Krt8 loss by utilizing K8flox/flox;Villin-CreERt2 mice with tamoxifen-inducible Krt8 deletion in intestinal epithelial cells, and assess stool analysis as a noninvasive method to monitor real-time gene expression changes following Krt8 loss. K8 protein was significantly decreased within a day after induction, followed by its binding partners, K18 and K19 from day 4 onward. The sequential colonic K8 downregulation in adult mice leads to immediate diarrhea and crypt elongation with activation of proliferation signaling, followed by crypt loss and increased neutrophil activity within 6-8 days, highlighting impaired water balance and crypt elongation as the earliest colonic changes upon Krt8 loss. Furthermore, epithelial gene expression patterns were comparable between colon tissue and stool samples, demonstrating the feasibility of noninvasive monitoring of gut epithelia in preclinical research utilizing Cre-LoxP-based intestinal disease models.NEW & NOTEWORTHY Understanding the order in which physiological and molecular events occur helps to recognize the onset of diseases and improve their preclinical models. We utilized Cre-Lox-based inducible keratin 8 deletion in mouse intestinal epithelium to characterize the earliest events after keratin 8 loss leading to colitis. These include diarrhea and crypt elongation, followed by erosion and neutrophil activity. Our results also support noninvasive methodology for monitoring colon diseases in preclinical models.
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Affiliation(s)
- Maria A Ilomäki
- Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, Åbo Akademi University, Turku, Finland
| | - Lauri Polari
- Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, Åbo Akademi University, Turku, Finland
| | - Carl-Gustaf A Stenvall
- Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, Åbo Akademi University, Turku, Finland
| | - Mina Tayyab
- Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, Åbo Akademi University, Turku, Finland
| | - Kirah Kähärä
- Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
| | - Karen M Ridge
- Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois, United States
| | - Diana M Toivola
- Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, Åbo Akademi University, Turku, Finland
- Turku Center for Disease Modeling, University of Turku, Turku, Finland
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13
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Harusato A, Seo W, Abo H, Nakanishi Y, Nishikawa H, Itoh Y. Protocol for acquiring samples to assess the impact of microplastics on immune microenvironments in the mouse intestine. STAR Protoc 2023; 4:102648. [PMID: 37865913 PMCID: PMC10598693 DOI: 10.1016/j.xpro.2023.102648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/08/2023] [Accepted: 09/26/2023] [Indexed: 10/24/2023] Open
Abstract
Environmental nano- and microplastics (NMPs) pose serious environmental issues, yet there is no established technique to assess their impact on health through oral ingestion. Here, we present a protocol to assess the impact of NMPs in the intestinal immune microenvironments by employing chronic exposure to NMPs in a mouse model. We describe steps for administration of NMPs, feces and tissue collection, and colonic gut digestion. We then detail procedures for isolation of intestinal immune cells and RNA isolation. For complete details on the use and execution of this protocol, please refer to Harusato et al.1.
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Affiliation(s)
- Akihito Harusato
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | - Wooseok Seo
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hirohito Abo
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Yoshitaka Nakanishi
- Faculty of Advanced Science and Technology, Kumamoto University, Kumamoto, Japan
| | - Hiroyoshi Nishikawa
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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14
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Schülke S, Gilles S, Jirmo AC, Mayer JU. Tissue-specific antigen-presenting cells contribute to distinct phenotypes of allergy. Eur J Immunol 2023; 53:e2249980. [PMID: 36938688 DOI: 10.1002/eji.202249980] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 01/19/2023] [Accepted: 03/13/2023] [Indexed: 03/21/2023]
Abstract
Antigen-presenting cells (APCs) are critical cells bridging innate and adaptive immune responses by taking up, processing, and presenting antigens to naïve T cells. At steady state, APCs thus control both tissue homeostasis and the induction of tolerance. In allergies however, APCs drive a Th2-biased immune response that is directed against otherwise harmless antigens from the environment. The main types of APCs involved in the induction of allergy are dendritic cells, monocytes, and macrophages. However, these cell types can be further divided into local, tissue-specific populations that differ in their phenotype, migratory capacity, T-cell activating potential, and production of effector molecules. Understanding if distinct populations of APCs contribute to either tissue-specific immune tolerance, allergen sensitization, or allergic inflammation will allow us to better understand disease pathology and develop targeted treatment options for different stages of allergic disease. Therefore, this review describes the main characteristics, phenotypes, and effector molecules of the APCs involved in the induction of allergen-specific Th2 responses in affected barrier sites, such as the skin, nose, lung, and gastrointestinal tract. Furthermore, we highlight open questions that remain to be addressed to fully understand the contribution of different APCs to allergic disease.
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Affiliation(s)
- Stefan Schülke
- Vice President´s Research Group: Molecular Allergology, Paul-Ehrlich-Institut, Langen (Hesse), Germany
| | - Stefanie Gilles
- Environmental Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Adan C Jirmo
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
| | - Johannes U Mayer
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
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15
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Johnston LJ, Barningham L, Campbell EL, Cerovic V, Duckworth CA, Luu L, Wastling J, Derricott H, Coombes JL. A novel in vitro model of the small intestinal epithelium in co-culture with 'gut-like' dendritic cells. DISCOVERY IMMUNOLOGY 2023; 2:kyad018. [PMID: 38567056 PMCID: PMC10917230 DOI: 10.1093/discim/kyad018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 08/31/2023] [Accepted: 10/05/2023] [Indexed: 04/04/2024]
Abstract
Cross-talk between dendritic cells (DCs) and the intestinal epithelium is important in the decision to mount a protective immune response to a pathogen or to regulate potentially damaging responses to food antigens and the microbiota. Failures in this decision-making process contribute to the development of intestinal inflammation, making the molecular signals that pass between DCs and intestinal epithelial cells potential therapeutic targets. Until now, in vitro models with sufficient complexity to understand these interactions have been lacking. Here, we outline the development of a co-culture model of in vitro differentiated 'gut-like' DCs with small intestinal organoids (enteroids). Sequential exposure of murine bone marrow progenitors to Flt3L, granulocyte macrophage colony-stimulating factor (GM-CSF) and all-trans-retinoic acid (RA) resulted in the generation of a distinct population of conventional DCs expressing CD11b+SIRPα+CD103+/- (cDC2) exhibiting retinaldehyde dehydrogenase (RALDH) activity. These 'gut-like' DCs extended transepithelial dendrites across the intact epithelium of enteroids. 'Gut-like' DC in co-culture with enteroids can be utilized to define how epithelial cells and cDCs communicate in the intestine under a variety of different physiological conditions, including exposure to different nutrients, natural products, components of the microbiota, or pathogens. Surprisingly, we found that co-culture with enteroids resulted in a loss of RALDH activity in 'gut-like' DCs. Continued provision of GM-CSF and RA during co-culture was required to oppose putative negative signals from the enteroid epithelium. Our data contribute to a growing understanding of how intestinal cDCs assess environmental conditions to ensure appropriate activation of the immune response.
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Affiliation(s)
- Luke J Johnston
- Department of Infection Biology, Institute of Infection and Global Health & School of Veterinary Science, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK
| | - Liam Barningham
- Department of Infection Biology, Institute of Infection and Global Health & School of Veterinary Science, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Eric L Campbell
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK
| | - Vuk Cerovic
- Institute of Molecular Medicine, RWTH University Hospital, Aachen, Germany
| | - Carrie A Duckworth
- Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Lisa Luu
- Department of Infection Biology, Institute of Infection and Global Health & School of Veterinary Science, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Jonathan Wastling
- Department of Infection Biology, Institute of Infection and Global Health & School of Veterinary Science, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
- College of Health, Medicine and Life Sciences, Brunel University London, Kingston Lane, Uxbridge, Middlesex, UK
| | - Hayley Derricott
- Department of Infection Biology, Institute of Infection and Global Health & School of Veterinary Science, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Janine L Coombes
- Department of Infection Biology, Institute of Infection and Global Health & School of Veterinary Science, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
- School of Pharmacy and Life Sciences, Robert Gordon University, Aberdeen, UK
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16
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Bennett CL, Perona-Wright G. Metabolic adaption of mucosal macrophages: Is metabolism a driver of persistence across tissues? Mucosal Immunol 2023; 16:753-763. [PMID: 37385586 PMCID: PMC10564628 DOI: 10.1016/j.mucimm.2023.06.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/27/2023] [Accepted: 06/17/2023] [Indexed: 07/01/2023]
Abstract
Macrophages play essential roles in tissue homeostasis, defense, and repair. Their functions are highly tissue-specific, and when damage and inflammation stimulate repopulation by circulating monocytes, the incoming monocytes rapidly acquire the same, tissue-specific functions as the previous, resident macrophages. Several environmental factors are thought to guide the functional differentiation of recruited monocytes, including metabolic pressures imposed by the fuel sources available in each tissue. Here we discuss whether such a model of metabolic determinism can be applied to macrophage differentiation across barrier sites, from the lung to the skin. We suggest an alternative model, in which metabolic phenotype is a consequence of macrophage longevity rather than an early driver of tissue-specific adaption.
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Affiliation(s)
- Clare L Bennett
- Department of Haematology, UCL Cancer Institute, University College London, London, UK.
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17
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Manoharan I, Shanmugam A, Ramalingam M, Patel N, Thangaraju M, Ande S, Pacholczyk R, Prasad PD, Manicassamy S. The Transcription Factor RXRα in CD11c+ APCs Regulates Intestinal Immune Homeostasis and Inflammation. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:853-861. [PMID: 37477694 PMCID: PMC10538854 DOI: 10.4049/jimmunol.2200909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 07/05/2023] [Indexed: 07/22/2023]
Abstract
APCs such as dendritic cells and macrophages play a pivotal role in mediating immune tolerance and restoring intestinal immune homeostasis by limiting inflammatory responses against commensal bacteria. However, cell-intrinsic molecular regulators critical for programming intestinal APCs to a regulatory state rather than an inflammatory state are unknown. In this study, we report that the transcription factor retinoid X receptor α (RXRα) signaling in CD11c+ APCs is essential for suppressing intestinal inflammation by imparting an anti-inflammatory phenotype. Using a mouse model of ulcerative colitis, we demonstrated that targeted deletion of RXRα in CD11c+ APCs in mice resulted in the loss of T cell homeostasis with enhanced intestinal inflammation and increased histopathological severity of colonic tissue. This was due to the increased production of proinflammatory cytokines that drive Th1/Th17 responses and decreased expression of immune-regulatory factors that promote regulatory T cell differentiation in the colon. Consistent with these findings, pharmacological activation of the RXRα pathway alleviated colitis severity in mice by suppressing the expression of inflammatory cytokines and limiting Th1/Th17 cell differentiation. These findings identify an essential role for RXRα in APCs in regulating intestinal immune homeostasis and inflammation. Thus, manipulating the RXRα pathway could provide novel opportunities for enhancing regulatory responses and dampening colonic inflammation.
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Affiliation(s)
- Indumathi Manoharan
- Georgia Cancer Center, Augusta University, Augusta, GA, USA
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, USA
| | | | | | - Nikhil Patel
- Department of Pathology, Augusta University, Augusta, GA USA
| | - Muthusamy Thangaraju
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, USA
| | - Satyanarayana Ande
- Georgia Cancer Center, Augusta University, Augusta, GA, USA
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, USA
| | | | - Puttur D. Prasad
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, USA
| | - Santhakumar Manicassamy
- Georgia Cancer Center, Augusta University, Augusta, GA, USA
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, USA
- Department of Medicine, Augusta University, Augusta, Georgia, USA
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18
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Venkatesh H, Tracy SI, Farrar MA. Cytotoxic CD4 T cells in the mucosa and in cancer. Front Immunol 2023; 14:1233261. [PMID: 37654482 PMCID: PMC10466411 DOI: 10.3389/fimmu.2023.1233261] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 07/24/2023] [Indexed: 09/02/2023] Open
Abstract
CD4 T cells were initially described as helper cells that promote either the cellular immune response (Th1 cells) or the humoral immune response (Th2 cells). Since then, a plethora of functionally distinct helper and regulatory CD4 T cell subsets have been described. CD4 T cells with cytotoxic function were first described in the setting of viral infections and autoimmunity, and more recently in cancer and gut dysbiosis. Regulatory CD4 T cell subsets such as Tregs and T-regulatory type 1 (Tr1) cells have also been shown to have cytotoxic potential. Indeed, Tr1 cells have been shown to be important for maintenance of stem cell niches in the bone marrow and the gut. This review will provide an overview of cytotoxic CD4 T cell development, and discuss the role of inflammatory and Tr1-like cytotoxic CD4 T cells in maintenance of intestinal stem cells and in anti-cancer immune responses.
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Affiliation(s)
- Hrishi Venkatesh
- Center for Immunology, Masonic Cancer Center, Minneapolis, MN, United States
- University of Minnesota, Department of Laboratory Medicine and Pathology, Minneapolis, MN, United States
| | - Sean I. Tracy
- Center for Immunology, Masonic Cancer Center, Minneapolis, MN, United States
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Michael A. Farrar
- Center for Immunology, Masonic Cancer Center, Minneapolis, MN, United States
- University of Minnesota, Department of Laboratory Medicine and Pathology, Minneapolis, MN, United States
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19
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Bedree JK, Kerns K, Chen T, Lima BP, Liu G, Ha P, Shi J, Pan HC, Kim JK, Tran L, Minot SS, Hendrickson EL, Lamont EI, Schulte F, Hardt M, Stephens D, Patel M, Kokaras A, Stodieck L, Shirazi-Fard Y, Wu B, Kwak JH, Ting K, Soo C, McLean JS, He X, Shi W. Specific host metabolite and gut microbiome alterations are associated with bone loss during spaceflight. Cell Rep 2023; 42:112299. [PMID: 37080202 PMCID: PMC10344367 DOI: 10.1016/j.celrep.2023.112299] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 10/30/2022] [Accepted: 03/07/2023] [Indexed: 04/22/2023] Open
Abstract
Understanding the axis of the human microbiome and physiological homeostasis is an essential task in managing deep-space-travel-associated health risks. The NASA-led Rodent Research 5 mission enabled an ancillary investigation of the gut microbiome, varying exposure to microgravity (flight) relative to ground controls in the context of previously shown bone mineral density (BMD) loss that was observed in these flight groups. We demonstrate elevated abundance of Lactobacillus murinus and Dorea sp. during microgravity exposure relative to ground control through whole-genome sequencing and 16S rRNA analyses. Specific functionally assigned gene clusters of L. murinus and Dorea sp. capable of producing metabolites, lactic acid, leucine/isoleucine, and glutathione are enriched. These metabolites are elevated in the microgravity-exposed host serum as shown by liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomic analysis. Along with BMD loss, ELISA reveals increases in osteocalcin and reductions in tartrate-resistant acid phosphatase 5b signifying additional loss of bone homeostasis in flight.
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Affiliation(s)
- Joseph K Bedree
- Section of Oral Biology, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, The Forsyth Institute, Cambridge, MA 02142, USA.
| | - Kristopher Kerns
- Department of Periodontics, School of Dentistry, University of Washington, Seattle, WA 98195, USA
| | - Tsute Chen
- Department of Microbiology, The Forsyth Institute, Cambridge, MA 02142, USA; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA
| | - Bruno P Lima
- Department of Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, MN 55455, USA
| | - Guo Liu
- Section of Oral Biology, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Pin Ha
- Section of Orthodontics, Division of Growth & Development, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Division of Plastic and Reconstructive Surgery, School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Jiayu Shi
- Section of Oral Biology, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA
| | - Hsin Chuan Pan
- Section of Oral Biology, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Jong Kil Kim
- Section of Oral Biology, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Luan Tran
- Section of Oral Biology, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Samuel S Minot
- Microbiome Research Initiative, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Erik L Hendrickson
- Department of Periodontics, School of Dentistry, University of Washington, Seattle, WA 98195, USA
| | - Eleanor I Lamont
- Department of Periodontics, School of Dentistry, University of Washington, Seattle, WA 98195, USA
| | - Fabian Schulte
- Forsyth Center for Salivary Diagnostics, Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA 02142, USA; Harvard School of Dental Medicine, Department of Developmental Biology, Boston, MA 02115, USA
| | - Markus Hardt
- Forsyth Center for Salivary Diagnostics, Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA 02142, USA; Harvard School of Dental Medicine, Department of Developmental Biology, Boston, MA 02115, USA
| | - Danielle Stephens
- Multiplex Core, Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA 02142, USA
| | - Michele Patel
- Multiplex Core, Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA 02142, USA
| | - Alexis Kokaras
- Department of Microbiology, The Forsyth Institute, Cambridge, MA 02142, USA
| | - Louis Stodieck
- BioServe Space Technologies, Department of Aerospace Engineering Sciences, University of Colorado, Boulder, CO 80303, USA
| | - Yasaman Shirazi-Fard
- Bone and Signaling Laboratory, Space Biosciences Division, NASA Ames Research Center, Mail Stop 288-2, Moffett Field, CA 94035, USA
| | - Benjamin Wu
- Department of Bioengineering, School of Engineering, University of California, Los Angeles, Los Angeles, CA 90095, USA; Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Jin Hee Kwak
- Section of Orthodontics, Division of Growth & Development, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Kang Ting
- Section of Orthodontics, Division of Growth & Development, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Chia Soo
- Division of Plastic and Reconstructive Surgery, School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Orthopedic Surgery, School of Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Jeffrey S McLean
- Department of Periodontics, School of Dentistry, University of Washington, Seattle, WA 98195, USA
| | - Xuesong He
- Department of Microbiology, The Forsyth Institute, Cambridge, MA 02142, USA; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA
| | - Wenyuan Shi
- Department of Microbiology, The Forsyth Institute, Cambridge, MA 02142, USA.
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20
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Cheru N, Hafler DA, Sumida TS. Regulatory T cells in peripheral tissue tolerance and diseases. Front Immunol 2023; 14:1154575. [PMID: 37197653 PMCID: PMC10183596 DOI: 10.3389/fimmu.2023.1154575] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 04/13/2023] [Indexed: 05/19/2023] Open
Abstract
Maintenance of peripheral tolerance by CD4+Foxp3+ regulatory T cells (Tregs) is essential for regulating autoreactive T cells. The loss of function of Foxp3 leads to autoimmune disease in both animals and humans. An example is the rare, X-linked recessive disorder known as IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy X-linked) syndrome. In more common human autoimmune diseases, defects in Treg function are accompanied with aberrant effector cytokines such as IFNγ. It has recently become appreciated that Tregs plays an important role in not only maintaining immune homeostasis but also in establishing the tissue microenvironment and homeostasis of non-lymphoid tissues. Tissue resident Tregs show profiles that are unique to their local environments which are composed of both immune and non-immune cells. Core tissue-residence gene signatures are shared across different tissue Tregs and are crucial to homeostatic regulation and maintaining the tissue Treg pool in a steady state. Through interaction with immunocytes and non-immunocytes, tissue Tregs exert a suppressive function via conventional ways involving contact dependent and independent processes. In addition, tissue resident Tregs communicate with other tissue resident cells which allows Tregs to adopt to their local microenvironment. These bidirectional interactions are dependent on the specific tissue environment. Here, we summarize the recent advancements of tissue Treg studies in both human and mice, and discuss the molecular mechanisms that maintain tissue homeostasis and prevent pathogenesis.
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Affiliation(s)
- Nardos Cheru
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, United States
| | - David A. Hafler
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, United States
- Department of Neurology, Yale School of Medicine, New Haven, CT, United States
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
| | - Tomokazu S. Sumida
- Department of Neurology, Yale School of Medicine, New Haven, CT, United States
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21
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Tucker JS, Cho J, Albrecht TM, Ferrell JL, D’Orazio SEF. Egress of Listeria monocytogenes from Mesenteric Lymph Nodes Depends on Intracellular Replication and Cell-to-Cell Spread. Infect Immun 2023; 91:e0006423. [PMID: 36916918 PMCID: PMC10112146 DOI: 10.1128/iai.00064-23] [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: 02/15/2023] [Accepted: 02/20/2023] [Indexed: 03/15/2023] Open
Abstract
The mesenteric lymph nodes (MLN) function as a barrier to systemic spread for both commensal and pathogenic bacteria in the gut. Listeria monocytogenes, a facultative intracellular foodborne pathogen, readily overcomes this barrier and spreads into the bloodstream, causing life-threatening systemic infections. We show here that intracellular replication protected L. monocytogenes from clearance by monocytes and neutrophils and promoted colonization of the small intestine-draining MLN (sMLN) but was not required for dissemination to the colon-draining MLN (cMLN). Intestinal tissue had enough free lipoate to support LplA2-dependent extracellular growth of L. monocytogenes, but exogenous lipoate in the MLN was severely limited, and so the bacteria could replicate only inside cells, where they used LplA1 to scavenge lipoate from host peptides. When foodborne infection was manipulated to allow ΔlplA1 L. monocytogenes to colonize the MLN to the same extent as wild-type bacteria, the mutant was still never recovered in the spleen or liver of any animal. We found that intracellular replication in the MLN promoted actin-based motility and cell-to-cell spread of L. monocytogenes and that rapid efficient exit from the MLN was actA dependent. We conclude that intracellular replication of L. monocytogenes in intestinal tissues is not essential and serves primarily to amplify bacterial burdens above a critical threshold needed to efficiently colonize the cMLN. In contrast, intracellular replication in the MLN is absolutely required for further systemic spread and serves primarily to promote ActA-mediated cell-to-cell spread.
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Affiliation(s)
- Jamila S. Tucker
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA
| | - Jooyoung Cho
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA
| | - Taylor M. Albrecht
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA
| | - Jessica L. Ferrell
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA
| | - Sarah E. F. D’Orazio
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA
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22
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Gholami H, Chmiel JA, Burton JP, Maleki Vareki S. The Role of Microbiota-Derived Vitamins in Immune Homeostasis and Enhancing Cancer Immunotherapy. Cancers (Basel) 2023; 15:1300. [PMID: 36831641 PMCID: PMC9954268 DOI: 10.3390/cancers15041300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 02/15/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Not all cancer patients who receive immunotherapy respond positively and emerging evidence suggests that the gut microbiota may be linked to treatment efficacy. Though mechanisms of microbial contributions to the immune response have been postulated, one likely function is the supply of basic co-factors to the host including selected vitamins. Bacteria, fungi, and plants can produce their own vitamins, whereas humans primarily obtain vitamins from exogenous sources, yet despite the significance of microbial-derived vitamins as crucial immune system modulators, the microbiota is an overlooked source of these nutrients in humans. Microbial-derived vitamins are often shared by gut bacteria, stabilizing bioenergetic pathways amongst microbial communities. Compositional changes in gut microbiota can affect metabolic pathways that alter immune function. Similarly, the immune system plays a pivotal role in maintaining the gut microbiota, which parenthetically affects vitamin biosynthesis. Here we elucidate the immune-interactive mechanisms underlying the effects of these microbially derived vitamins and how they can potentially enhance the activity of immunotherapies in cancer.
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Affiliation(s)
- Hasti Gholami
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
| | - John A. Chmiel
- Department of Microbiology and Immunology, Western University, London, ON N6A 3K7, Canada
- Canadian Research and Development Centre for Probiotics, Lawson Research Health Research Institute, London, ON N6A 5W9, Canada
| | - Jeremy P. Burton
- Department of Microbiology and Immunology, Western University, London, ON N6A 3K7, Canada
- Canadian Research and Development Centre for Probiotics, Lawson Research Health Research Institute, London, ON N6A 5W9, Canada
- Division of Urology, Department of Surgery, Western University, London, ON N6A 3K7, Canada
| | - Saman Maleki Vareki
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
- London Regional Cancer Program, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Oncology, Western University, London, ON N6A 3K7, Canada
- Department of Medical Biophysics, Western University, London, ON N6A 3K7, Canada
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23
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Nguyen NM, Cho J, Lee C. Gut Microbiota and Alzheimer's Disease: How to Study and Apply Their Relationship. Int J Mol Sci 2023; 24:ijms24044047. [PMID: 36835459 PMCID: PMC9958597 DOI: 10.3390/ijms24044047] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/06/2023] [Accepted: 02/14/2023] [Indexed: 02/19/2023] Open
Abstract
Gut microbiota (GM), the microorganisms in the gastrointestinal tract, contribute to the regulation of brain homeostasis through bidirectional communication between the gut and the brain. GM disturbance has been discovered to be related to various neurological disorders, including Alzheimer's disease (AD). Recently, the microbiota-gut-brain axis (MGBA) has emerged as an enticing subject not only to understand AD pathology but also to provide novel therapeutic strategies for AD. In this review, the general concept of the MGBA and its impacts on the development and progression of AD are described. Then, diverse experimental approaches for studying the roles of GM in AD pathogenesis are presented. Finally, the MGBA-based therapeutic strategies for AD are discussed. This review provides concise guidance for those who wish to obtain a conceptual and methodological understanding of the GM and AD relationship with an emphasis on its practical application.
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24
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Korchagina AA, Koroleva E, Tumanov AV. Innate Lymphoid Cell Plasticity in Mucosal Infections. Microorganisms 2023; 11:461. [PMID: 36838426 PMCID: PMC9967737 DOI: 10.3390/microorganisms11020461] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/06/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
Mucosal tissue homeostasis is a dynamic process that involves multiple mechanisms including regulation of innate lymphoid cells (ILCs). ILCs are mostly tissue-resident cells which are critical for tissue homeostasis and immune response against pathogens. ILCs can sense environmental changes and rapidly respond by producing effector cytokines to limit pathogen spread and initiate tissue recovery. However, dysregulation of ILCs can also lead to immunopathology. Accumulating evidence suggests that ILCs are dynamic population that can change their phenotype and functions under rapidly changing tissue microenvironment. However, the significance of ILC plasticity in response to pathogens remains poorly understood. Therefore, in this review, we discuss recent advances in understanding the mechanisms regulating ILC plasticity in response to intestinal, respiratory and genital tract pathogens. Key transcription factors and lineage-guiding cytokines regulate this plasticity. Additionally, we discuss the emerging data on the role of tissue microenvironment, gut microbiota, and hypoxia in ILC plasticity in response to mucosal pathogens. The identification of new pathways and molecular mechanisms that control functions and plasticity of ILCs could uncover more specific and effective therapeutic targets for infectious and autoimmune diseases where ILCs become dysregulated.
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Affiliation(s)
| | | | - Alexei V. Tumanov
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA
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25
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Saez A, Herrero-Fernandez B, Gomez-Bris R, Sánchez-Martinez H, Gonzalez-Granado JM. Pathophysiology of Inflammatory Bowel Disease: Innate Immune System. Int J Mol Sci 2023; 24:ijms24021526. [PMID: 36675038 PMCID: PMC9863490 DOI: 10.3390/ijms24021526] [Citation(s) in RCA: 191] [Impact Index Per Article: 95.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 12/30/2022] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation with no exact known cause. Intestinal innate immunity is enacted by neutrophils, monocytes, macrophages, and dendritic cells (DCs), and innate lymphoid cells and NK cells, characterized by their capacity to produce a rapid and nonspecific reaction as a first-line response. Innate immune cells (IIC) defend against pathogens and excessive entry of intestinal microorganisms, while preserving immune tolerance to resident intestinal microbiota. Changes to this equilibrium are linked to intestinal inflammation in the gut and IBD. IICs mediate host defense responses, inflammation, and tissue healing by producing cytokines and chemokines, activating the complement cascade and phagocytosis, or presenting antigens to activate the adaptive immune response. IICs exert important functions that promote or ameliorate the cellular and molecular mechanisms that underlie and sustain IBD. A comprehensive understanding of the mechanisms underlying these clinical manifestations will be important for developing therapies targeting the innate immune system in IBD patients. This review examines the complex roles of and interactions among IICs, and their interactions with other immune and non-immune cells in homeostasis and pathological conditions.
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Affiliation(s)
- Angela Saez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria (UFV), 28223 Pozuelo de Alarcón, Spain
| | - Beatriz Herrero-Fernandez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Raquel Gomez-Bris
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Hector Sánchez-Martinez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
| | - Jose M. Gonzalez-Granado
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-913908766
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26
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Rivera CA, Lennon-Duménil AM. Gut immune cells and intestinal niche imprinting. Semin Cell Dev Biol 2023:S1084-9521(23)00006-X. [PMID: 36635104 DOI: 10.1016/j.semcdb.2023.01.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 11/30/2022] [Accepted: 01/06/2023] [Indexed: 01/11/2023]
Abstract
The intestine comprises the largest proportion of immune cells in the body. It is continuously exposed to new antigens and immune stimuli from the diet, microbiota but also from intestinal pathogens. In this review, we describe the main populations of immune cells present along the intestine, both from the innate and adaptive immune system. We later discuss how intestinal niches significantly impact the phenotype and function of gut immune populations at steady state and upon infection.
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Affiliation(s)
- Claudia A Rivera
- Institut Curie, INSERM U932, PSL Research University, 75005 Paris, France
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27
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Jiang S, Miao Z. High-fat diet induces intestinal mucosal barrier dysfunction in ulcerative colitis: emerging mechanisms and dietary intervention perspective. Am J Transl Res 2023; 15:653-677. [PMID: 36915785 PMCID: PMC10006746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 01/09/2023] [Indexed: 03/16/2023]
Abstract
The incidence of ulcerative colitis (UC) is increasing worldwide, but its pathogenesis remains largely unclear. The intestinal mucosa is a barrier that maintains the stability of the body's internal environment, and dysfunction of this barrier leads to the occurrence and aggravation of UC. A high-fat diet (HFD) contains more animal fat and low fiber, and accumulating evidence has shown that long-term intake of an HFD is associated with UC. The mechanism linking an HFD with intestinal mucosal barrier disruption is multifactorial, and it typically involves microbiota dysbiosis and altered metabolism of fatty acids, bile acids, and tryptophan. Dysbiosis-induced metabolic changes can enhance intestinal permeability through multiple pathways. These changes modulate the programmed death of intestinal epithelial cells, inhibit the secretion of goblet cells and Paneth cells, and impair intercellular interactions. Gut metabolites can also induce intestinal immune imbalance by stimulating multiple proinflammatory signaling pathways and decreasing the effect of anti-inflammatory immune cells. In this review, we critically analyze the molecular mechanisms by which an HFD disrupts the intestinal mucosal barrier (IMB) and contributes to the development of UC. We also discuss the application and future direction of dietary intervention in the treatment of the IMB and prevention of UC.
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Affiliation(s)
- Shijing Jiang
- First Clinical Medical College, Nanjing University of Chinese Medicine Nanjing, Jiangsu, China
| | - Zhiwei Miao
- Department of Gastroenterology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine Zhangjiagang, Suzhou, Jiangsu, China
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28
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Luda KM, Da Silva C, Ahmadi F, Mowat AM, Ohno H, Kotarsky K, Agace WW. Identification and characterization of murine glycoprotein 2-expressing intestinal dendritic cells. Scand J Immunol 2022; 96:e13219. [PMID: 37807915 PMCID: PMC9786990 DOI: 10.1111/sji.13219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/18/2022] [Accepted: 09/23/2022] [Indexed: 11/30/2022]
Abstract
The intestinal lamina propria (LP) contains distinct subsets of classical dendritic cells (cDC), each playing key non-redundant roles in intestinal immune homeostasis. Here, we show that glycoprotein 2 (GP2), a GPI-anchored protein and receptor for bacterial type-I fimbriae, is selectively expressed by CD103+CD11b+ cDC in the murine small intestine (SI). GP2 expression was induced on CD103+CD11b+ cDC within the SI-LP and was regulated by IRF4, TGFβR1- and retinoic acid signalling. Mice selectively lacking Gp2 on CD103+CD11b+ cDC (huLang-Cre.gp2fl/fl mice) had normal numbers and proportions of innate and adaptive immune cells in the SI-LP suggesting that GP2 expression by CD103+CD11b+ cDC is not required for intestinal immune homoeostasis.
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Affiliation(s)
- Katarzyna M Luda
- Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Clement Da Silva
- Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Fatemeh Ahmadi
- Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Allan Mcl Mowat
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary Medicine and Life Sciences, University of Glasgow, Glasgow, UK
| | - Hiroshi Ohno
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Knut Kotarsky
- Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - William W Agace
- Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden
- Mucosal Immunology Laboratory, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark
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29
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Canesso MCC, Moreira TG, Faria AMC. Compartmentalization of gut immune responses: mucosal niches and lymph node peculiarities. Immunol Lett 2022; 251-252:86-90. [DOI: 10.1016/j.imlet.2022.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 10/16/2022] [Accepted: 10/25/2022] [Indexed: 11/05/2022]
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30
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Region specificity of fibroblast-like cells in the mucosa of the rat large intestine. Cell Tissue Res 2022; 389:427-441. [PMID: 35779135 DOI: 10.1007/s00441-022-03660-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 06/22/2022] [Indexed: 11/02/2022]
Abstract
Our previous studies using immunohistochemistry and serial block-face scanning electron microscopy (SBF-SEM) clarified that fibroblast-like cells (FBLCs) in the rat ileal mucosa are classifiable into several subtypes, but their characteristics throughout the large intestine remain unknown. In this study, we investigated the region-specific characteristics of FBLCs in the rat large intestine using histological analysis including SBF-SEM. Immunohistochemistry revealed that CD34+CD31- FBLCs were localized in the lamina propria beneath the crypt bases throughout the large intestine and were more abundant in the descending colon than in the other regions. In addition, platelet-derived growth factor receptor α (PDGFRα)+ FBLCs were ubiquitously present just below the epithelium throughout the large intestine, and those at the crypt base were slightly more abundant in the descending colon than in the other regions. SBF-SEM analysis revealed that there were two types of FBLCs around the crypt base in both the cecum and the descending colon: sub-epithelial FBLCs localizing just beneath the epithelium in the manner of PDGFRα+ FBLCs, and lamina propria FBLCs localizing farther away from the epithelium than sub-epithelial FBLCs in the manner of CD34+CD31- FBLCs. The lamina propria FBLCs were closely apposed to various immune cells in the lamina propria, and their endoplasmic reticulum in the descending colon exhibited various dilatation levels, unlike that in the cecum. These findings indicate that FBLCs, especially around the crypt base, differed in each region of the large intestine with respect to localization, abundance, and ultrastructure, which could lead to the region-specific microenvironment around the crypt base.
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31
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Hamade H, Stamps JT, Stamps DT, More SK, Thomas LS, Blackwood AY, Lahcene NL, Castanon SL, Salumbides BC, Shimodaira Y, Goodridge HS, Targan SR, Michelsen KS. BATF3 Protects Against Metabolic Syndrome and Maintains Intestinal Epithelial Homeostasis. Front Immunol 2022; 13:841065. [PMID: 35812447 PMCID: PMC9257242 DOI: 10.3389/fimmu.2022.841065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 05/23/2022] [Indexed: 11/13/2022] Open
Abstract
The intestinal immune system and microbiota are emerging as important contributors to the development of metabolic syndrome, but the role of intestinal dendritic cells (DCs) in this context is incompletely understood. BATF3 is a transcription factor essential in the development of mucosal conventional DCs type 1 (cDC1). We show that Batf3-/- mice developed metabolic syndrome and have altered localization of tight junction proteins in intestinal epithelial cells leading to increased intestinal permeability. Treatment with the glycolysis inhibitor 2-deoxy-D-glucose reduced intestinal inflammation and restored barrier function in obese Batf3-/- mice. High-fat diet further enhanced the metabolic phenotype and susceptibility to dextran sulfate sodium colitis in Batf3-/- mice. Antibiotic treatment of Batf3-/- mice prevented metabolic syndrome and impaired intestinal barrier function. Batf3-/- mice have altered IgA-coating of fecal bacteria and displayed microbial dysbiosis marked by decreased obesity protective Akkermansia muciniphila, and Bifidobacterium. Thus, BATF3 protects against metabolic syndrome and preserves intestinal epithelial barrier by maintaining beneficial microbiota.
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Affiliation(s)
- Hussein Hamade
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Jasmine T. Stamps
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Dalton T. Stamps
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Shyam K. More
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Lisa S. Thomas
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Anna Y. Blackwood
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Nawele L. Lahcene
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Sofi L. Castanon
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Brenda C. Salumbides
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Yosuke Shimodaira
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Helen S. Goodridge
- Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Stephan R. Targan
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Kathrin S. Michelsen
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
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32
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Liu X, Zhou L, Xin W, Hua Z. Exogenous Annexin 1 inhibits Th17 cell differentiation induced by anti-TNF treatment via activating FPR2 in DSS-induced colitis. Int Immunopharmacol 2022; 107:108685. [DOI: 10.1016/j.intimp.2022.108685] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 02/24/2022] [Accepted: 03/03/2022] [Indexed: 02/08/2023]
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Sasaki I, Kato T, Hemmi H, Fukuda-Ohta Y, Wakaki-Nishiyama N, Yamamoto A, Kaisho T. Conventional Type 1 Dendritic Cells in Intestinal Immune Homeostasis. Front Immunol 2022; 13:857954. [PMID: 35693801 PMCID: PMC9184449 DOI: 10.3389/fimmu.2022.857954] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 05/04/2022] [Indexed: 11/15/2022] Open
Abstract
Dendritic cells (DC) play critical roles in linking innate and adaptive immunity. DC are heterogenous and there are subsets with various distinct functions. One DC subset, conventional type 1 DC (cDC1), can be defined by expression of CD8α/CD103 in mice and CD141 in humans, or by expression of a chemokine receptor, XCR1, which is a conserved marker in both mice and human. cDC1 are characterized by high ability to ingest dying cells and to cross-present antigens for generating cytotoxic CD8 T cell responses. Through these activities, cDC1 play crucial roles in immune responses against infectious pathogens or tumors. Meanwhile, cDC1 involvement in homeostatic situations is not fully understood. Analyses by using mutant mice, in which cDC1 are ablated in vivo, revealed that cDC1 are critical for maintaining intestinal immune homeostasis. Here, we review the homeostatic roles of cDC1, focusing upon intestinal immunity.
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Affiliation(s)
- Izumi Sasaki
- Department of Immunology, Institute for Advanced Medicine, Wakayama Medical University, Wakayama, Japan
- *Correspondence: Izumi Sasaki, ; Tsuneyasu Kaisho,
| | - Takashi Kato
- Department of Immunology, Institute for Advanced Medicine, Wakayama Medical University, Wakayama, Japan
| | - Hiroaki Hemmi
- Department of Immunology, Institute for Advanced Medicine, Wakayama Medical University, Wakayama, Japan
- Laboratory of Immunology, Faculty of Veterinary Medicine, Okayama University of Science, Ehime, Japan
| | - Yuri Fukuda-Ohta
- Department of Immunology, Institute for Advanced Medicine, Wakayama Medical University, Wakayama, Japan
| | - Naoko Wakaki-Nishiyama
- Department of Immunology, Institute for Advanced Medicine, Wakayama Medical University, Wakayama, Japan
| | - Asumi Yamamoto
- Department of Immunology, Institute for Advanced Medicine, Wakayama Medical University, Wakayama, Japan
| | - Tsuneyasu Kaisho
- Department of Immunology, Institute for Advanced Medicine, Wakayama Medical University, Wakayama, Japan
- *Correspondence: Izumi Sasaki, ; Tsuneyasu Kaisho,
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34
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Immunomodulatory Role of BLG-Derived Peptides Based on Simulated Gastrointestinal Digestion and DC-T Cell from Mice Allergic to Cow's Milk. Foods 2022; 11:foods11101450. [PMID: 35627020 PMCID: PMC9140701 DOI: 10.3390/foods11101450] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/09/2022] [Accepted: 05/11/2022] [Indexed: 02/01/2023] Open
Abstract
Peptides, but not whole protein, elicit an allergic reaction since food allergens should be consumed by digestion. In this study, we explored the remaining peptides after simulated digestion of cow’s milk in order to search for β-lactoglobulin (BLG)-derived peptides that could play an immunomodulatory role. As a major allergen in milk, BLG-derived peptides, 109 in total, were identified both from simulated infant and adult digestion in vitro. These peptides were mainly located in four regions, and they were synthesized as five peptides, namely, BLG1–14, BLG24–35, BLG40–60, BLG82–101, and BLG123–139. Then, the effect of peptides on the Caco-2 cell’s transport absorption, the co-stimulatory molecules of DC, and the T-cell phenotype was explored. The results suggested all peptides showed better transport absorption capacity with the apparent permeability coefficient higher than 2 × 10−6 cm·s−1. The ability of BLG40–60 for promoting lamina propria-derived DC cell (LPDC) maturation was observed by the increase in MHC II. Moreover, BLG1–14 and BLG40–60 directed activation of T lymphocytes towards a Th1 phenotype. This is the first report of the immunomodulatory potential of peptides in the sensitization of allergic reaction, and one peptide, BLG40–60, was regarded as an immunomodulatory peptide, one that should be further explored in an animal model in depth.
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35
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Russell A, Copio JN, Shi Y, Kang S, Franklin CL, Ericsson AC. Reduced housing density improves statistical power of murine gut microbiota studies. Cell Rep 2022; 39:110783. [PMID: 35545042 PMCID: PMC9161176 DOI: 10.1016/j.celrep.2022.110783] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 12/28/2021] [Accepted: 04/13/2022] [Indexed: 11/25/2022] Open
Abstract
The gut microbiome of humans and animals is critical to host health. Mice are used to investigate the microbiome and its influences; however, the predictive value of such studies is hindered by cage effects due to coprophagy. Our objectives were to evaluate the influence of cage density on the statistical power to detect treatment-dependent effects of a selective pressure on microbiome composition. C57BL/6 mice were separated into groups of 2 or 4 mice per cage and then assigned to groups receiving enrofloxacin, broad-spectrum antibiotics, or control. Fecal samples were collected at weeks 0, 1, and 4, along with contents of the jejunum and cecum. Bacterial DNA analysis examined microbiome richness, diversity, and variability within and between cages. Statistical analyses reveal that reduced housing density consistently results in comparable susceptibility to antibiotics, reduced cage effects, and increased statistical power to detect treatment-associated effects, justifying the practice of reduced housing density.
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Affiliation(s)
- Amber Russell
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65201, USA
| | - Joanna N Copio
- College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210 USA
| | - Yushu Shi
- Department of Statistics, College of Arts and Sciences, University of Missouri, Columbia, MO 65201 USA
| | - Sumin Kang
- Department of Statistics, College of Arts and Sciences, University of Missouri, Columbia, MO 65201 USA
| | - Craig L Franklin
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65201, USA; University of Missouri Metagenomics Center, University of Missouri, Columbia, MO 65201 USA; Mutant Mouse Resource and Research Center, University of Missouri, Columbia, MO 65201 USA
| | - Aaron C Ericsson
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65201, USA; University of Missouri Metagenomics Center, University of Missouri, Columbia, MO 65201 USA; Mutant Mouse Resource and Research Center, University of Missouri, Columbia, MO 65201 USA.
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36
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Bahlool AZ, Grant C, Cryan SA, Keane J, O'Sullivan MP. All trans retinoic acid as a host-directed immunotherapy for tuberculosis. CURRENT RESEARCH IN IMMUNOLOGY 2022; 3:54-72. [PMID: 35496824 PMCID: PMC9040133 DOI: 10.1016/j.crimmu.2022.03.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 03/11/2022] [Accepted: 03/22/2022] [Indexed: 12/22/2022] Open
Abstract
Tuberculosis (TB) is the top bacterial infectious disease killer and one of the top ten causes of death worldwide. The emergence of strains of multiple drug-resistant tuberculosis (MDR-TB) has pushed our available stock of anti-TB agents to the limit of effectiveness. This has increased the urgent need to develop novel treatment strategies using currently available resources. An adjunctive, host-directed therapy (HDT) designed to act on the host, instead of the bacteria, by boosting the host immune response through activation of intracellular pathways could be the answer. The integration of multidisciplinary approaches of repurposing currently FDA-approved drugs, with a targeted drug-delivery platform is a very promising option to reduce the long timeline associated with the approval of new drugs - time that cannot be afforded given the current levels of morbidity and mortality associated with TB infection. The deficiency of vitamin A has been reported to be highly associated with the increased susceptibility of TB. All trans retinoic acid (ATRA), the active metabolite of vitamin A, has proven to be very efficacious against TB both in vitro and in vivo. In this review, we discuss and summarise the importance of vitamin A metabolites in the fight against TB and what is known regarding the molecular mechanisms of ATRA as a host-directed therapy for TB including its effect on macrophages cytokine profile and cellular pathways. Furthermore, we focus on the issues behind why previous clinical trials with vitamin A supplementation have failed, and how these issues might be overcome.
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Affiliation(s)
- Ahmad Z. Bahlool
- School of Pharmacy and Biomolecular Sciences (PBS), Royal College of Surgeons in Ireland (RCSI), 123 St Stephens Green, Dublin 2, Ireland
- Tissue Engineering Research Group (TERG), Royal College of Surgeons in Ireland (RCSI), 123 St Stephens Green, Dublin 2, Ireland
- Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, Ireland
| | - Conor Grant
- Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, Ireland
| | - Sally-Ann Cryan
- School of Pharmacy and Biomolecular Sciences (PBS), Royal College of Surgeons in Ireland (RCSI), 123 St Stephens Green, Dublin 2, Ireland
- Tissue Engineering Research Group (TERG), Royal College of Surgeons in Ireland (RCSI), 123 St Stephens Green, Dublin 2, Ireland
- SFI Advanced Materials and Bioengineering Research (AMBER) Centre, RCSI & TCD, Dublin, Ireland
- SFI Centre for Research in Medical Devices (CURAM), RCSI, Dublin and National University of Ireland, Galway, Ireland
| | - Joseph Keane
- Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, Ireland
| | - Mary P. O'Sullivan
- Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, Ireland
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37
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Tai SL, Mortha A. Macrophage control of Crohn's disease. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 367:29-64. [PMID: 35461659 DOI: 10.1016/bs.ircmb.2022.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The intestinal tract is the body's largest mucosal surface and permanently exposed to microbial and environmental signals. Maintaining a healthy intestine requires the presence of sentinel grounds keeper cells, capable of controlling immunity and tissue homeostasis through specialized functions. Intestinal macrophages are such cells and important players in steady-state functions and during acute and chronic inflammation. Crohn's disease, a chronic inflammatory condition of the intestinal tract is proposed to be the consequence of an altered immune system through microbial and environmental stimulation. This hypothesis suggests an involvement of macrophages in the regulation of this pathology. Within this chapter, we will discuss intestinal macrophage development and highlight data suggesting their implication in chronic intestinal pathologies like Crohn's disease.
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Affiliation(s)
- Siu Ling Tai
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Arthur Mortha
- Department of Immunology, University of Toronto, Toronto, ON, Canada.
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38
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Chen Y, Zheng X, Wu C. The Role of the Tumor Microenvironment and Treatment Strategies in Colorectal Cancer. Front Immunol 2021; 12:792691. [PMID: 34925375 PMCID: PMC8674693 DOI: 10.3389/fimmu.2021.792691] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/15/2021] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) has the second highest mortality rate among all cancers worldwide. Surgery, chemotherapy, radiotherapy, molecular targeting and other treatment methods have significantly prolonged the survival of patients with CRC. Recently, the emergence of tumor immunotherapy represented by immune checkpoint inhibitors (ICIs) has brought new immunotherapy options for the treatment of advanced CRC. As the efficacy of ICIs is closely related to the tumor immune microenvironment (TME), it is necessary to clarify the relationship between the immune microenvironment of CRC and the efficacy of immunotherapy to ensure that the appropriate drugs are selected. We herein review the latest research progress in the immune microenvironment and strategies related to immunotherapy for CRC. We hope that this review helps in the selection of appropriate treatment strategies for CRC patients.
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Affiliation(s)
- Yaping Chen
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xiao Zheng
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Changping Wu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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39
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Chikina AS, Matic Vignjevic D, Lennon-Dumenil AM. Roles of the macrophages in colon homeostasis. C R Biol 2021; 344:337-356. [DOI: 10.5802/crbiol.67] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 11/04/2021] [Indexed: 11/24/2022]
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40
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Guryanova SV, Kudryashova NA, Kataeva AA, Orozbekova BT, Kolesnikova NV, Chuchalin AG. Novel approaches to increase resistance to acute respiratory infections. RUDN JOURNAL OF MEDICINE 2021. [DOI: 10.22363/2313-0245-2021-25-3-181-195] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Relevance . Respiratory infections are the most common in the world. In order to prevent epidemics, there is a need to improve the strategies for organizing medical care and develop new approaches in order to increase the nonspecific resistance, mobilize innate immunity. Objective . The aim of this study was to investigate the effect of glucosaminylmuramyldipeptide (GMDP) on the level of expression of markers of differentiation and activation of functionally significant subpopulations of dendritic cells in peripheral blood mononuclear cells of healthy donors,the second aim was to assess the effectiveness of GMDP in the prevention of acute respiratory infections in an unfavorable epidemiological period of the COVID-19 pandemic. Materials and Methods . An open comparative study included 309 apparently healthy participants, aged 19-22 years. At the first stage of the study, 42 participants (22 female and 20 male) took the drug Licopid 1 mg for 10 days according to the instructions, 1 tablet 3 times a day in order to prevent acute respiratory infections. Peripheral blood sampling was performed before taking the drug (day 0) and the next day after the last dose of the drug (day 12). Evaluation of the expression of markers of differentiation and activation of dendritic cell subpopulations HLA-DR, CD11c, CD123, CD80, CD83, CCR7, CD3, CD14, CD20 was assessed by flow cytometry. At the same time, mRNA was isolated from mononuclear cells of perfusion blood and, after reverse transcription, the level of gene expression was determined by RT PCR. At the next stage, the effectiveness of the prophylactic use of the drug Licopid in 267 students of the Institute of Physical Culture was assessed in order to prevent acute respiratory infections in an unfavorable epidemiological period; the observation period was 12 months. Results and Discussion . A study of the relative quantitative composition of DCs in the peripheral blood of healthy donors by flow cytometry revealed the possibility of an increase in their total number, as well as subpopulations of MDC and PDC under the influence of GMDP. There was a statistically significant increase in the receptors for the chemokine CCR7, which is responsible for the recruitment of DCs to the secondary lymphoid organs. Analysis of the levels of expression of genes XCR1, CD11b , and CD103 showed a statistically significant effect of GMDP on an increase in their expression compared to the baseline level (before GMDP intake), with the mean value being higher in participants undergoing moderate exercise. It was found that the use of the drug Licopid 1mg for the purpose of preventing and reducing the seasonal incidence of acute respiratory infections at the stage of basic training of students of the Institute of Physical Culture contributed to a decrease in the incidence of acute respiratory infections within 12 months of observation after taking the drug. The number of episodes of acute respiratory infections decreased 3.7 times, while the group with 3 or more episodes of acute respiratory infections during the year, which constituted 14.5 % of participants, completely disappeared. The maximum efficiency of GMDP was observed in the track and field command, in which the number of participants who had no episodes of acute respiratory infections during the year increased by 7 times. Conclusion . Our data complement the modern understanding of the molecular mechanism of action of GMDP and substantiate the possibility of its experimental and clinical use in order to develop new strategies for organizing medical care in order to increase the nonspecific resistance of the organism.
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41
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Zhong YB, Kang ZP, Wang MX, Long J, Wang HY, Huang JQ, Wei SY, Zhou W, Zhao HM, Liu DY. Curcumin ameliorated dextran sulfate sodium-induced colitis via regulating the homeostasis of DCs and Treg and improving the composition of the gut microbiota. J Funct Foods 2021; 86:104716. [DOI: 10.1016/j.jff.2021.104716] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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42
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Chiaranunt P, Tai SL, Ngai L, Mortha A. Beyond Immunity: Underappreciated Functions of Intestinal Macrophages. Front Immunol 2021; 12:749708. [PMID: 34650568 PMCID: PMC8506163 DOI: 10.3389/fimmu.2021.749708] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/03/2021] [Indexed: 12/12/2022] Open
Abstract
The gastrointestinal tract hosts the largest compartment of macrophages in the body, where they serve as mediators of host defense and immunity. Seeded in the complex tissue-environment of the gut, an array of both hematopoietic and non-hematopoietic cells forms their immediate neighborhood. Emerging data demonstrate that the functional diversity of intestinal macrophages reaches beyond classical immunity and includes underappreciated non-immune functions. In this review, we discuss recent advances in research on intestinal macrophage heterogeneity, with a particular focus on how non-immune functions of macrophages impact tissue homeostasis and function. We delve into the strategic localization of distinct gut macrophage populations, describe the potential factors that regulate their identity and functional heterogeneity within these locations, and provide open questions that we hope will inspire research dedicated to elucidating a holistic view on macrophage-tissue cell interactions in the body's largest mucosal organ.
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Affiliation(s)
- Pailin Chiaranunt
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Siu Ling Tai
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Louis Ngai
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Arthur Mortha
- Department of Immunology, University of Toronto, Toronto, ON, Canada
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43
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Glowacki RWP, Engelhart MJ, Ahern PP. Controlled Complexity: Optimized Systems to Study the Role of the Gut Microbiome in Host Physiology. Front Microbiol 2021; 12:735562. [PMID: 34646255 PMCID: PMC8503645 DOI: 10.3389/fmicb.2021.735562] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 08/24/2021] [Indexed: 12/26/2022] Open
Abstract
The profound impact of the gut microbiome on host health has led to a revolution in biomedical research, motivating researchers from disparate fields to define the specific molecular mechanisms that mediate host-beneficial effects. The advent of genomic technologies allied to the use of model microbiomes in gnotobiotic mouse models has transformed our understanding of intestinal microbial ecology and the impact of the microbiome on the host. However, despite incredible advances, our understanding of the host-microbiome dialogue that shapes host physiology is still in its infancy. Progress has been limited by challenges associated with developing model systems that are both tractable enough to provide key mechanistic insights while also reflecting the enormous complexity of the gut ecosystem. Simplified model microbiomes have facilitated detailed interrogation of transcriptional and metabolic functions of the microbiome but do not recapitulate the interactions seen in complex communities. Conversely, intact complex communities from mice or humans provide a more physiologically relevant community type, but can limit our ability to uncover high-resolution insights into microbiome function. Moreover, complex microbiomes from lab-derived mice or humans often do not readily imprint human-like phenotypes. Therefore, improved model microbiomes that are highly defined and tractable, but that more accurately recapitulate human microbiome-induced phenotypic variation are required to improve understanding of fundamental processes governing host-microbiome mutualism. This improved understanding will enhance the translational relevance of studies that address how the microbiome promotes host health and influences disease states. Microbial exposures in wild mice, both symbiotic and infectious in nature, have recently been established to more readily recapitulate human-like phenotypes. The development of synthetic model communities from such "wild mice" therefore represents an attractive strategy to overcome the limitations of current approaches. Advances in microbial culturing approaches that allow for the generation of large and diverse libraries of isolates, coupled to ever more affordable large-scale genomic sequencing, mean that we are now ideally positioned to develop such systems. Furthermore, the development of sophisticated in vitro systems is allowing for detailed insights into host-microbiome interactions to be obtained. Here we discuss the need to leverage such approaches and highlight key challenges that remain to be addressed.
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Affiliation(s)
- Robert W. P. Glowacki
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Morgan J. Engelhart
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Philip P. Ahern
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States
- Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH, United States
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44
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Bang YJ, Hu Z, Li Y, Gattu S, Ruhn KA, Raj P, Herz J, Hooper LV. Serum amyloid A delivers retinol to intestinal myeloid cells to promote adaptive immunity. Science 2021; 373:eabf9232. [PMID: 34529485 DOI: 10.1126/science.abf9232] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Ye-Ji Bang
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Zehan Hu
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yun Li
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Sureka Gattu
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Kelly A Ruhn
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Prithvi Raj
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Joachim Herz
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.,Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.,Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.,Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Lora V Hooper
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.,Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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45
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Pierre N, Salée C, Vieujean S, Bequet E, Merli AM, Siegmund B, Meuwis MA, Louis E. Review article: distinctions between ileal and colonic Crohn's disease: from physiology to pathology. Aliment Pharmacol Ther 2021; 54:779-791. [PMID: 34297423 DOI: 10.1111/apt.16536] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 05/15/2021] [Accepted: 07/05/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Ileal and colonic Crohn's disease seem to be two separate entities. AIMS To describe the main physiological distinctions between the small and the large intestine and to analyse the differences between ileal and colonic Crohn's disease. METHODS The relevant literature was critically examined and synthesised. RESULTS The small and large intestine have fundamental distinctions (anatomy, cellular populations, immune defence, microbiota). The differences between ileal and colonic Crohn's disease are highlighted by a heterogeneous body of evidence including clinical features (natural history of the disease, efficacy of treatments, and monitoring), epidemiological data (smoking status, age, gender) and biological data (genetics, microbiota, immunity, mesenteric fat). However, the contribution of these factors to disease location remains poorly understood. CONCLUSION The classification of ileal and colonic Crohn's disease as distinct subphenotypes is well supported by the literature. Understanding of these differences could be exploited to develop more individualised patient care.
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Affiliation(s)
- Nicolas Pierre
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium
| | - Catherine Salée
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium
| | - Sophie Vieujean
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium.,Hepato-Gastroenterology and Digestive Oncology Department, Liège University Hospital, Liège, Belgium
| | - Emeline Bequet
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium.,Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Liège University Hospital, Liège, Belgium
| | - Angela-Maria Merli
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium
| | - Britta Siegmund
- Division of Gastroenterology, Infectiology and Rheumatology, Medical Department, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Marie-Alice Meuwis
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium.,Hepato-Gastroenterology and Digestive Oncology Department, Liège University Hospital, Liège, Belgium
| | - Edouard Louis
- Laboratory of Translational Gastroenterology, GIGA-Institute, University of Liège, Liège, Belgium.,Hepato-Gastroenterology and Digestive Oncology Department, Liège University Hospital, Liège, Belgium
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Moreira TG, Mangani D, Cox LM, Leibowitz J, Lobo ELC, Oliveira MA, Gauthier CD, Nakagaki BN, Willocq V, Song A, Guo L, Lima DCA, Murugaiyan G, Butovsky O, Gabriely G, Anderson AC, Rezende RM, Faria AMC, Weiner HL. PD-L1 + and XCR1 + dendritic cells are region-specific regulators of gut homeostasis. Nat Commun 2021; 12:4907. [PMID: 34389726 PMCID: PMC8363668 DOI: 10.1038/s41467-021-25115-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 07/26/2021] [Indexed: 12/12/2022] Open
Abstract
The intestinal mucosa constitutes an environment of closely regulated immune cells. Dendritic cells (DC) interact with the gut microbiome and antigens and are important in maintaining gut homeostasis. Here, we investigate DC transcriptome, phenotype and function in five anatomical locations of the gut lamina propria (LP) which constitute different antigenic environments. We show that DC from distinct gut LP compartments induce distinct T cell differentiation and cytokine secretion. We also find that PD-L1+ DC in the duodenal LP and XCR1+ DC in the colonic LP comprise distinct tolerogenic DC subsets that are crucial for gut homeostasis. Mice lacking PD-L1+ and XCR1+ DC have a proinflammatory gut milieu associated with an increase in Th1/Th17 cells and a decrease in Treg cells and have exacerbated disease in the models of 5-FU-induced mucositis and DSS-induced colitis. Our findings identify PD-L1+ and XCR1+ DC as region-specific physiologic regulators of intestinal homeostasis.
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Affiliation(s)
- Thais G Moreira
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Davide Mangani
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Laura M Cox
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jeffrey Leibowitz
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Eduardo L C Lobo
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Mariana A Oliveira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Christian D Gauthier
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Brenda N Nakagaki
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Valerie Willocq
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Anya Song
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Lydia Guo
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - David C A Lima
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Gopal Murugaiyan
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Oleg Butovsky
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Galina Gabriely
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ana C Anderson
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Rafael M Rezende
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ana Maria C Faria
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Howard L Weiner
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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Jacobse J, Li J, Rings EHHM, Samsom JN, Goettel JA. Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease. Front Immunol 2021; 12:716499. [PMID: 34421921 PMCID: PMC8371910 DOI: 10.3389/fimmu.2021.716499] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/16/2021] [Indexed: 12/28/2022] Open
Abstract
FOXP3+ regulatory T cells (Treg cells) are a specialized population of CD4+ T cells that restrict immune activation and are essential to prevent systemic autoimmunity. In the intestine, the major function of Treg cells is to regulate inflammation as shown by a wide array of mechanistic studies in mice. While Treg cells originating from the thymus can home to the intestine, the majority of Treg cells residing in the intestine are induced from FOXP3neg conventional CD4+ T cells to elicit tolerogenic responses to microbiota and food antigens. This process largely takes place in the gut draining lymph nodes via interaction with antigen-presenting cells that convert circulating naïve T cells into Treg cells. Notably, dysregulation of Treg cells leads to a number of chronic inflammatory disorders, including inflammatory bowel disease. Thus, understanding intestinal Treg cell biology in settings of inflammation and homeostasis has the potential to improve therapeutic options for patients with inflammatory bowel disease. Here, the induction, maintenance, trafficking, and function of intestinal Treg cells is reviewed in the context of intestinal inflammation and inflammatory bowel disease. In this review we propose intestinal Treg cells do not compose fixed Treg cell subsets, but rather (like T helper cells), are plastic and can adopt different programs depending on microenvironmental cues.
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Affiliation(s)
- Justin Jacobse
- Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Jing Li
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
| | - Edmond H. H. M. Rings
- Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
- Department of Pediatrics, Sophia Children’s Hospital, Erasmus University, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Janneke N. Samsom
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Jeremy A. Goettel
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States
- Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United States
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, United States
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48
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Hansen AK, Hansen CHF. The microbiome and rodent models of immune mediated diseases. Mamm Genome 2021; 32:251-262. [PMID: 33792799 PMCID: PMC8012743 DOI: 10.1007/s00335-021-09866-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 03/12/2021] [Indexed: 02/07/2023]
Abstract
Over the last six decades production of laboratory rodents have been refined with the aim of eliminating all pathogens, which could influence research results. This has, however, also created rodents with little diversity in their microbiota. Until 10 years ago the impact of the microbiota on the outcome of rodent studies was ignored, but today it is clear that the phenotype of rodent models differs essentially in relation to the environment of origin, i.e. different breeders or different rooms. In this review, we outline the mechanisms behind gut bacterial impact on rodent models of immune mediated diseases, and how differences in environment of origin leads to phenotypic model differences within research areas such as infectious diseases and vaccine development, the metabolic syndrome, gut immunity and inflammation, autoimmunity and allergy. Finally, we sum up some tools to handle this impact to increase reproducibility and translatability of rodent models.
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Affiliation(s)
- Axel Kornerup Hansen
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg C, Denmark.
| | - Camilla Hartmann Friis Hansen
- Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg C, Denmark.
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49
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Probiotic-Induced Tolerogenic Dendritic Cells: A Novel Therapy for Inflammatory Bowel Disease? Int J Mol Sci 2021; 22:ijms22158274. [PMID: 34361038 PMCID: PMC8348973 DOI: 10.3390/ijms22158274] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/22/2021] [Accepted: 07/24/2021] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) are immune-mediated, chronic relapsing diseases with a rising prevalence worldwide in both adult and pediatric populations. Treatment options for immune-mediated diseases, including IBDs, are traditional steroids, immunomodulators, and biologics, none of which are capable of inducing long-lasting remission in all patients. Dendritic cells (DCs) play a fundamental role in inducing tolerance and regulating T cells and their tolerogenic functions. Hence, modulation of intestinal mucosal immunity by DCs could provide a novel, additional tool for the treatment of IBD. Recent evidence indicates that probiotic bacteria might impact immunomodulation both in vitro and in vivo by regulating DCs’ maturation and producing tolerogenic DCs (tolDCs) which, in turn, might dampen inflammation. In this review, we will discuss this evidence and the mechanisms of action of probiotics and their metabolites in inducing tolDCs in IBDs and some conditions associated with them.
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50
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Prins MMC, van Roest M, Vermeulen JLM, Tjabringa GS, van de Graaf SFJ, Koelink PJ, Wildenberg ME. Applicability of different cell line-derived dendritic cell-like cells in autophagy research. J Immunol Methods 2021; 497:113106. [PMID: 34324891 DOI: 10.1016/j.jim.2021.113106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/09/2021] [Accepted: 07/20/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Immortalized cell lines have been long used as substitute for ex vivo murine and human material, but exhibit features that are not found in healthy tissue. True human dendritic cells (DC) cannot be cultured or passaged as opposed to immortalized cell lines. Research in the fields of immunogenic responses and immunotolerance in DCs has increased over the last decade. Autophagy has gained interest in these fields as well, and has been researched extensively in many other cell types as well. Here we have studied the applicability of cell line-derived dendritic cell-like cells of six myeloid cell lines aimed at research focussed on autophagy. METHODS Six myeloid leukaemia cell lines were differentiated towards cell line-derived dendritic cell-like cells (cd-DC) using GM-CSF, IL-4, Ionomycine and PMA: HL60, KG1, MM6, MV-4-11, THP1 and U937. Autophagy was modulated using Rapamycin, Bafilomycin A1 and 3MA. Cell lines were genotyped for autophagy-related SNPs using RFLP. Marker expression was determined with FACS analysis and cytokine profiles were determined using Human Cytometric Bead Assay. Antigen uptake was assessed using Fluoresbrite microspheres. RESULTS AND DISCUSSION All researched cell lines harboured SNPs in the autophagy pathways. MM6 and THP1 derived cd-DCs resembled monocyte-derived DCs (moDC) most closely in marker expression, cytokine profiles and autophagy response. The HL60 and U937 cell lines proved least suitable for autophagy-related dendritic cell research. CONCLUSION The genetic background of cell lines should be taken into account upon studying (the effects of) autophagy in any cell line. Although none of the studied cell lines recapitulate the full spectrum of DC characteristics, MM6 and THP1 derived cd-DCs are most suitable for autophagy-related research in dendritic cells.
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Affiliation(s)
- Marileen M C Prins
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
| | - Manon van Roest
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
| | - Jacqueline L M Vermeulen
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
| | - G Sandra Tjabringa
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
| | - Stan F J van de Graaf
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
| | - Pim J Koelink
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
| | - Manon E Wildenberg
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
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