|
1
|
Askarizadeh F, Butler AE, Kesharwani P, Sahebkar A. Regulatory effect of curcumin on CD40:CD40L interaction and therapeutic implications. Food Chem Toxicol 2025; 200:115369. [PMID: 40043936 DOI: 10.1016/j.fct.2025.115369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 01/24/2025] [Accepted: 03/02/2025] [Indexed: 04/21/2025]
Abstract
Natural compounds have garnered significant attention as potential therapeutic agents due to their inherent properties. Their notable qualities, including safety, efficacy, favorable pharmacokinetic properties, and heightened effectiveness against certain diseases, particularly inflammatory conditions, make them particularly appealing. Among these compounds, curcumin has attracted considerable interest for its unique therapeutic properties and has therefore been extensively studied as a potential therapeutic agent for treating various diseases. Curcumin exhibits diverse anti-inflammatory, antioxidant, and antimicrobial effects. Curcumin's immune system regulatory ability has made it a promising compound for treatment of various inflammatory diseases, such as psoriasis, atherosclerosis, asthma, colitis, IBD, and arthritis. Among the signaling pathways implicated in these conditions, the CD40 receptor together with its ligand, CD40L, are recognized as central players. Studies have demonstrated that the interaction between CD40 and CD40L interaction acts as the primary mediator of the immune response in inflammatory diseases. Numerous studies have explored the impact of curcumin on the CD40:CD40L pathway, highlighting its regulatory effects on this inflammatory pathway and its potential therapeutic use in related inflammatory conditions. In this review, we will consider the evidence concerning curcumin's modulatory effects in inflammatory disease and its potential therapeutic role in regulating the CD40:CD40L pathway.
Collapse
Affiliation(s)
- Fatemeh Askarizadeh
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Institute of Medical and Technical Sciences, Saveetha Medical College and Hospitals, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| |
Collapse
|
|
2
|
Smythies LE, Belyaeva OV, Alexander KL, Bimczok D, Nick HJ, Serrano CA, Huff KR, Nearing M, Musgrove L, Poovey EH, Garth J, Russ K, Baig KRKK, Crossman DK, Peter S, Cannon JA, Elson CO, Kedishvili NY, Smith PD. Human intestinal stromal cells promote homeostasis in normal mucosa but inflammation in Crohn's disease in a retinoic acid-deficient manner. Mucosal Immunol 2024; 17:958-972. [PMID: 38945396 PMCID: PMC11530961 DOI: 10.1016/j.mucimm.2024.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 06/18/2024] [Accepted: 06/24/2024] [Indexed: 07/02/2024]
Abstract
Intestinal stromal cells (SCs), which synthesize the extracellular matrix that gives the mucosa its structure, are newly appreciated to play a role in mucosal inflammation. Here, we show that human intestinal vimentin+CD90+smooth muscle actin- SCs synthesize retinoic acid (RA) at levels equivalent to intestinal epithelial cells, a function in the human intestine previously attributed exclusively to epithelial cells. Crohn's disease SCs (Crohn's SCs), however, synthesized markedly less RA than SCs from healthy intestine (normal SCs). We also show that microbe-stimulated Crohn's SCs, which are more inflammatory than stimulated normal SCs, induced less RA-regulated differentiation of mucosal dendritic cells (DCs) (circulating pre-DCs and monocyte-derived DCs), leading to the generation of more potent inflammatory interferon-γhi/interleukin-17hi T cells than normal SCs. Explaining these results, Crohn's SCs expressed more DHRS3, a retinaldehyde reductase that inhibits retinol conversion to retinal and, thus, synthesized less RA than normal SCs. These findings uncover a microbe-SC-DC crosstalk in which luminal microbes induce Crohn's disease SCs to initiate and perpetuate inflammation through impaired synthesis of RA.
Collapse
Affiliation(s)
- Lesley E Smythies
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Olga V Belyaeva
- Department of Biochemistry and Molecular Genetics, Schools of Medicine and Dentistry, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Katie L Alexander
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Diane Bimczok
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT, USA
| | - Heidi J Nick
- Department of Pediatrics, National Jewish Health, Denver, CO, USA
| | - Carolina A Serrano
- Department of Pediatric Gastroenterology and Nutrition, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Kayci R Huff
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Marie Nearing
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Lois Musgrove
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Emily H Poovey
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jaleesa Garth
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kirk Russ
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kondal R K K Baig
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - David K Crossman
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Shajan Peter
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jamie A Cannon
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Charles O Elson
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Natalia Y Kedishvili
- Department of Biochemistry and Molecular Genetics, Schools of Medicine and Dentistry, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Phillip D Smith
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
| |
Collapse
|
|
3
|
Asgari F, Khodadoust M, Nikzamir A, Jahani‐Sherafat S, Rezaei Tavirani M, Rostami‐Nejad M. The role of tryptophan metabolism and tolerogenic dendritic cells in maintaining immune tolerance: Insights into celiac disease pathogenesis. Immun Inflamm Dis 2024; 12:e1354. [PMID: 39150219 PMCID: PMC11328117 DOI: 10.1002/iid3.1354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 07/06/2024] [Accepted: 07/08/2024] [Indexed: 08/17/2024] Open
Abstract
BACKGROUND In mammals, amino acid metabolism has evolved to control immune responses. Tryptophan (Trp) is the rarest essential amino acid found in food and its metabolism has evolved to be a primary regulatory node in the control of immune responses. Celiac disease (CeD) is a developed immunological condition caused by gluten intolerance and is linked to chronic small intestine enteropathy in genetically predisposed individuals. Dendritic cells (DCs), serving as the bridge between innate and adaptive immunities, can influence immunological responses in CeD through phenotypic alterations. OBJECTIVE This review aims to highlight the connection between Trp metabolism and tolerogenic DCs, and the significance of this interaction in the pathogenesis of CeD. RESULTS It is been recognized that various DC subtypes contribute to the pathogenesis of CeD. Tolerogenic DCs, in particular, are instrumental in inducing immune tolerance, leading to T-reg differentiation that helps maintain intestinal immune tolerance against inflammatory responses in CeD patients and those with other autoimmune disorders. T-regs, a subset of T-cells, play a crucial role in maintaining intestinal immunological homeostasis by regulating the activities of other immune cells. Notably, Trp metabolism, essential for T-reg function, facilitates T-reg differentiation through microbiota-mediated degradation and the kynurenine pathway. CONCLUSION Therefore, alterations in Trp metabolism could potentially influence the immune response in CeD, affecting both the development of the disease and the persistence of symptoms despite adherence to a gluten-free diet.
Collapse
Affiliation(s)
- Fatemeh Asgari
- Student Research Committee, Department of Clinical Biochemistry, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Mahdi Khodadoust
- Department of Parasitology and Mycology, School of MedicineShiraz University of Medical SciencesShirazIran
| | - Abdolrahim Nikzamir
- Student Research Committee, Department of Clinical Biochemistry, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Somayeh Jahani‐Sherafat
- Laser Application in Medical Sciences Research CenterShahid Beheshti University of Medical SciencesTehranIran
| | | | - Mohammad Rostami‐Nejad
- Celiac Disease and Gluten Related Disorders Research Center, Research Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| |
Collapse
|
|
4
|
Nagy NA, Hafkamp FMJ, Sparrius R, Bas R, Lozano Vigario F, van Capel TMM, van Ree R, Geijtenbeek TBH, Slütter B, Tas SW, de Jong EC. Retinoic acid-loaded liposomes induce human mucosal CD103 + dendritic cells that inhibit Th17 cells and drive regulatory T-cell development in vitro. Eur J Immunol 2024; 54:e2350839. [PMID: 38430190 DOI: 10.1002/eji.202350839] [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: 10/16/2023] [Revised: 02/18/2024] [Accepted: 02/20/2024] [Indexed: 03/03/2024]
Abstract
The active vitamin A metabolite, all-trans-retinoic acid (RA), primes precursor dendritic cells (DCs) into a mucosal phenotype with tolerogenic properties characterized by the expression of integrin CD103. CD103+ DCs can counteract pathogenic Th1 and Th17 in inflammatory bowel disease (IBD) or celiac disease (CD). Tolerogenic manipulation of DCs using nanoparticles carrying tolerogenic adjuvants and disease-specific antigens is a valuable treatment strategy to induce antigen-specific mucosal tolerance in vivo. Here, we investigated the effects of RA-loaded liposomes on human DC phenotype and function, including DC-driven T-cell development, both during the generation of monocyte-derived DCs (moDCs) as well as by priming immature moDCs. RA liposomes drove CD103+ DC differentiation as well as ALDH1A2 expression in DCs. Neutrophil-dependent Th17 cell development was reduced by RA-liposome-differentiated and RA-liposome-primed DCs. Moreover, RA liposome treatment shifted T-cell development toward a Th2 cell profile. Importantly, RA liposomes induced the development of IL-10-producing and FoxP3+ regulatory T cells (Tregs) of various Treg subsets, including ICOS+ Tregs, that were potent inhibitors of bystander memory T-cell proliferation. Taken together, RA-loaded liposomes could be a novel treatment avenue for IBD or CD patients.
Collapse
Affiliation(s)
- Noémi Anna Nagy
- Department of Experimental Immunology, Amsterdam University Medical Centers, Amsterdam Institute for Infection & Immunity, University of Amsterdam, Amsterdam, The Netherlands
| | - Florianne M J Hafkamp
- Department of Experimental Immunology, Amsterdam University Medical Centers, Amsterdam Institute for Infection & Immunity, University of Amsterdam, Amsterdam, The Netherlands
| | - Rinske Sparrius
- Department of Experimental Immunology, Amsterdam University Medical Centers, Amsterdam Institute for Infection & Immunity, University of Amsterdam, Amsterdam, The Netherlands
| | - Rico Bas
- Department of Experimental Immunology, Amsterdam University Medical Centers, Amsterdam Institute for Infection & Immunity, University of Amsterdam, Amsterdam, The Netherlands
| | - Fernando Lozano Vigario
- Division of BioTherapeutics, Leiden Academic Center for Drug Research, Leiden, The Netherlands
| | - Toni M M van Capel
- Department of Experimental Immunology, Amsterdam University Medical Centers, Amsterdam Institute for Infection & Immunity, University of Amsterdam, Amsterdam, The Netherlands
| | - Ronald van Ree
- Department of Experimental Immunology, Amsterdam University Medical Centers, Amsterdam Institute for Infection & Immunity, University of Amsterdam, Amsterdam, The Netherlands
- Department of Otorhinolaryngology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Teunis B H Geijtenbeek
- Department of Experimental Immunology, Amsterdam University Medical Centers, Amsterdam Institute for Infection & Immunity, University of Amsterdam, Amsterdam, The Netherlands
| | - Bram Slütter
- Division of BioTherapeutics, Leiden Academic Center for Drug Research, Leiden, The Netherlands
| | - Sander W Tas
- Department of Experimental Immunology, Amsterdam University Medical Centers, Amsterdam Institute for Infection & Immunity, University of Amsterdam, Amsterdam, The Netherlands
- Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Centers, Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands
| | - Esther C de Jong
- Department of Experimental Immunology, Amsterdam University Medical Centers, Amsterdam Institute for Infection & Immunity, University of Amsterdam, Amsterdam, The Netherlands
| |
Collapse
|
|
5
|
Didriksen BJ, Eshleman EM, Alenghat T. Epithelial regulation of microbiota-immune cell dynamics. Mucosal Immunol 2024; 17:303-313. [PMID: 38428738 PMCID: PMC11412483 DOI: 10.1016/j.mucimm.2024.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 02/09/2024] [Accepted: 02/23/2024] [Indexed: 03/03/2024]
Abstract
The mammalian gastrointestinal tract hosts a diverse community of trillions of microorganisms, collectively termed the microbiota, which play a fundamental role in regulating tissue physiology and immunity. Recent studies have sought to dissect the cellular and molecular mechanisms mediating communication between the microbiota and host immune system. Epithelial cells line the intestine and form an initial barrier separating the microbiota from underlying immune cells, and disruption of epithelial function has been associated with various conditions ranging from infection to inflammatory bowel diseases and cancer. From several studies, it is now clear that epithelial cells integrate signals from commensal microbes. Importantly, these non-hematopoietic cells also direct regulatory mechanisms that instruct the recruitment and function of microbiota-sensitive immune cells. In this review, we discuss the central role that has emerged for epithelial cells in orchestrating intestinal immunity and highlight epithelial pathways through which the microbiota can calibrate tissue-intrinsic immune responses.
Collapse
Affiliation(s)
- Bailey J Didriksen
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Emily M Eshleman
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
| | - Theresa Alenghat
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
| |
Collapse
|
|
6
|
Prame Kumar K, Ooi JD, Goldberg R. The interplay between the microbiota, diet and T regulatory cells in the preservation of the gut barrier in inflammatory bowel disease. Front Microbiol 2023; 14:1291724. [PMID: 38107848 PMCID: PMC10722198 DOI: 10.3389/fmicb.2023.1291724] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 11/06/2023] [Indexed: 12/19/2023] Open
Abstract
Inflammatory bowel disease (IBD) is becoming more common in the Western world due to changes in diet-related microbial dysbiosis, genetics and lifestyle. Incidences of gut permeability can predate IBD and continued gut barrier disruptions increase the exposure of bacterial antigens to the immune system thereby perpetuating chronic inflammation. Currently, most of the approved IBD therapies target individual pro-inflammatory cytokines and pathways. However, they fail in approximately 50% of patients due to their inability to overcome the redundant pro inflammatory immune responses. There is increasing interest in the therapeutic potential of T regulatory cells (Tregs) in inflammatory conditions due to their widespread capability to dampen inflammation, promote tolerance of intestinal bacteria, facilitate healing of the mucosal barrier and ability to be engineered for more targeted therapy. Intestinal Treg populations are inherently shaped by dietary molecules and gut microbiota-derived metabolites. Thus, understanding how these molecules influence Treg-mediated preservation of the intestinal barrier will provide insights into immune tolerance-mediated mucosal homeostasis. This review comprehensively explores the interplay between diet, gut microbiota, and immune system in influencing the intestinal barrier function to attenuate the progression of colitis.
Collapse
Affiliation(s)
- Kathryn Prame Kumar
- Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash Medical Centre, Monash University, Clayton, VIC, Australia
| | | | | |
Collapse
|
|
7
|
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.
Collapse
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
| |
Collapse
|
|
8
|
Schimpel C, Passegger C, Egger S, Tam-Amersdorfer C, Strobl H. A novel 3D cell culture model to study the human small intestinal immune landscape. Eur J Immunol 2023; 53:e2250131. [PMID: 36527196 DOI: 10.1002/eji.202250131] [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: 08/17/2022] [Revised: 11/21/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
Several subsets of mononuclear phagocytes and DCs (MDC) populate the small intestine (SI), and these cells reportedly exert specialized functions in anti-microbial immunity and tolerance. Given the specialized phenotype of these cells, differing from other MDC family members, including their putative circulating blood precursors, local intestinal factors play key instructive roles in their differentiation. We designed an SI cell culture model composed of three intestinal epithelial cell (IEC) types, including absorptive enterocytes (E cells), antigen delivering microfold (M) cells, and mucus-producing goblet (G) cells plus T lymphocytes and soluble B cell-derived factors. This model was used to study the differentiation fate of CD34+ hematopoietic progenitor cell-derived monocyte/DC precursors. Progeny cells can be analyzed after a 3-week co-culture period, mimicking the physiologic turn-over time of intestinal MDC. A dominant monocyte differentiation pathway was suppressed, in favor of partial differentiation along DC and macrophage pathways, with low percentages of cells acquired DC or macrophage markers. Moreover, E and G cells play opposing roles in CX3CR1+ vs CD103dim cell differentiation, indicating that both together might counter-balance M/DC differentiation. Thus, SI epithelial cells suppress M/DC differentiation, supporting a key role for exogenous factors in M/DC differentiation.
Collapse
Affiliation(s)
- Christa Schimpel
- Medical University of Graz, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology and Pathophysiology, Graz, Austria
| | - Christina Passegger
- Medical University of Graz, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology and Pathophysiology, Graz, Austria
| | - Simone Egger
- Medical University of Graz, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology and Pathophysiology, Graz, Austria
| | - Carmen Tam-Amersdorfer
- Medical University of Graz, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology and Pathophysiology, Graz, Austria
| | - Herbert Strobl
- Medical University of Graz, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology and Pathophysiology, Graz, Austria
| |
Collapse
|
|
9
|
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.
Collapse
Affiliation(s)
- Claudia A Rivera
- Institut Curie, INSERM U932, PSL Research University, 75005 Paris, France
| | | |
Collapse
|
|
10
|
Lee J, Khang D. Mucosal delivery of nanovaccine strategy against COVID-19 and its variants. Acta Pharm Sin B 2022; 13:S2211-3835(22)00489-0. [PMID: 36438851 PMCID: PMC9676163 DOI: 10.1016/j.apsb.2022.11.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/08/2022] [Accepted: 11/16/2022] [Indexed: 11/22/2022] Open
Abstract
Despite the global administration of approved COVID-19 vaccines (e.g., ChAdOx1 nCoV-19®, mRNA-1273®, BNT162b2®), the number of infections and fatalities continue to rise at an alarming rate because of the new variants such as Omicron and its subvariants. Including COVID-19 vaccines that are licensed for human use, most of the vaccines that are currently in clinical trials are administered via parenteral route. However, it has been proven that the parenteral vaccines do not induce localized immunity in the upper respiratory mucosal surface, and administration of the currently approved vaccines does not necessarily lead to sterilizing immunity. This further supports the necessity of a mucosal vaccine that blocks the main entrance route of COVID-19: nasal and oral mucosal surfaces. Understanding the mechanism of immune regulation of M cells and dendritic cells and targeting them can be another promising approach for the successful stimulation of the mucosal immune system. This paper reviews the basic mechanisms of the mucosal immunity elicited by mucosal vaccines and summarizes the practical aspects and challenges of nanotechnology-based vaccine platform development, as well as ligand hybrid nanoparticles as potentially effective target delivery agents for mucosal vaccines.
Collapse
Affiliation(s)
- Junwoo Lee
- College of Medicine, Gachon University, Incheon 21999, South Korea
| | - Dongwoo Khang
- College of Medicine, Gachon University, Incheon 21999, South Korea
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, South Korea
- Gachon Advanced Institute for Health Science & Technology, Gachon University, Incheon 21999, South Korea
- Department of Physiology, College of Medicine, Gachon University, Incheon 21999, South Korea
| |
Collapse
|
|
11
|
Matzinger P. Autoimmunity: Are we asking the right question? Front Immunol 2022; 13:864633. [PMID: 36405714 PMCID: PMC9671104 DOI: 10.3389/fimmu.2022.864633] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 09/20/2022] [Indexed: 09/07/2023] Open
Abstract
For decades, the main question immunologists have asked about autoimmunity is "what causes a break in self-tolerance?" We have not found good answers to that question, and I believe we are still so ignorant because it's the wrong question. Rather than a break in self-tolerance, I suggest that many autoimmune diseases might be due to defects in normal tissue physiology.
Collapse
Affiliation(s)
- Polly Matzinger
- Ghost Lab, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD, United States
| |
Collapse
|
|
12
|
Abstract
Vitamin A (retinol) is a critical micronutrient required for the control of stem cell functions, cell differentiation, and cell metabolism in many different cell types, both during embryogenesis and in the adult organism. However, we must obtain vitamin A from food sources. Thus, the uptake and metabolism of vitamin A by intestinal epithelial cells, the storage of vitamin A in the liver, and the metabolism of vitamin A in target cells to more biologically active metabolites, such as retinoic acid (RA) and 4-oxo-RA, must be precisely regulated. Here, I will discuss the enzymes that metabolize vitamin A to RA and the cytochrome P450 Cyp26 family of enzymes that further oxidize RA. Because much progress has been made in understanding the regulation of ALDH1a2 (RALDH2) actions in the intestine, one focus of this review is on the metabolism of vitamin A in intestinal epithelial cells and dendritic cells. Another focus is on recent data that 4-oxo-RA is a ligand required for the maintenance of hematopoietic stem cell dormancy and the important role of RARβ (RARB) in these stem cells. Despite this progress, many questions remain in this research area, which links vitamin A metabolism to nutrition, immune functions, developmental biology, and nuclear receptor pharmacology.
Collapse
Affiliation(s)
- Lorraine J Gudas
- Department of Pharmacology, and Revlon Pharmaceutical Professor of Pharmacology and Toxicology, Pharmacology Department, and the Meyer Cancer Center of Weill Cornell Medicine of Cornell University, 1300 York Ave, New York, NY 10065
| |
Collapse
|
|
13
|
Jiang Z, Wu C. Reciprocal Interactions Between Regulatory T Cells and Intestinal Epithelial Cells. Front Immunol 2022; 13:951339. [PMID: 35860233 PMCID: PMC9289291 DOI: 10.3389/fimmu.2022.951339] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 06/09/2022] [Indexed: 11/25/2022] Open
Abstract
It has been well established that Foxp3+ regulatory T cells (Treg cells) play a crucial role for immune repression and tolerance, protecting the body from autoimmunity and inflammation. Previous studies indicate that intestinal Treg cells are one specialized population of Treg cells, distinct from those in other organ compartments, both functionally and phenotypically. Specific external and internal signals, particularly the presence of microbiota, shape these Treg cells to better cooperate with the gut ecosystem, controlling intestinal physiology. The integrity of intestinal epithelial barrier represents a key feature of gut immune tolerance, which can be regulated by multiple factors. Emerging evidence suggests that bidirectional interactions between gut epithelium and resident T cells significantly contribute to intestinal barrier function. Understanding how Treg cells regulate intestinal barrier integrity provides insights into immune tolerance-mediated mucosal homeostasis, which can further illuminate potential therapeutic strategies for treating inflammatory bowel disease and colon cancer.
Collapse
Affiliation(s)
- Zhiqiang Jiang
- Sun-Yat Sen University, School of Medicine, Guangzhou, China
- *Correspondence: Zhiqiang Jiang, ; Chuan Wu,
| | - Chuan Wu
- Experimental Immunology Branch, National Cancer Institute, National Institute of Health (NIH), Bethesda, MD, United States
- *Correspondence: Zhiqiang Jiang, ; Chuan Wu,
| |
Collapse
|
|
14
|
Sidell N, Kane MA. Actions of Retinoic Acid in the Pathophysiology of HIV Infection. Nutrients 2022; 14:nu14081611. [PMID: 35458172 PMCID: PMC9029687 DOI: 10.3390/nu14081611] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/01/2022] [Accepted: 04/02/2022] [Indexed: 02/05/2023] Open
Abstract
The vitamin A metabolite all-trans retinoic acid (RA) plays a key role in tissue homeostasis and mucosal immunity. RA is produced by gut-associated dendritic cells, which are among the first cells encountered by HIV. Acute HIV infection results in rapid reduction of RA levels and dysregulation of immune cell populations whose identities and function are largely controlled by RA. Here, we discuss the potential link between the roles played by RA in shaping intestinal immune responses and the manifestations and pathogenesis of HIV-associated enteropathy and similar conditions observed in SIV-infected non-human primate models. We also present data demonstrating the ability of RA to enhance the activation of replication-competent viral reservoirs from subjects on suppressive anti-retroviral therapy. The data suggest that retinoid supplementation may be a useful adjuvant for countering the pathologic condition of the gastro-intestinal tract associated with HIV infection and as part of a strategy for reactivating viral reservoirs as a means of depleting latent viral infection.
Collapse
Affiliation(s)
- Neil Sidell
- Department of Obstetrics and Gynecology, Emory University School of Medicine, Atlanta, GA 30322, USA
- Correspondence: (N.S.); (M.A.K.)
| | - Maureen A. Kane
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA
- Correspondence: (N.S.); (M.A.K.)
| |
Collapse
|
|
15
|
The Role of the Intestinal Epithelium in the "Weep and Sweep" Response during Gastro-Intestinal Helminth Infections. Animals (Basel) 2022; 12:ani12020175. [PMID: 35049796 PMCID: PMC8772803 DOI: 10.3390/ani12020175] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/25/2021] [Accepted: 01/10/2022] [Indexed: 02/08/2023] Open
Abstract
Simple Summary The immune system actively combats intruders such as bacteria, viruses, fungi, and protozoan and metazoan parasites using leukocytes. During an infection white blood cells are activated to internalize bacteria or viruses and release a number of molecules to kill pathogens. Unfortunately, those mechanisms are ineffective against larger intruders like helminths, which are too large to be killed by a single immune cell. To eliminate gastro-intestinal helminths an integrated response involving the nervous, endocrine, and immune systems are used to expel the parasites. This is achieved through increased gut hydration and muscle contractions which detach worms from the gut and lead to release outside the body in a “weep and sweep” response. Epithelial cells of the intestine are significant players in this process, being responsible for detecting the presence of helminths in the gut and participating in the regulation of parasite expulsion. This paper describes the role of the gut epithelium in detecting and eliminating helminths from the intestine. Abstract Helminths are metazoan parasites infecting around 1.5 billion people all over the world. During coevolution with hosts, worms have developed numerous ways to trick and evade the host immune response, and because of their size, they cannot be internalized and killed by immune cells in the same way as bacteria or viruses. During infection, a substantial Th2 component to the immune response is evoked which helps restrain Th1-mediated tissue damage. Although an enhanced Th2 response is often not enough to kill the parasite and terminate an infection in itself, when tightly coordinated with the nervous, endocrine, and motor systems it can dislodge parasites from tissues and expel them from the gut. A significant role in this “weep and seep” response is attributed to intestinal epithelial cells (IEC). This review highlights the role of various IEC lineages (enterocytes, tuft cells, Paneth cells, microfold cells, goblet cells, and intestine stem cells) during the course of helminth infections and summarizes their roles in regulating gut architecture and permeability, and muscle contractions and interactions with the immune and nervous system.
Collapse
|
|
16
|
Rivera CA, Randrian V, Richer W, Gerber-Ferder Y, Delgado MG, Chikina AS, Frede A, Sorini C, Maurin M, Kammoun-Chaari H, Parigi SM, Goudot C, Cabeza-Cabrerizo M, Baulande S, Lameiras S, Guermonprez P, Reis e Sousa C, Lecuit M, Moreau HD, Helft J, Vignjevic DM, Villablanca EJ, Lennon-Duménil AM. Epithelial colonization by gut dendritic cells promotes their functional diversification. Immunity 2022; 55:129-144.e8. [PMID: 34910930 PMCID: PMC8751639 DOI: 10.1016/j.immuni.2021.11.008] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 08/19/2021] [Accepted: 11/15/2021] [Indexed: 12/23/2022]
Abstract
Dendritic cells (DCs) patrol tissues and transport antigens to lymph nodes to initiate adaptive immune responses. Within tissues, DCs constitute a complex cell population composed of distinct subsets that can exhibit different activation states and functions. How tissue-specific cues orchestrate DC diversification remains elusive. Here, we show that the small intestine included two pools of cDC2s originating from common pre-DC precursors: (1) lamina propria (LP) CD103+CD11b+ cDC2s that were mature-like proinflammatory cells and (2) intraepithelial cDC2s that exhibited an immature-like phenotype as well as tolerogenic properties. These phenotypes resulted from the action of food-derived retinoic acid (ATRA), which enhanced actomyosin contractility and promoted LP cDC2 transmigration into the epithelium. There, cDC2s were imprinted by environmental cues, including ATRA itself and the mucus component Muc2. Hence, by reaching distinct subtissular niches, DCs can exist as immature and mature cells within the same tissue, revealing an additional mechanism of DC functional diversification.
Collapse
Affiliation(s)
- Claudia A Rivera
- Institut Curie, INSERM U932, PSL Research University, 75005 Paris, France
| | - Violaine Randrian
- Institut Curie, INSERM U932, PSL Research University, 75005 Paris, France
| | - Wilfrid Richer
- Institut Curie, INSERM U932, PSL Research University, 75005 Paris, France
| | | | | | - Aleksandra S Chikina
- Institut Curie, INSERM U932, PSL Research University, 75005 Paris, France; Institut Curie, CNRS UMR 144, PSL Research University, 75005 Paris, France
| | - Annika Frede
- Immunology and Allergy division, Department of Medicine, Solna, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden; Center of Molecular Medicine, 17176 Stockholm, Sweden
| | - Chiara Sorini
- Immunology and Allergy division, Department of Medicine, Solna, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden; Center of Molecular Medicine, 17176 Stockholm, Sweden
| | - Mathieu Maurin
- Institut Curie, INSERM U932, PSL Research University, 75005 Paris, France
| | - Hana Kammoun-Chaari
- Biology of Infection Unit, Institut Pasteur, INSERM U1117, 75015 Paris, France
| | - Sara M Parigi
- Immunology and Allergy division, Department of Medicine, Solna, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden; Center of Molecular Medicine, 17176 Stockholm, Sweden
| | - Christel Goudot
- Institut Curie, INSERM U932, PSL Research University, 75005 Paris, France
| | | | - Sylvain Baulande
- ICGex Next-Generation Sequencing Platform, Institut Curie, PSL Research University, 75005 Paris, France
| | - Sonia Lameiras
- ICGex Next-Generation Sequencing Platform, Institut Curie, PSL Research University, 75005 Paris, France
| | - Pierre Guermonprez
- Université de Paris, Centre for Inflammation Research, CNRS ERL8252, INSERM1149, Paris, France
| | | | - Marc Lecuit
- Biology of Infection Unit, Institut Pasteur, INSERM U1117, 75015 Paris, France; Université de Paris, Necker-Enfants Malades University Hospital, Department of Infectious Diseases and Tropical Medicine, APHP, Institut Imagine, Paris, France
| | - Hélène D Moreau
- Institut Curie, INSERM U932, PSL Research University, 75005 Paris, France
| | - Julie Helft
- Institut Curie, INSERM U932, PSL Research University, 75005 Paris, France
| | | | - Eduardo J Villablanca
- Immunology and Allergy division, Department of Medicine, Solna, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden; Center of Molecular Medicine, 17176 Stockholm, Sweden
| | | |
Collapse
|
|
17
|
Yu Y, Li J, Liu C. Oxytocin suppresses epithelial cell-derived cytokines production and alleviates intestinal inflammation in food allergy. Biochem Pharmacol 2022; 195:114867. [PMID: 34863977 DOI: 10.1016/j.bcp.2021.114867] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/29/2021] [Accepted: 11/30/2021] [Indexed: 12/12/2022]
Abstract
Food allergy is a growing healthcare problem worldwide, but prophylactic options and regulatory therapies are limited. Oxytocin (OXT), conventionally acknowledged as a hormone, was recently proven to have potent anti-inflammatory and immunomodulatory activities in certain diseases. Here, we reported the novel function and its underlying mechanisms of OXT on food allergy in vivo and in vitro. We showed that the levels of OXT were elevated in ovalbumin (OVA)-allergic mice and patients with food allergy. In HT-29 cells, OXT inhibited the production of the epithelial cell-derived cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)-25 and IL-33 by suppressing NF-κB signaling, in which β-arrestin2 participated. These functions of OXT were abolished by oxytocin receptor (OXTR) depletion. Treating OVA-induced BALB/c mice with OXT suppressed TSLP, IL-25 and IL-33 production and attenuated systemic anaphylaxis and intestinal inflammation. OXTR-/- mice showed extreme increases in TSLP, IL-25 and IL-33 levels as well as severe systemic anaphylaxis and intestinal inflammation. In conclusion, through OXTRs, OXT has a promising antiallergic effect on experimental food allergy by suppressing epithelial TSLP, IL-25 and IL-33 production via inhibiting NF-κB signaling and upregulating β-arrestin2 expression. Our study provides a new therapeutic perspective for food allergy in humans.
Collapse
Affiliation(s)
- Yiang Yu
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jingxin Li
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
| | - Chuanyong Liu
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Provincial Key Lab of Mental Disorders, Shandong University, Jinan, Shandong, China.
| |
Collapse
|
|
18
|
Stephens WZ, Kubinak JL, Ghazaryan A, Bauer KM, Bell R, Buhrke K, Chiaro TR, Weis AM, Tang WW, Monts JK, Soto R, Ekiz HA, O'Connell RM, Round JL. Epithelial-myeloid exchange of MHC class II constrains immunity and microbiota composition. Cell Rep 2021; 37:109916. [PMID: 34731608 PMCID: PMC9012449 DOI: 10.1016/j.celrep.2021.109916] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/13/2021] [Accepted: 10/11/2021] [Indexed: 12/12/2022] Open
Abstract
Intestinal epithelial cells (IECs) have long been understood to express high levels of major histocompatibility complex class II (MHC class II) molecules but are not considered canonical antigen-presenting cells, and the impact of IEC-MHC class II signaling on gut homeostasis remains enigmatic. As IECs serve as the primary barrier between underlying host immune cells, we reasoned that IEC-intrinsic antigen presentation may play a role in responses toward the microbiota. Mice with an IEC-intrinsic deletion of MHC class II (IECΔMHC class II) are healthy but have fewer microbial-bound IgA, regulatory T cells (Tregs), and immune repertoire selection. This was associated with increased interindividual microbiota variation and altered proportions of two taxa in the ileum where MHC class II on IECs is highest. Intestinal mononuclear phagocytes (MNPs) have similar MHC class II transcription but less surface MHC class II and are capable of acquiring MHC class II from IECs. Thus, epithelial-myeloid interactions mediate development of adaptive responses to microbial antigens within the gastrointestinal tract.
Collapse
Affiliation(s)
- W Zac Stephens
- University of Utah School of Medicine, Department of Pathology, Division of Microbiology and Immunology, Salt Lake City, UT 84112, USA
| | - Jason L Kubinak
- University of South Carolina School of Medicine, Department of Pathology, Microbiology and Immunology, Columbia, SC 29209, USA
| | - Arevik Ghazaryan
- University of Utah School of Medicine, Department of Pathology, Division of Microbiology and Immunology, Salt Lake City, UT 84112, USA
| | - Kaylyn M Bauer
- University of Utah School of Medicine, Department of Pathology, Division of Microbiology and Immunology, Salt Lake City, UT 84112, USA
| | - Rickesha Bell
- University of Utah School of Medicine, Department of Pathology, Division of Microbiology and Immunology, Salt Lake City, UT 84112, USA
| | - Kate Buhrke
- University of Utah School of Medicine, Department of Pathology, Division of Microbiology and Immunology, Salt Lake City, UT 84112, USA
| | - Tyson R Chiaro
- University of Utah School of Medicine, Department of Pathology, Division of Microbiology and Immunology, Salt Lake City, UT 84112, USA
| | - Allison M Weis
- University of Utah School of Medicine, Department of Pathology, Division of Microbiology and Immunology, Salt Lake City, UT 84112, USA
| | - William W Tang
- University of Utah School of Medicine, Department of Pathology, Division of Microbiology and Immunology, Salt Lake City, UT 84112, USA
| | - Josh K Monts
- University of Utah School of Medicine, Flow Cytometry Core, Health Sciences Center, Salt Lake City, UT 84112, USA
| | - Ray Soto
- University of Utah School of Medicine, Department of Pathology, Division of Microbiology and Immunology, Salt Lake City, UT 84112, USA
| | - H Atakan Ekiz
- University of Utah School of Medicine, Department of Pathology, Division of Microbiology and Immunology, Salt Lake City, UT 84112, USA; Izmir Institute of Technology, Molecular Biology and Genetics Department, Gulbahce, Izmir 35430, Turkey
| | - Ryan M O'Connell
- University of Utah School of Medicine, Department of Pathology, Division of Microbiology and Immunology, Salt Lake City, UT 84112, USA.
| | - June L Round
- University of Utah School of Medicine, Department of Pathology, Division of Microbiology and Immunology, Salt Lake City, UT 84112, USA.
| |
Collapse
|
|
19
|
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
|
|
20
|
Everts HB, Silva KA, Schmidt AN, Opalenik S, Duncan FJ, King LE, Sundberg JP, Ong DE. Estrogen regulates the expression of retinoic acid synthesis enzymes and binding proteins in mouse skin. Nutr Res 2021; 94:10-24. [PMID: 34571215 PMCID: PMC8845065 DOI: 10.1016/j.nutres.2021.08.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 08/17/2021] [Accepted: 08/17/2021] [Indexed: 11/21/2022]
Abstract
Topical 17-beta-estradiol (E2) regulates the hair cycle, hair shaft differentiation, and sebum production. Vitamin A also regulates sebum production. Vitamin A metabolism proteins localized to the pilosebaceous unit (PSU; hair follicle and sebaceous gland); and were regulated by E2 in other tissues. This study tests the hypothesis that E2 also regulates vitamin A metabolism in the PSU. First, aromatase and estrogen receptors localized to similar sites as retinoid metabolism proteins during mid-anagen. Next, female and male wax stripped C57BL/6J mice were topically treated with E2, the estrogen receptor antagonist ICI 182,780 (ICI), letrozole, E2 plus letrozole, or vehicle control (acetone) during mid-anagen. E2 or one of its inhibitors regulated most of the vitamin A metabolism genes and proteins examined in a sex-dependent manner. Most components were higher in females and reduced with ICI in females. ICI reductions occurred in the premedulla, sebaceous gland, and epidermis. Reduced E2 also reduced RA receptors in the sebaceous gland and bulge in females. However, reduced E2 increased the number of retinal dehydrogenase 2 positive hair follicle associated dermal dendritic cells in males. These results suggest that estrogen regulates vitamin A metabolism in the skin. Interactions between E2 and vitamin A have implications in acne treatment, hair loss, and skin immunity.
Collapse
Affiliation(s)
- Helen B Everts
- Department of Nutrition and Food Sciences, Texas Woman's University, Denton, TX, USA; Department of Nutrition, The Ohio State University, Columbus, OH, USA; Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN, USA.
| | | | - Adriana N Schmidt
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Susan Opalenik
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - F Jason Duncan
- Department of Nutrition, The Ohio State University, Columbus, OH, USA
| | - Lloyd E King
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - John P Sundberg
- The Jackson Laboratory, Bar Harbor, ME, USA; Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - David E Ong
- Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN, USA
| |
Collapse
|
|
21
|
Zou J, Liu C, Jiang S, Qian D, Duan J. Cross Talk between Gut Microbiota and Intestinal Mucosal Immunity in the Development of Ulcerative Colitis. Infect Immun 2021; 89:e0001421. [PMID: 33526559 PMCID: PMC8370674 DOI: 10.1128/iai.00014-21] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC), a nonspecific inflammatory disease, is characterized by inflammation and mucosal damage in the colon, and its prevalence in the world is increasing. Nevertheless, the exact pathogenesis of UC is still unclear. Accumulating data have suggested that its pathogenesis is multifactorial, involving genetic predisposition, environmental factors, microbial dysbiosis, and dysregulated immune responses. Generally, UC is aroused by inappropriate immune activation based on the interaction of host and intestinal microbiota. The relationship between microbiota and host immune system in the pathogenesis of UC is complicated. However, increasing evidence indicates that the shift of microbiota composition can substantially influence intestinal immunity. In this review, we primarily focus on the delicate balance between microbiota and gut mucosal immunity during UC progression.
Collapse
Affiliation(s)
- Junfeng Zou
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
| | - Chen Liu
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
| | - Shu Jiang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
| | - Dawei Qian
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
| | - Jinao Duan
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
| |
Collapse
|
|
22
|
Parodi B, Sanna A, Cedola A, Uccelli A, Kerlero de Rosbo N. Hydroxycarboxylic Acid Receptor 2, a Pleiotropically Linked Receptor for the Multiple Sclerosis Drug, Monomethyl Fumarate. Possible Implications for the Inflammatory Response. Front Immunol 2021; 12:655212. [PMID: 34084164 PMCID: PMC8167049 DOI: 10.3389/fimmu.2021.655212] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 05/06/2021] [Indexed: 12/12/2022] Open
Abstract
Monomethyl fumarate (MMF), metabolite of dimethyl fumarate (DMF), an immunosuppressive drug approved for the treatment of multiple sclerosis (MS), is a potent agonist for hydroxycarboxylic acid receptor 2 (HCAR2), eliciting signals that dampen cell activation or lead to inflammation such as the skin flushing reaction that is one of the main side effects of the treatment, together with gastrointestinal inflammation. Our aim is to further understand the molecular basis underlying these differential effects of the drug. We have used wild-type and HCAR2 knock-out mice to investigate, in vitro and ex vivo under steady-state and pathological conditions, the HCAR2-mediated signaling pathways activated by MMF in dendritic cells (DC), which promote differentiation of T cells, and in intestinal epithelial cells (IEC) where activation of a pro-inflammatory pathway, such as the cyclooxygenase-2 pathway involved in skin flushing, could underlie gastrointestinal side effects of the drug. To understand how DMF treatment might impact on gut inflammation induced by experimental autoimmune encephalomyelitis (EAE), the animal model for MS, we have used 3D X-ray phase contrast tomography and flow cytometry to monitor possible intestinal alterations at morphological and immunological levels, respectively. We show that HCAR2 is a pleiotropically linked receptor for MMF, mediating activation of different pathways leading to different outcomes in different cell types, depending on experimental in-vitro and in-vivo conditions. In the small intestine of EAE-affected mice, DMF treatment affected migration of tolerogenic DC from lamina propria to mesenteric lymph nodes, and/or reverted their profile to pro-inflammatory, probably as a result of reduced expression of aldehyde dehydrogenase and transforming growth factor beta as well as the inflammatory environment. Nevertheless, DMF treatment did not amplify the morphological alterations induced by EAE. On the basis of our further understanding of MMF signaling through HCAR2, we suggest that the pleiotropic signaling of fumarate via HCAR2 should be addressed for its pharmaceutical relevance in devising new lead compounds with reduced inflammatory side effects.
Collapse
Affiliation(s)
- Benedetta Parodi
- Neuroimmunology Laboratory, DINOGMI, University of Genoa, Genoa, Italy
| | | | | | - Antonio Uccelli
- Neuroimmunology Laboratory, DINOGMI, University of Genoa, Genoa, Italy.,IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | | |
Collapse
|
|
23
|
Guo J, Han X, Huang W, You Y, Jicheng Z. Interaction between IgA and gut microbiota and its role in controlling metabolic syndrome. Obes Rev 2021; 22:e13155. [PMID: 33150692 DOI: 10.1111/obr.13155] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/21/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023]
Abstract
Immunoglobulin A (IgA) is the most abundant immunoglobulin isotype secreted into the mucosal tissues, mainly intestinal mucus. Humans can produce several grams of IgA every day, accounting for three quarters of the body's total immunoglobulin content. IgA, together with mucus and antimicrobial peptides, forms the first line of defence for intestinal epithelial cells, protecting them from a significant number of intestinal antigens. IgA also plays a principal role in controlling the gut microbiota (GM), and disruption in IgA can result in dysbiosis, such as the enrichment of Proteobacteria, which are generally bound by IgA. Proteobacteria overexpansion is also usually seen in obesity and colitis. Consistent with this, IgA dysfunction frequently results in metabolic syndrome (MetS), including conditions such as obesity, adiposity, insulin resistance, and inflammation. In contrast, enhanced IgA function can improve, and even prevent, MetS. Interactions among IgA, GM, and metabolism provide a promising avenue to combat MetS.
Collapse
Affiliation(s)
- Jielong Guo
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Viticulture and Enology, China Agricultural University, Beijing, China
| | - Xue Han
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Viticulture and Enology, China Agricultural University, Beijing, China
| | - Weidong Huang
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Viticulture and Enology, China Agricultural University, Beijing, China
| | - Yilin You
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Viticulture and Enology, China Agricultural University, Beijing, China
| | - Zhan Jicheng
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Viticulture and Enology, China Agricultural University, Beijing, China
| |
Collapse
|
|
24
|
Liu EG, Yin X, Swaminathan A, Eisenbarth SC. Antigen-Presenting Cells in Food Tolerance and Allergy. Front Immunol 2021; 11:616020. [PMID: 33488627 PMCID: PMC7821622 DOI: 10.3389/fimmu.2020.616020] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 11/20/2020] [Indexed: 12/12/2022] Open
Abstract
Food allergy now affects 6%-8% of children in the Western world; despite this, we understand little about why certain people become sensitized to food allergens. The dominant form of food allergy is mediated by food-specific immunoglobulin E (IgE) antibodies, which can cause a variety of symptoms, including life-threatening anaphylaxis. A central step in this immune response to food antigens that differentiates tolerance from allergy is the initial priming of T cells by antigen-presenting cells (APCs), primarily different types of dendritic cells (DCs). DCs, along with monocyte and macrophage populations, dictate oral tolerance versus allergy by shaping the T cell and subsequent B cell antibody response. A growing body of literature has shed light on the conditions under which antigen presentation occurs and how different types of T cell responses are induced by different APCs. We will review APC subsets in the gut and discuss mechanisms of APC-induced oral tolerance versus allergy to food identified using mouse models and patient samples.
Collapse
Affiliation(s)
- Elise G. Liu
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, United States
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, United States
- Section of Rheumatology, Allergy & Immunology, Yale University School of Medicine, New Haven, CT, United States
| | - Xiangyun Yin
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, United States
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, United States
| | - Anush Swaminathan
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, United States
| | - Stephanie C. Eisenbarth
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, United States
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, United States
- Section of Rheumatology, Allergy & Immunology, Yale University School of Medicine, New Haven, CT, United States
| |
Collapse
|
|
25
|
Cassinotti A, Passamonti F, Segato S. CELL THERAPY IN INFLAMMATORY BOWEL DISEASE. Pharmacol Res 2021; 163:105247. [PMID: 33069755 DOI: 10.1016/j.phrs.2020.105247] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 10/06/2020] [Accepted: 10/07/2020] [Indexed: 12/14/2022]
Abstract
In recent years, cell-based therapies have been explored in various immune-mediated inflammatory diseases, including inflammatory bowel disease (IBD). Cell therapy is the process of introducing new cells into an organism or tissue in order to treat a disease. The most studied cellular treatment in IBD was "stem cells-based therapy", which was explored according to different protocols in terms of type of donors, stem cells sources, study design and clinical endpoints. More recently, preliminary studies have also described the clinical use of "regulatory cells", which include T-reg and Tr1 cells, and "tolerogenic" dendritic cells. Finally, induced pluripotent stem cells are the subject of an intensive preclinical research program on animal models, including those related to colitis.
Collapse
Affiliation(s)
| | | | - Sergio Segato
- Gastroenterology Unit, ASST Sette Laghi, Varese Italy
| |
Collapse
|
|
26
|
Arranz E, De Prado Á, Fiz-López A, Arribas E, Garrote JA, Bernardo D. Human intestinal dendritic cell and macrophage subsets in coeliac disease. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 358:85-104. [PMID: 33707058 DOI: 10.1016/bs.ircmb.2020.09.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Dendritic cells (DC) and macrophages (Mϕ) constitute the most abundant antigen presenting cells in the human intestinal mucosa. In resting conditions, they are essential to maintain the mechanisms of immune tolerance toward food antigens and commensals, at the time that they keep the capacity to initiate and maintain antigen-specific pro-inflammatory immune responses toward invading pathogens. Nevertheless, this delicate equilibrium between immunity and tolerance is not perfect, like in coeliac disease (CD), where DC and Mϕ drive the development of antigen-specific immune responses toward dietary gluten peptides. In this review, we provide therefore a comprehensive discussion about CD pathogenesis, the human intestinal immune system and the biology of intestinal DC and Mϕ both in resting conditions and in CD. Last, but not least, we discuss about all the remaining issues pending to be studied regarding DC and Mϕ contribution toward CD pathogenesis. This may allow the identification of unique and specific factors which may be useful in the clinical practice, as well as identify new therapeutic targets in order to reestablish the loss intestinal homeostasis in CD.
Collapse
Affiliation(s)
- Eduardo Arranz
- Mucosal Immunology Lab. Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid-CSIC, Valladolid, Spain
| | - Ángel De Prado
- Mucosal Immunology Lab. Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid-CSIC, Valladolid, Spain
| | - Aida Fiz-López
- Mucosal Immunology Lab. Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid-CSIC, Valladolid, Spain
| | - Elisa Arribas
- Mucosal Immunology Lab. Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid-CSIC, Valladolid, Spain
| | - José A Garrote
- Mucosal Immunology Lab. Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid-CSIC, Valladolid, Spain; Servicio de Análisis Clínicos, Hospital Universitario Río Hortega, Valladolid, Spain
| | - David Bernardo
- Mucosal Immunology Lab. Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid-CSIC, Valladolid, Spain.
| |
Collapse
|
|
27
|
Anti-Inflammatory Properties and Gut Microbiota Modulation of Porphyra tenera Extracts in Dextran Sodium Sulfate-Induced Colitis in Mice. Antioxidants (Basel) 2020; 9:antiox9100988. [PMID: 33066339 PMCID: PMC7602078 DOI: 10.3390/antiox9100988] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 10/05/2020] [Accepted: 10/07/2020] [Indexed: 12/14/2022] Open
Abstract
Porphyra tenera (PT) is a functional seaweed food that has been reported for health benefits such as antioxidant, immunostimulant, anti-inflammation, and hepatoprotective effects. In this study, we investigated the effect of PT extracts on gut microbiota modulation in colitis-induced mice. The mice experiment was designed as three groups including normal mice (CTL), dextran sodium sulfate (DSS)-fed mice, and DSS plus PT extracts-fed mice (PTE). DSS was administrated through drinking water containing DSS for 1 week, and the PT extract was ingested into the gastrointestinal tract in mice. PT extract ameliorated the decreased body weight and colon length and improved disease activity index and pro-inflammatory cytokine expression. In addition, PT extract significantly shifted the gut microbiota of mice. DSS treatment significantly increased the portion of harmful bacteria (i.e., Helicobacter, Mucipirillum, and Parasutterella) and decreased the butyrate producing bacteria (i.e., Acetatifactor, Alistipes, Oscillibacter, and Clostridium_XIVb). PT extract increased the abundance of genera Clostridium_XIVb and also enriched some of predicted metabolic activities such as glyoxylate cycle, ethylmalonyl-CoA pathway, nitrate reduction, creatinine degradation, and glycine betaine metabolism. These results suggest that PT extract may ameliorate the DSS-induced colitis inflammation through regulating the compositions and functions of gut microbiota in mice.
Collapse
|
|
28
|
Saraf S, Jain S, Sahoo RN, Mallick S. Present Scenario of M-Cell Targeting Ligands for Oral Mucosal Immunization. Curr Drug Targets 2020; 21:1276-1284. [DOI: 10.2174/1389450121666200609113252] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 04/18/2020] [Accepted: 04/23/2020] [Indexed: 02/07/2023]
Abstract
The immune system plays an important role in the prevention of infection and forms the
first line of defense against pathogen attack. Delivering of antigen through mucosal route may elicit
mucosal immune system as the mucosal surface is the most common site of pathogen entry. Mucosal
immune system will be capable to counter pathogen at mucosal surface. Oral mucosal immunization
opens the ways to deliver antigens at gut-associated lymphoid tissue. This can elicit both local and
systemic immune response. Mucosal vaccines are economical, highly accessible, non parenteral delivery
and capacity to produce mass immunization at the time of pandemics. To deliver antigens on the
mucosal surface of the gastrointestinal tract, the immune system relies on specialized epithelial cell
i.e. Microfold (M)-cell. An approach to exploit the targeting specific receptors on M-cell for entry of
antigens has made a breakthrough in vaccine development. In this review, various strategies have been
discussed for the possible entry of antigens through M-cells and an approach to increase the uptake
and efficacy of vaccines for oral mucosal immunization.
Collapse
Affiliation(s)
- Surendra Saraf
- School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar-751030, Orissa, India
| | - Shailesh Jain
- Dean, Faculty of Pharmacy and Pharmaceutical Sciences at Madhyanchal Professional University Bhopal (MP), India
| | - Rudra Narayan Sahoo
- School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar-751030, Orissa, India
| | - Subrata Mallick
- School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar-751030, Orissa, India
| |
Collapse
|
|
29
|
Ko HJ, Hong SW, Verma R, Jung J, Lee M, Kim N, Kim D, Surh CD, Kim KS, Rudra D, Im SH. Dietary Glucose Consumption Promotes RALDH Activity in Small Intestinal CD103 +CD11b + Dendritic Cells. Front Immunol 2020; 11:1897. [PMID: 32849649 PMCID: PMC7433714 DOI: 10.3389/fimmu.2020.01897] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 07/14/2020] [Indexed: 12/21/2022] Open
Abstract
Retinal dehydrogenase (RALDH) enzymatic activities catalyze the conversion of vitamin A to its metabolite Retinoic acid (RA) in intestinal dendritic cells (DCs) and promote immunological tolerance. However, precise understanding of the exogenous factors that act as initial trigger of RALDH activity in these cells is still evolving. By using germ-free (GF) mice raised on an antigen free (AF) elemental diet, we find that certain components in diet are critically required to establish optimal RALDH expression and activity, most prominently in small intestinal CD103+CD11b+ DCs (siLP-DCs) right from the beginning of their lives. Surprisingly, systematic screens using modified diets devoid of individual dietary components indicate that proteins, starch and minerals are dispensable for this activity. On the other hand, in depth comparison between subtle differences in dietary composition among different dietary regimes reveal that adequate glucose concentration in diet is a critical determinant for establishing RALDH activity specifically in siLP-DCs. Consequently, pre-treatment of siLP-DCs, and not mesenteric lymph node derived MLNDCs with glucose, results in significant enhancement in the in vitro generation of induced Regulatory T (iTreg) cells. Our findings reveal previously underappreciated role of dietary glucose concentration in establishing regulatory properties in intestinal DCs, thereby extending a potential therapeutic module against intestinal inflammation.
Collapse
Affiliation(s)
- Hyun-Ja Ko
- Academy of Immunology and Microbiology, Institute for Basic Science, Pohang-si, South Korea
| | - Sung-Wook Hong
- Academy of Immunology and Microbiology, Institute for Basic Science, Pohang-si, South Korea
| | - Ravi Verma
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology, Pohang-si, South Korea.,ImmunoBiome Inc., Pohang-si, South Korea
| | - Jisun Jung
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology, Pohang-si, South Korea
| | - Minji Lee
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology, Pohang-si, South Korea
| | - Nahyun Kim
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology, Pohang-si, South Korea
| | - Daeun Kim
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology, Pohang-si, South Korea
| | - Charles D Surh
- Academy of Immunology and Microbiology, Institute for Basic Science, Pohang-si, South Korea.,Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology, Pohang-si, South Korea
| | - Kwang Soon Kim
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology, Pohang-si, South Korea
| | - Dipayan Rudra
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology, Pohang-si, South Korea
| | - Sin-Hyeog Im
- Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology, Pohang-si, South Korea.,ImmunoBiome Inc., Pohang-si, South Korea
| |
Collapse
|
|
30
|
Blaner WS, Brun PJ, Calderon RM, Golczak M. Retinol-binding protein 2 (RBP2): biology and pathobiology. Crit Rev Biochem Mol Biol 2020; 55:197-218. [PMID: 32466661 DOI: 10.1080/10409238.2020.1768207] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Retinol-binding protein 2 (RBP2; originally cellular retinol-binding protein, type II (CRBPII)) is a 16 kDa cytosolic protein that in the adult is localized predominantly to absorptive cells of the proximal small intestine. It is well established that RBP2 plays a central role in facilitating uptake of dietary retinoid, retinoid metabolism in enterocytes, and retinoid actions locally within the intestine. Studies of mice lacking Rbp2 establish that Rbp2 is not required in times of dietary retinoid-sufficiency. However, in times of dietary retinoid-insufficiency, the complete lack of Rbp2 gives rise to perinatal lethality owing to RBP2 absence in both placental (maternal) and neonatal tissues. Moreover, when maintained on a high-fat diet, Rbp2-knockout mice develop obesity, glucose intolerance and a fatty liver. Unexpectedly, recent investigations have demonstrated that RBP2 binds long-chain 2-monoacylglycerols (2-MAGs), including the canonical endocannabinoid 2-arachidonoylglycerol, with very high affinity, equivalent to that of retinol binding. Crystallographic studies establish that 2-MAGs bind to a site within RBP2 that fully overlaps with the retinol binding site. When challenged orally with fat, mucosal levels of 2-MAGs in Rbp2 null mice are significantly greater than those of matched controls establishing that RBP2 is a physiologically relevant MAG-binding protein. The rise in MAG levels is accompanied by elevations in circulating levels of the hormone glucose-dependent insulinotropic polypeptide (GIP). It is not understood how retinoid and/or MAG binding to RBP2 affects the functions of this protein, nor is it presently understood how these contribute to the metabolic and hormonal phenotypes observed for Rbp2-deficient mice.
Collapse
Affiliation(s)
- William S Blaner
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Pierre-Jacques Brun
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Rossana M Calderon
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Marcin Golczak
- Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, OH, USA
| |
Collapse
|
|
31
|
Mbongue JC, Alhoshani A, Rawson J, Garcia PA, Gonzalez N, Ferreri K, Kandeel F, Husseiny MI. Tracking of an Oral Salmonella-Based Vaccine for Type 1 Diabetes in Non-obese Diabetic Mice. Front Immunol 2020; 11:712. [PMID: 32411136 PMCID: PMC7198770 DOI: 10.3389/fimmu.2020.00712] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 03/30/2020] [Indexed: 11/28/2022] Open
Abstract
Type 1 diabetes (T1D) arises secondary to immune-driven destruction of pancreatic β-cells and manifests as insulin-deficient hyperglycemia. We showed that oral vaccination with live attenuated Salmonella, which simultaneously delivers autoantigens and a TGFβ expression vector to immune cells in the gut mucosa, provides protection against the progression of T1D in non-obese diabetic (NOD) mice. In this study we employed the Sleeping Beauty (SB) transposon system that is composed of a transposase and transposon encoding the td-Tomato to express red fluorescent protein (RFP) to permanently mark the cells that take up the Salmonella vaccine. After animal vaccination, the transposon labeled-dendritic cells (DCs) with red fluorescence appeared throughout the secondary lymphoid tissues. Furthermore, Sleeping Beauty containing tgfβ1 gene (SB-tgfβ1) co-expressed TGFβ and RFP. The labeled DCs were detected predominantly in Peyer's patches (PP) and mesenteric lymph nodes (MLN) and expressed CD103 surface marker. CD103+ DCs induced tolerogenic effects and gut homing. TGFβ significantly increased programmed death-ligand-1 (PDL-1 or CD274) expression in the DCs in the MLN and PP of treated mice. Also, TGFβ increased cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) levels in CD4+ cells in MLN and PP. Interestingly, DCs increased in all lymphatic organs of mice vaccinated with oral live Salmonella-based vaccine expressing preproinsulin (PPI), in combination with TGFβ, IL10, and subtherapeutic-doses of anti-CD3 mAb compared with vehicle-treated mice. These DCs are mostly tolerogenic in MLN and PP. Furthermore the DCs obtained from vaccine-treated but not vehicle-treated mice suppressed in vitro T cell proliferation. These data suggest that the MLN and the PP are a central hub for the beneficial anti-diabetic effects of an oral Salmonella-based vaccine prevention of diabetes in rodents.
Collapse
Affiliation(s)
- Jacques C. Mbongue
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
| | - Ali Alhoshani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Jeffrey Rawson
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
| | - Pablo A. Garcia
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
| | - Nelson Gonzalez
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
| | - Kevin Ferreri
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
| | - Fouad Kandeel
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
| | - Mohamed I. Husseiny
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
- Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| |
Collapse
|
|
32
|
Iyer N, Grizotte-Lake M, Duncan K, Gordon SR, Palmer ACS, Calvin C, Zhong G, Isoherranen N, Vaishnava S. Epithelium intrinsic vitamin A signaling co-ordinates pathogen clearance in the gut via IL-18. PLoS Pathog 2020; 16:e1008360. [PMID: 32330185 PMCID: PMC7202665 DOI: 10.1371/journal.ppat.1008360] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 05/06/2020] [Accepted: 01/27/2020] [Indexed: 01/17/2023] Open
Abstract
Intestinal epithelial cells (IECs) are at the forefront of host-pathogen interactions, coordinating a cascade of immune responses to protect against pathogens. Here we show that IEC-intrinsic vitamin A signaling restricts pathogen invasion early in the infection and subsequently activates immune cells to promote pathogen clearance. Mice blocked for retinoic acid receptor (RAR) signaling selectively in IECs (stopΔIEC) showed higher Salmonella burden in colonic tissues early in the infection that associated with higher luminal and systemic loads of the pathogen at later stages. Higher pathogen burden in stopΔIEC mice correlated with attenuated mucosal interferon gamma (IFNγ) production by underlying immune cells. We found that, at homeostasis, the intestinal epithelium of stopΔIEC mice produced significantly lower amounts of interleukin 18 (IL-18), a potent inducer of IFNγ. Regulation of IL-18 by vitamin A was also observed in a dietary model of vitamin A supplementation. IL-18 reconstitution in stopΔIEC mice restored resistance to Salmonella by promoting epithelial cell shedding to eliminate infected cells and limit pathogen invasion early in infection. Further, IL-18 augmented IFNγ production by underlying immune cells to restrict pathogen burden and systemic spread. Our work uncovers a critical role for vitamin A in coordinating a biphasic immune response to Salmonella infection by regulating IL-18 production by IECs. Epithelial cells line the intestinal lumen, forming a barrier between the body and dietary and microbial contents in the lumen. Apart from absorbing nutrients from diet, these epithelial cells help mediate a stable, symbiotic relationship between commensal bacteria and the immune cells. During infection, they help co-ordinate the immune response to counter the infection. How dietary micronutrients, such as vitamin A, inform epithelial cell function during infection is poorly understood. Using a model where epithelial cells in the gut cannot respond to vitamin A signals, we find that epithelial vitamin A signaling promotes resistance to Salmonella infection. We show that, vitamin A increases the production of a key cytokine, interleukin 18, by epithelial cells. IL-18 promotes shedding of infected epithelial cells to reduce the pathogen invasion while also inducing the production of interferon gamma by immune cells to mediate pathogen clearance. Thus, epithelial cells dynamically respond to dietary vitamin A to regulate interleukin 18 production and potentiate resistance to infection.
Collapse
Affiliation(s)
- Namrata Iyer
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, United States of America
| | - Mayara Grizotte-Lake
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, United States of America
| | - Kellyanne Duncan
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, United States of America
| | - Sarah R. Gordon
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, United States of America
| | - Ana C. S. Palmer
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, United States of America
| | - Crystle Calvin
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, United States of America
| | - Guo Zhong
- Department of Pharmaceutics, University of Washington, Seattle, WA, United States of America
| | - Nina Isoherranen
- Department of Pharmaceutics, University of Washington, Seattle, WA, United States of America
| | - Shipra Vaishnava
- Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, United States of America
- * E-mail:
| |
Collapse
|
|
33
|
Thomson CA, Nibbs RJ, McCoy KD, Mowat AM. Immunological roles of intestinal mesenchymal cells. Immunology 2020; 160:313-324. [PMID: 32181492 DOI: 10.1111/imm.13191] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 03/09/2020] [Accepted: 03/10/2020] [Indexed: 12/20/2022] Open
Abstract
The intestine is continuously exposed to an enormous variety and quantity of antigens and innate immune stimuli derived from both pathogens and harmless materials, such as food and commensal bacteria. Accordingly, the intestinal immune system is uniquely adapted to ensure appropriate responses to the different kinds of challenge; maintaining tolerance to harmless antigens in the steady-state, whilst remaining poised to deal with potential pathogens. To accomplish this, leucocytes of the intestinal immune system have to adapt to a constantly changing environment and interact with many different non-leucocytic intestinal cell types, including epithelial and endothelial cells, neurons, and a heterogenous network of intestinal mesenchymal cells (iMC). These interactions are intricately involved in the generation of protective immunity, the elaboration of inflammatory responses, and the development of inflammatory conditions, such as inflammatory bowel diseases. Here we discuss recent insights into the immunological functions of iMC under homeostatic and inflammatory conditions, focusing particularly on iMC in the mucosa and submucosa, and highlighting how an appreciation of the immunology of iMC may help understand the pathogenesis and treatment of disease.
Collapse
Affiliation(s)
- Carolyn A Thomson
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Robert J Nibbs
- Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary Medicine and Life Sciences, University of Glasgow, Glasgow, UK
| | - Kathy D McCoy
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Allan Mcl Mowat
- Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary Medicine and Life Sciences, University of Glasgow, Glasgow, UK
| |
Collapse
|
|
34
|
Shao H, Zhang X, Ruan L, Li J, Chen F, Guo L, Zhu J. Methane suppressed dendritic cells activation in trinitrobenzene sulfonic acid induced colitis. Int Immunopharmacol 2020; 82:106360. [PMID: 32143009 DOI: 10.1016/j.intimp.2020.106360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 02/26/2020] [Accepted: 02/26/2020] [Indexed: 10/24/2022]
Affiliation(s)
- Han Shao
- Department of Intensive Care Unit, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221003, China
| | - Xu Zhang
- Department of Anesthesiology, Xuzhou Central Hospital, Xuzhou 221009, China
| | - Linxing Ruan
- Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Jinbao Li
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai 200080, China
| | - Feng Chen
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai 200080, China
| | - Long Guo
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai 200080, China.
| | - Jiali Zhu
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Shanghai 200080, China.
| |
Collapse
|
|
35
|
Kimura S, Nakamura Y, Kobayashi N, Shiroguchi K, Kawakami E, Mutoh M, Takahashi-Iwanaga H, Yamada T, Hisamoto M, Nakamura M, Udagawa N, Sato S, Kaisho T, Iwanaga T, Hase K. Osteoprotegerin-dependent M cell self-regulation balances gut infection and immunity. Nat Commun 2020; 11:234. [PMID: 31932605 PMCID: PMC6957684 DOI: 10.1038/s41467-019-13883-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Accepted: 12/05/2019] [Indexed: 02/08/2023] Open
Abstract
Microfold cells (M cells) are responsible for antigen uptake to initiate immune responses in the gut-associated lymphoid tissue (GALT). Receptor activator of nuclear factor-κB ligand (RANKL) is essential for M cell differentiation. Follicle-associated epithelium (FAE) covers the GALT and is continuously exposed to RANKL from stromal cells underneath the FAE, yet only a subset of FAE cells undergoes differentiation into M cells. Here, we show that M cells express osteoprotegerin (OPG), a soluble inhibitor of RANKL, which suppresses the differentiation of adjacent FAE cells into M cells. Notably, OPG deficiency increases M cell number in the GALT and enhances commensal bacterium-specific immunoglobulin production, resulting in the amelioration of disease symptoms in mice with experimental colitis. By contrast, OPG-deficient mice are highly susceptible to Salmonella infection. Thus, OPG-dependent self-regulation of M cell differentiation is essential for the balance between the infectious risk and the ability to perform immunosurveillance at the mucosal surface. Microfold cells (M cells) sit at the gut epithelial surface to sample antigens and maintain local immune homeostasis. Here the authors show that M cells are feedback-regulated by M cell-originated osteoprotegerin (OPG) to suppress RNAKL-induced M cell differentiation, and that OPG deficiency alters both gut colitis and infection phenotypes.
Collapse
Affiliation(s)
- Shunsuke Kimura
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, 105-8512, Japan. .,Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, 060-8638, Japan. .,PRESTO, Japan Science and Technology Agency, Saitama, 332-0012, Japan.
| | - Yutaka Nakamura
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, 105-8512, Japan
| | - Nobuhide Kobayashi
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, 105-8512, Japan
| | - Katsuyuki Shiroguchi
- PRESTO, Japan Science and Technology Agency, Saitama, 332-0012, Japan.,Laboratory for Prediction of Cell Systems Dynamics, RIKEN Center for Biosystems Dynamics Research (BDR), Suita, 565-0874, Japan.,Laboratory for Immunogenetics, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, 230-0045, Japan
| | - Eiryo Kawakami
- RIKEN Medical Sciences Innovation Hub Program (MIH), Yokohama, 230-0045, Japan
| | - Mami Mutoh
- Department of Orthodontics, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Sapporo, 060-8586, Japan
| | - Hiromi Takahashi-Iwanaga
- Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, 060-8638, Japan
| | - Takahiro Yamada
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, 105-8512, Japan
| | - Meri Hisamoto
- Department of Oral Functional Prosthodontics, Division of Oral Functional Science, Graduate School of Dental Medicine, Hokkaido University, Sapporo, 060-8586, Japan
| | - Midori Nakamura
- Department of Biochemistry, Matsumoto Dental University, Nagano, 399-0781, Japan
| | - Nobuyuki Udagawa
- Department of Biochemistry, Matsumoto Dental University, Nagano, 399-0781, Japan
| | - Shintaro Sato
- Mucosal Vaccine Project, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan.,Mucosal Vaccine Project, BIKEN Center for Innovative Vaccine Research and Development, The Research Foundation for Microbial Diseases of Osaka University, Osaka, 565-0871, Japan
| | - Tsuneyasu Kaisho
- Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, 641-8509, Japan
| | - Toshihiko Iwanaga
- Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, 060-8638, Japan
| | - Koji Hase
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, 105-8512, Japan. .,Division of Mucosal Barriology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo, 108-8639, Japan.
| |
Collapse
|
|
36
|
Nagata Y, Yamamoto T, Kadowaki M. Ginger Increases ALDH1A1 Expression and Enhances Retinoic Acid Signaling in a Human Colonic Epithelial Cell Line. J Nutr Sci Vitaminol (Tokyo) 2020; 66:462-467. [PMID: 33132350 DOI: 10.3177/jnsv.66.462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Aldehyde dehydrogenase 1A1 (ALDH1A1) in intestinal epithelial cells (IECs) plays a critical role in regulating immune responses through the production of retinoic acid (RA). However, little is known about its regulation by dietary components. We previously demonstrated that kakkonto, a Japanese traditional herbal medicine, and its constituent puerarin induce the expression of ALDH1A1 mRNA in colonic IECs and thereby attenuate food allergy symptoms in mice. This study aims to investigate the cellular responses of IECs to ALDH1A1 expression as a result of natural food components. The seven medicinal herbs that compose kakkonto were used to treat cultured an IEC line: Caco-2 cells. Expressions levels of ALDH1A1 were analyzed in Caco-2 cells by quantitative RT-PCR, immunocytochemistry and western blotting. Ginger increased the expression levels of ALDH1A1 mRNA and protein in Caco-2 cells. In addition, ginger significantly upregulated the gene expression of retinoic acid receptor (RAR) alpha (RARA), thereby enhancing RA signaling. Furthermore, ginger downregulated the expression of histone deacetylase (HDAC)2 (HDAC2) and HDAC3 in Caco-2 cells. The present study suggests the possibility that food ingredients such as a ginger modulate vitamin A metabolism in the gut through the regulation of RA synthesis, which may contribute to RA-mediated regulation of immune responses and the regulation of allergic inflammation.
Collapse
Affiliation(s)
- Yuka Nagata
- Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama
- Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
| | - Takeshi Yamamoto
- Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama
| | - Makoto Kadowaki
- Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama
| |
Collapse
|
|
37
|
Zou YF, Zhang YY, Fu YP, Inngjerdingen KT, Paulsen BS, Feng B, Zhu ZK, Li LX, Jia RY, Huang C, Song X, Lv C, Ye G, Liang XX, He CL, Yin LZ, Yin ZQ. A Polysaccharide Isolated from Codonopsis pilosula with Immunomodulation Effects Both In Vitro and In Vivo. Molecules 2019; 24:3632. [PMID: 31600890 PMCID: PMC6832355 DOI: 10.3390/molecules24203632] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/07/2019] [Accepted: 10/07/2019] [Indexed: 02/02/2023] Open
Abstract
In this study, an acidic polysaccharide from Codonopsis pilosula Nannf. var. modesta (Nannf.) L. T. Shen (WCP-I) and its main fragment, WCP-Ia, obtained after pectinase digestion, were structurally elucidated and found to consist of a rhamnogalacturonan I (RG-I) region containing both arabinogalactan type I (AG-I) and type II (AG-II) as sidechains. They both expressed immunomodulating activity against Peyer's patch cells. Endo-1,4-β-galactanase degradation gave a decrease of interleukine 6 (IL-6) production compared with native WCP-I and WCP-Ia, but exo-α-l-arabinofuranosidase digestion showed no changes in activity. This demonstrated that the stimulation activity partly disappeared with removal of β-d-(1→4)-galactan chains, proving that the AG-I side chain plays an important role in immunoregulation activity. WCP-Ia had a better promotion effect than WCP-I in vivo, shown through an increased spleen index, higher concentrations of IL-6, transforming growth factor-β (TGF-β), and tumor necrosis factor-α (TNF-α) in serum, and a slight increment in the secretory immunoglobulin A (sIgA) and CD4+/CD8+ T lymphocyte ratio. These results suggest that β-d-(1→4)-galactan-containing chains in WCP-I play an essential role in the expression of immunomodulating activity. Combining all the results in this and previous studies, the intestinal immune system might be the target site of WCP-Ia.
Collapse
Affiliation(s)
- Yuan-Feng Zou
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
| | - Yan-Yun Zhang
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
| | - Yu-Ping Fu
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
| | - Kari Tvete Inngjerdingen
- Department of Pharmacy, Section Pharmaceutical Chemistry, University of Oslo, P.O. Box 1068 Blindern, 0316 Oslo, Norway.
| | - Berit Smestad Paulsen
- Department of Pharmacy, Section Pharmaceutical Chemistry, University of Oslo, P.O. Box 1068 Blindern, 0316 Oslo, Norway.
| | - Bin Feng
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China.
| | - Zhong-Kai Zhu
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
| | - Li-Xia Li
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
| | - Ren-Yong Jia
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
| | - Chao Huang
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
| | - Xu Song
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
| | - Cheng Lv
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
| | - Gang Ye
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
| | - Xiao-Xia Liang
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
| | - Chang-Liang He
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
| | - Li-Zi Yin
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
| | - Zhong-Qiong Yin
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China.
| |
Collapse
|
|
38
|
Branca JJ, Gulisano M, Nicoletti C. Intestinal epithelial barrier functions in ageing. Ageing Res Rev 2019; 54:100938. [PMID: 31369869 DOI: 10.1016/j.arr.2019.100938] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 07/19/2019] [Accepted: 07/24/2019] [Indexed: 12/11/2022]
Abstract
The intestinal epithelial barrier protects the mucosa of the gastrointestinal (GI)-tract and plays a key role in maintaining the host homeostasis. It encompasses several elements that include the intestinal epithelium and biochemical and immunological products, such as the mucus layer, antimicrobial peptides (AMPs) and secretory immunologlobulin A (sIgA). These components are interlinked with the large microbial community inhabiting the gut to form a highly sophisticated biological system that plays an important role on many aspects of human health both locally and systemically. Like any other organ and tissue, the intestinal epithelial barrier is affected by the ageing process. New insights have surfaced showing that critical functions, including intestinal stem cell regeneration and regulation of the intestinal crypt homeostasis, barrier integrity, production of regulatory cytokines, and epithelial innate immunity to pathogenic antigens change across life. Here we review the age-associated changes of the various components of the intestinal epithelial barrier and we highlight the necessity to elucidate further the mechanisms underlying these changes. Expanding our knowledge in this area is a goal of high medical relevance and it will help to define intervention strategies to ameliorate the quality of life of the ever-expanding elderly population.
Collapse
|
|
39
|
Mowat AM. To respond or not to respond - a personal perspective of intestinal tolerance. Nat Rev Immunol 2019; 18:405-415. [PMID: 29491358 DOI: 10.1038/s41577-018-0002-x] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research.
Collapse
Affiliation(s)
- Allan McI Mowat
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary Medicine and Life Sciences, University of Glasgow, Glasgow, UK.
| |
Collapse
|
|
40
|
Xiao Y, de Paiva CS, Yu Z, de Souza RG, Li DQ, Pflugfelder SC. Goblet cell-produced retinoic acid suppresses CD86 expression and IL-12 production in bone marrow-derived cells. Int Immunol 2019; 30:457-470. [PMID: 30010888 DOI: 10.1093/intimm/dxy045] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 07/09/2018] [Indexed: 12/22/2022] Open
Abstract
Conjunctival goblet cell loss in ocular surface diseases is accompanied by increased number of interleukin-12 (IL-12)-producing antigen-presenting cells (APCs) and increased interferon-γ (IFN-γ) expression. This study tested the hypothesis that mouse conjunctival goblet cells produce biologically active retinoic acid (RA) that suppresses CD86 expression and IL-12 production by myeloid cells. We found that conditioned media from cultured conjunctival goblet cells (CjCM) suppressed stimulated CD86 expression, NF-κB p65 activation and IL-12 and IFN-γ production in unstimulated and lipopolysaccharide-stimulated cultured bone marrow-derived cells (BMDCs) containing a mixed population of APCs. Goblet cell-conditioned, ovalbumin-loaded APCs suppressed IFN-γ production and increased IL-13 production in co-cultured OTII cells. The goblet cell suppressive activity is due in part to their ability to synthesize RA from retinol. Conjunctival goblet cells had greater expression of aldehyde dehydrogenases Aldh1a1 and a3 and ALDEFLUOR activity than cornea epithelium lacking goblet cells. The conditioning activity was lost in goblet cells treated with an ALDH inhibitor, and a retinoid receptor alpha antagonist blocked the suppressive effects of CjCM on IL-12 production. Similar to RA, CjCM increased expression of suppressor of cytokine signaling 3 (SOCS3) in BMDCs. SOCS3 silencing reversed the IL-12-suppressive effects of CjCM. Our findings indicate that conjunctival goblet cells are capable of synthesizing RA from retinol secreted by the lacrimal gland into tears that can condition APCs. Evidence suggests goblet cell RA may function in maintaining conjunctival immune tolerance and loss of conjunctival goblet cells may contribute to increased Th1 priming in dry eye.
Collapse
Affiliation(s)
- Yangyan Xiao
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA.,Second Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
| | - Cintia S de Paiva
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
| | - Zhiyuan Yu
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
| | - Rodrigo G de Souza
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
| | - De-Quan Li
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
| | - Stephen C Pflugfelder
- Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
| |
Collapse
|
|
41
|
McKeen S, Young W, Fraser K, Roy NC, McNabb WC. Glycan Utilisation and Function in the Microbiome of Weaning Infants. Microorganisms 2019; 7:microorganisms7070190. [PMID: 31277402 PMCID: PMC6681113 DOI: 10.3390/microorganisms7070190] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 06/23/2019] [Accepted: 06/25/2019] [Indexed: 12/12/2022] Open
Abstract
Glycans are present exogenously in the diet, expressed and secreted endogenously by host cells, and produced by microbes. All of these processes result in them being available to the gut microbiome, firmly placing glycans at the interface of diet–microbe–host interactions. The most dramatic shift in dietary sources of glycans occurs during the transition from the milk-based neonatal diet to the diverse omnivorous adult diet, and this has profound effects on the composition of the gut microbiome, gene expression by microbes and host cells, mucin composition, and immune development from innate towards adaptive responses. Understanding the glycan-mediated interactions occurring during this transitional window may inform dietary recommendations to support gut and immune development during a vulnerable age. This review aims to summarise the current state of knowledge on dietary glycan mediated changes that may occur in the infant gut microbiome and immune system during weaning.
Collapse
Affiliation(s)
- Starin McKeen
- Food Nutrition & Health, AgResearch, Grasslands Research Centre, Private Bag 11008, Palmerston north 4442, New Zealand
- Riddet Institute, Massey University, Private Bag 11222, Palmerston North 4442, New Zealand
- High-Value Nutrition National Science Challenge, Auckland 1023, New Zealand
| | - Wayne Young
- Food Nutrition & Health, AgResearch, Grasslands Research Centre, Private Bag 11008, Palmerston north 4442, New Zealand
- Riddet Institute, Massey University, Private Bag 11222, Palmerston North 4442, New Zealand
- High-Value Nutrition National Science Challenge, Auckland 1023, New Zealand
| | - Karl Fraser
- Food Nutrition & Health, AgResearch, Grasslands Research Centre, Private Bag 11008, Palmerston north 4442, New Zealand
- Riddet Institute, Massey University, Private Bag 11222, Palmerston North 4442, New Zealand
- High-Value Nutrition National Science Challenge, Auckland 1023, New Zealand
| | - Nicole C Roy
- Food Nutrition & Health, AgResearch, Grasslands Research Centre, Private Bag 11008, Palmerston north 4442, New Zealand
- Riddet Institute, Massey University, Private Bag 11222, Palmerston North 4442, New Zealand
- High-Value Nutrition National Science Challenge, Auckland 1023, New Zealand
| | - Warren C McNabb
- Riddet Institute, Massey University, Private Bag 11222, Palmerston North 4442, New Zealand.
- High-Value Nutrition National Science Challenge, Auckland 1023, New Zealand.
| |
Collapse
|
|
42
|
Molero-Abraham M, Sanchez-Trincado JL, Gomez-Perosanz M, Torres-Gomez A, Subiza JL, Lafuente EM, Reche PA. Human Oral Epithelial Cells Impair Bacteria-Mediated Maturation of Dendritic Cells and Render T Cells Unresponsive to Stimulation. Front Immunol 2019; 10:1434. [PMID: 31316504 PMCID: PMC6611079 DOI: 10.3389/fimmu.2019.01434] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 06/07/2019] [Indexed: 01/03/2023] Open
Abstract
The oral mucosa is a first line of defense against pathogenic organisms and yet tolerates food antigens and resident bacteria. Mucosal epithelial cells are emerging as important regulators of innate and adaptive immune responses. However, the contribution of oral epithelial cells (OECs) determining oral immunity is understudied. Here, we evaluated the ability of H413 and TR146 cells, two OEC lines derived from human oral squamous cell carcinomas, and primary OECs to modulate immune responses to a cocktail of Gram+ and Gram− bacteria known as MV130. OECs expressed CD40 constitutively and class II major histocompatibility complex (MHC II) molecules when stimulated with IFNγ, but not CD80 or CD86. Dendritic cells (DCs) treated with bacteria in co-culture with OECs did not fully mature, as judged by the expression of MHC II, CD80 and CD86, and barely released IL-12 and TNFα, compared to control DCs. Furthermore, in the presence of OECs, DCs were unable to stimulate allogenic naive CD4 T cells to produce IFNγ and TNFα. Similarly, OECs in culture with total CD4 T cells or Th1 cells stimulated with anti-CD3 and anti-CD28 antibodies abrogated CD25 and CD69 expression, T cell proliferation and the release of IFNγ and TNFα. The inhibition on T cell activation by OECs was cell-contact dependent, TGFβ independent and largely irreversible. Overall, this behavior of OECs is likely key to avoid immune system over-reaction against resident bacteria.
Collapse
Affiliation(s)
| | - Jose L Sanchez-Trincado
- Department of Immunology, School of Medicine, Complutense University of Madrid, Madrid, Spain
| | - Marta Gomez-Perosanz
- Department of Immunology, School of Medicine, Complutense University of Madrid, Madrid, Spain
| | - Alvaro Torres-Gomez
- Department of Immunology, School of Medicine, Complutense University of Madrid, Madrid, Spain
| | | | - Esther M Lafuente
- Department of Immunology, School of Medicine, Complutense University of Madrid, Madrid, Spain
| | - Pedro A Reche
- Department of Immunology, School of Medicine, Complutense University of Madrid, Madrid, Spain
| |
Collapse
|
|
43
|
Lozano‐Ojalvo D, Martínez‐Blanco M, Pérez‐Rodríguez L, Molina E, López‐Fandiño R. Oral Immunotherapy with Egg Peptides Induces Innate and Adaptive Tolerogenic Responses. Mol Nutr Food Res 2019; 63:e1900144. [DOI: 10.1002/mnfr.201900144] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 04/30/2019] [Indexed: 01/27/2023]
Affiliation(s)
- Daniel Lozano‐Ojalvo
- Instituto de Investigación en Ciencias de la Alimentación (CIAL, CSIC‐UAM) Nicolás Cabrera 9 28049 Madrid Spain
| | - Mónica Martínez‐Blanco
- Instituto de Investigación en Ciencias de la Alimentación (CIAL, CSIC‐UAM) Nicolás Cabrera 9 28049 Madrid Spain
| | - Leticia Pérez‐Rodríguez
- Instituto de Investigación en Ciencias de la Alimentación (CIAL, CSIC‐UAM) Nicolás Cabrera 9 28049 Madrid Spain
| | - Elena Molina
- Instituto de Investigación en Ciencias de la Alimentación (CIAL, CSIC‐UAM) Nicolás Cabrera 9 28049 Madrid Spain
| | - Rosina López‐Fandiño
- Instituto de Investigación en Ciencias de la Alimentación (CIAL, CSIC‐UAM) Nicolás Cabrera 9 28049 Madrid Spain
| |
Collapse
|
|
44
|
Luongo D, Bonavita R, Rossi S, Rotondi Aufiero V, Feliciello NR, Maurano F, Iaquinto G, Mazzarella G, Rossi M. Tailoring the immune response to wheat gliadin by enzymatic transamidation. Cytokine 2019; 117:23-29. [PMID: 30784897 DOI: 10.1016/j.cyto.2019.02.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 01/10/2019] [Accepted: 02/01/2019] [Indexed: 02/08/2023]
Abstract
Enzymatic transamidation of wheat gliadin by microbial transglutaminase inhibits IFN-γ secretion by intestinal T cell lines from celiac disease (CD) patients. Here, we analysed its effects on intestinal biopsies from CD patients and studied the underlying mechanisms in HLA-DQ8 transgenic (tg) mice, a model of T-cell mediated gluten sensitivity. In vitro challenge with a soluble form of transamidated gliadin (spf) upregulated IL-10 transcript levels in human biopsy samples. Furthermore, the ratio of IL-10/IFN-γ transcripts was significantly increased following treatment with spf. In DQ8 tg mice, recall responses in vitro in the presence of dendritic cells pulsed with transamidated gliadin showed that gliadin-specific CD4+ T cells did not produce IFN-γ at any tested dose. On the contrary, spf-specific CD4+ T cells still secreted IFN-γ, but they also produced significant levels of IL-10 with both native and transamidated gliadin. Interestingly, this anti-inflammatory activity was restricted to a specific reverse-phase high-pressure liquid chromatography (RP-HPLC) fraction encompassing α-gliadins. These findings suggested an ability of transamidated gliadin to revert, as well as to prevent, the inflammatory phenotype triggered by native gliadin. This property was intrinsically associated with specific components of the α-gliadin fraction.
Collapse
Affiliation(s)
| | | | - Stefano Rossi
- Institute of Food Sciences, CNR, 83100 Avellino, Italy
| | | | | | | | - Gaetano Iaquinto
- Gastroenterology Department, San G. Moscati Hospital, 83100 Avellino, Italy
| | | | - Mauro Rossi
- Institute of Food Sciences, CNR, 83100 Avellino, Italy.
| |
Collapse
|
|
45
|
Gu MJ, Han SE, Hwang K, Mayer E, Reisinger N, Schatzmayr D, Park BC, Han SH, Yun CH. Hydrolyzed fumonisin B1 induces less inflammatory responses than fumonisin B1 in the co-culture model of porcine intestinal epithelial and immune cells. Toxicol Lett 2019; 305:110-116. [DOI: 10.1016/j.toxlet.2019.01.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 01/12/2019] [Accepted: 01/28/2019] [Indexed: 12/12/2022]
|
|
46
|
Giuffrida P, Cococcia S, Delliponti M, Lenti MV, Di Sabatino A. Controlling Gut Inflammation by Restoring Anti-Inflammatory Pathways in Inflammatory Bowel Disease. Cells 2019; 8:E397. [PMID: 31052214 PMCID: PMC6562982 DOI: 10.3390/cells8050397] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 04/24/2019] [Accepted: 04/25/2019] [Indexed: 12/15/2022] Open
Abstract
Inflammatory bowel disease (IBD) is caused by a dysregulated immune response against normal components of the intestinal microflora combined with defective functioning of anti-inflammatory pathways. Currently, all therapies approved for IBD manipulate the immune system by inhibiting pro-inflammatory mechanisms, such as tumor necrosis factor-α, gut-homing α4β7 integrin, interleukin-12/interleukin-23, and Janus kinases. However, some IBD patients are non-responders to these drugs, which are also associated with serious side effects. Thus, it has been hypothesized that therapies aimed at restoring anti-inflammatory signals, by exploiting the tolerogenic potential of cytokines (interleukin-10, transforming growth factor-β, granulocyte macrophage colony-stimulating factor), immune cells (regulatory T cells, tolerogenic dendritic cells), or mesenchymal stem cells, might offer promising results in terms of clinical efficacy with fewer side effects. In this review, we provide new insights into putative novel treatments aimed at restoring anti-inflammatory signaling pathways in IBD.
Collapse
Affiliation(s)
- Paolo Giuffrida
- First Department of Internal Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Sara Cococcia
- First Department of Internal Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Mariangela Delliponti
- First Department of Internal Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Marco Vincenzo Lenti
- First Department of Internal Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Antonio Di Sabatino
- First Department of Internal Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| |
Collapse
|
|
47
|
Abstract
The gut-associated lymphoid tissue (GALT) faces a considerable challenge. It encounters antigens derived from an estimated 1014 commensal microbes and greater than 30 kg of food proteins yearly. It must distinguish these harmless antigens from potential pathogens and mount the appropriate host immune response. Local and systemic hyporesponsiveness to dietary antigens, classically referred to as oral tolerance, comprises a distinct complement of adaptive cellular and humoral immune responses. It is increasingly evident that a functional epithelial barrier engaged in intimate interplay with innate immune cells and the resident microbiota is critical to establishing and maintaining oral tolerance. Moreover, innate immune cells serve as a bridge between the microbiota, epithelium, and the adaptive immune system, parlaying tonic microbial stimulation into signals critical for mucosal homeostasis. Dysregulation of gut homeostasis and the subsequent disruption of tolerance therefore have clinically significant consequences for the development of food allergy.
Collapse
Affiliation(s)
- Onyinye I Iweala
- UNC Food Allergy Initiative and Thurston Arthritis Research Center, Division of Rheumatology, Allergy, and Immunology, The University of North Carolina at Chapel Hill, North Carolina 27599-7280, USA;
| | - Cathryn R Nagler
- Department of Pathology, Biological Sciences Division, University of Chicago, Chicago, Illinois 60637-1824, USA;
- Committee on Immunology, Biological Sciences Division, University of Chicago, Chicago, Illinois 60637-1824, USA
| |
Collapse
|
|
48
|
Mukherjee R, van de Kaa M, Garssen J, Pieters RJ, Kraneveld AD, Willemsen LEM. Lactulose synergizes with CpG-ODN to modulate epithelial and immune cells cross talk. Food Funct 2019; 10:33-37. [PMID: 30632580 DOI: 10.1039/c8fo02376j] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Lactulose, a non-digestible oligosaccharide and functional food, promotes Bifidobacteria growth. Here we show that lactulose, beyond its prebiotic action, may have direct immunomodulatory effects as well. In synergy with CpG-ODN, a bacterial DNA mimetic, lactulose enhances basolateral concentrations of IFN-γ, IL-10, and galectin-9 in the co-culture model of epithelial and immune cells.
Collapse
Affiliation(s)
- R Mukherjee
- Division of Chemical Biology and Drug Discovery, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, The Netherlands.
| | | | | | | | | | | |
Collapse
|
|
49
|
Okeke EB, Uzonna JE. The Pivotal Role of Regulatory T Cells in the Regulation of Innate Immune Cells. Front Immunol 2019; 10:680. [PMID: 31024539 PMCID: PMC6465517 DOI: 10.3389/fimmu.2019.00680] [Citation(s) in RCA: 168] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 03/12/2019] [Indexed: 12/11/2022] Open
Abstract
The distinction between innate and adaptive immunity is one of the basic tenets of immunology. The co-operation between these two arms of the immune system is a major determinant of the resistance or susceptibility of the host following pathogen invasion. Hence, this interactive co-operation between cells of the innate and adaptive immunity is of significant interest to immunologists. The sub-population of CD4+ T cells with regulatory phenotype (regulatory T cells; Tregs), which constitute a part of the adaptive immune system, have been widely implicated in the regulation of the immune system and maintenance of immune homeostasis. In the last two decades, there has been an explosion in research describing the role of Tregs and their relevance in several immunopathologies ranging from inflammation to cancer. The majority of these studies focus on the role of Tregs on the cells of the adaptive immune system. Recently, there is significant interest in the role of Tregs on cells of the innate immune system. In this review, we examine the literature on the role of Tregs in immunology. Specifically, we focus on the emerging knowledge of Treg interaction with dendritic cells, macrophages, neutrophils, and γδ T cells. We highlight this interaction as an important link between innate and adaptive immune systems which also indicate the far-reaching role of Tregs in the regulation of immune responses and maintenance of self-tolerance and immune homeostasis.
Collapse
Affiliation(s)
- Emeka B Okeke
- Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, United States
| | - Jude E Uzonna
- Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada
| |
Collapse
|
|
50
|
Thangavelu G, Lee YC, Loschi M, Schaechter KM, Feser CJ, Koehn BH, Nowak EC, Zeiser R, Serody JS, Murphy WJ, Munn DH, Chambon P, Noelle RJ, Blazar BR. Dendritic Cell Expression of Retinal Aldehyde Dehydrogenase-2 Controls Graft-versus-Host Disease Lethality. THE JOURNAL OF IMMUNOLOGY 2019; 202:2795-2805. [PMID: 30885956 DOI: 10.4049/jimmunol.1800899] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 02/26/2019] [Indexed: 01/11/2023]
Abstract
Recent studies have underscored the critical role of retinoic acid (RA) in the development of lineage-committed CD4 and CD8 T cells in vivo. We have shown that under acute graft-versus-host disease (GVHD) inflammatory conditions, RA is upregulated in the intestine and is proinflammatory, as GVHD lethality was attenuated when donor allogeneic T cells selectively expressed a dominant negative RA receptor α that blunted RA signaling. RA can function in an autocrine and paracrine fashion, and as such, the host cell lineage responsible for the production of RA metabolism and the specific RA-metabolizing enzymes that potentiate GVHD severity are unknown. In this study, we demonstrate that enhancing RA degradation in the host and to a lesser extent donor hematopoietic cells by overexpressing the RA-catabolizing enzyme CYP26A1 reduced GVHD. RA production is facilitated by retinaldehyde isoform-2 (RALDH2) preferentially expressed in dendritic cells (DCs). Conditionally deleted RA-synthesizing enzyme RALDH2 in host or to a lesser extent donor DCs reduced GVHD lethality. Improved survival in recipients with RALDH2-deleted DCs was associated with increased T cell death, impaired T effector function, increased regulatory T cell frequency, and augmented coinhibitory molecule expression on donor CD4+ T cells. In contrast, retinaldehydrogenase isoform-1 (RALDH1) is dominantly expressed in intestinal epithelial cells. Unexpectedly, conditional host intestinal epithelial cells RALDH1 deletion failed to reduce GVHD. These data demonstrate the critical role of both donor and especially host RALDH2+ DCs in driving murine GVHD and suggest RALDH2 inhibition or CYP26A1 induction as novel therapeutic strategies to prevent GVHD.
Collapse
Affiliation(s)
- Govindarajan Thangavelu
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
| | - Yu-Chi Lee
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, NH 03756
| | - Michael Loschi
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
| | - K Melanie Schaechter
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
| | - Colby J Feser
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
| | - Brent H Koehn
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455
| | - Elizabeth C Nowak
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, NH 03756
| | - Robert Zeiser
- Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Albert Ludwig University of Freiburg, 79106 Freiburg, Germany
| | - Jonathan S Serody
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 79106
| | - William J Murphy
- Department of Dermatology, Center for Comparative Medicine, University of California, Davis School of Medicine, Sacramento, CA 95817
| | - David H Munn
- Department of Pediatrics, Georgia Health Sciences University, Augusta, GA 30912; and
| | - Pierre Chambon
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, INSERM U964, 67404 Illkirch Cedex, France
| | - Randolph J Noelle
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, NH 03756
| | - Bruce R Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455;
| |
Collapse
|