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Nature Apr 2024The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens....
The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens. Recognizing how the diverse network of local cells establish homeostasis and maintains it in the complex immune environment of the gut is critical to understanding how tolerance can be re-established following dysfunction, such as in inflammatory disorders. Although cell and molecular interactions that control T regulatory (T) cell development and function have been identified, less is known about the cellular neighbourhoods and spatial compartmentalization that shapes microorganism-reactive T cell function. Here we used in vivo live imaging, photo-activation-guided single-cell RNA sequencing and spatial transcriptomics to follow the natural history of T cells that are reactive towards Helicobacter hepaticus through space and time in the settings of tolerance and inflammation. Although antigen stimulation can occur anywhere in the tissue, the lamina propria-but not embedded lymphoid aggregates-is the key microniche that supports effector T (eT) cell function. eT cells are stable once their niche is established; however, unleashing inflammation breaks down compartmentalization, leading to dominance of CD103SIRPα dendritic cells in the lamina propria. We identify and validate the putative tolerogenic interaction between CD206 macrophages and eT cells in the lamina propria and identify receptor-ligand pairs that are likely to govern the interaction. Our results reveal a spatial mechanism of tolerance in the lamina propria and demonstrate how knowledge of local interactions may contribute to the next generation of tolerance-inducing therapies.
Topics: Animals; Female; Male; Mice; Antigens, CD; Dendritic Cells; Gene Expression Profiling; Helicobacter hepaticus; Helicobacter Infections; Immune Tolerance; Inflammation; Integrin alpha Chains; Intestinal Mucosa; Macrophages; Mice, Inbred C57BL; Mucous Membrane; Receptors, Immunologic; Single-Cell Gene Expression Analysis; T-Lymphocytes, Regulatory; Transcriptome
PubMed: 38570678
DOI: 10.1038/s41586-024-07251-0 -
Cell Stem Cell Oct 2020Epidermal growth factor (EGF) maintains intestinal stem cell (ISC) proliferation and is a key component of organoid growth media yet is dispensable for intestinal...
Epidermal growth factor (EGF) maintains intestinal stem cell (ISC) proliferation and is a key component of organoid growth media yet is dispensable for intestinal homeostasis, suggesting roles for multiple EGF family ligands in ISC function. Here, we identified neuregulin 1 (NRG1) as a key EGF family ligand that drives tissue repair following injury. NRG1, but not EGF, is upregulated upon damage and is expressed in mesenchymal stromal cells, macrophages, and Paneth cells. NRG1 deletion reduces proliferation in intestinal crypts and compromises regeneration capacity. NRG1 robustly stimulates proliferation in crypts and induces budding in organoids, in part through elevated and sustained activation of mitogen-activated protein kinase (MAPK) and AKT. Consistently, NRG1 treatment induces a proliferative gene signature and promotes organoid formation from progenitor cells and enhances regeneration following injury. These data suggest mesenchymal-derived NRG1 is a potent mediator of tissue regeneration and may inform the development of therapies for enhancing intestinal repair after injury.
Topics: Cell Proliferation; Epithelium; Intestines; Neuregulin-1; Paneth Cells
PubMed: 32693086
DOI: 10.1016/j.stem.2020.06.021 -
Clinical Oral Implants Research Mar 2018The goal of Working Group 1 at the 2nd Consensus Meeting of the Osteology Foundation was to comprehensively assess the effects of soft tissue augmentation procedures on... (Review)
Review
Evidence-based knowledge on the aesthetics and maintenance of peri-implant soft tissues: Osteology Foundation Consensus Report Part 1-Effects of soft tissue augmentation procedures on the maintenance of peri-implant soft tissue health.
OBJECTIVES
The goal of Working Group 1 at the 2nd Consensus Meeting of the Osteology Foundation was to comprehensively assess the effects of soft tissue augmentation procedures on peri-implant health or disease.
MATERIALS AND METHODS
A systematic review and meta-analysis on the effects of soft tissue augmentation procedures included a total of 10 studies (mucosal thickness: n = 6; keratinized tissue: n = 4). Consensus statements, clinical recommendations, and implications for future research were based on structured group discussions and a plenary session approval.
RESULTS
Soft tissue grafting to increase the width of keratinized tissue around implants was associated with greater reductions in gingival and plaque indices when compared to non-augmented sites. Statistically significant differences were noted for final marginal bone levels in favor of an apically positioned flap plus autogenous graft vs. all standard-of-care control treatments investigated. Soft tissue grafting (i.e., autogenous connective tissue) to increase the mucosal thickness around implants in the aesthetic zone was associated with significantly less marginal bone loss over time, but no significant changes in bleeding on probing, probing depths, or plaque scores when compared to sites without grafting.
CONCLUSIONS
The limited evidence available supports the use of soft tissue augmentation procedures to promote peri-implant health.
Topics: Alveolar Ridge Augmentation; Connective Tissue; Consensus; Dental Implantation; Dental Implantation, Endosseous; Dental Implants; Gingiva; Humans; Jaw, Edentulous, Partially; Meta-Analysis as Topic; Mucous Membrane; Osteology; Surgical Flaps
PubMed: 29498127
DOI: 10.1111/clr.13110 -
Peritoneal Dialysis International :... Jul 2021A pathophysiological classification of membrane dysfunction, which provides mechanistic links to functional characteristics, should be used when prescribing...
GUIDELINE 1
A pathophysiological classification of membrane dysfunction, which provides mechanistic links to functional characteristics, should be used when prescribing individualized dialysis or when planning modality transfer (e.g. to automated peritoneal dialysis (PD) or haemodialysis) in the context of shared and informed decision-making with the person on PD, taking individual circumstances and treatment goals into account. ().
GUIDELINE 2A
It is recommended that the PSTR is determined from a 4-h peritoneal equilibration test (PET), using either 2.5%/2.27% or 4.25%/3.86% dextrose/glucose concentration and creatinine as the index solute. () This should be done early in the course dialysis treatment (between 6 weeks and 12 weeks) () and subsequently when clinically indicated. ().
GUIDELINE 2B
A faster PSTR is associated with lower survival on PD. () This risk is in part due to the lower ultrafiltration (UF) and increased net fluid reabsorption that occurs when the PSTR is above the average value. The resulting lower net UF can be avoided by shortening glucose-based exchanges, using a polyglucose solution (icodextrin), and/or prescribing higher glucose concentrations. () Compared to glucose, use of icodextrin can translate into improved fluid status and fewer episodes of fluid overload. () Use of automated PD and icodextrin may mitigate the mortality risk associated with fast PSTR. ().
GUIDELINE 3
UF This is easy to measure and a valuable screening test. Insufficient UF should be suspected when either (a) the net UF from a 4-h PET is <400 ml (3.86% glucose/4.25% dextrose) or <100 ml (2.27% glucose /2.5% dextrose), () and/or (b) the daily UF is insufficient to maintain adequate fluid status. () Besides membrane dysfunction, low UF capacity can also result from mechanical problems, leaks or increased fluid absorption across the peritoneal membrane not explained by fast PSTR.
GUIDELINE 4A
Diagnosing intrinsic membrane dysfunction (manifesting as low osmotic conductance to glucose) as a cause of UF insufficiency: When insufficient UF is suspected, the 4-h PET should be supplemented by measurement of the sodium dip at 1 h using a 3.86% glucose/4.25% dextrose exchange for diagnostic purposes. A sodium dip ≤5 mmol/L and/or a sodium sieving ratio ≤0.03 at 1 h indicates UF insufficiency. ().
GUIDELINE 4B
in the absence of residual kidney function, this is likely to necessitate the use of hypertonic glucose exchanges and possible transfer to haemodialysis. Acquired membrane injury, especially in the context of prolonged time on treatment, should prompt discussions about the risk of encapsulating peritoneal sclerosis. ().
GUIDELINE 5
measures of peritoneal protein loss, intraperitoneal pressure and more complex tests that estimate osmotic conductance and 'lymphatic' reabsorption are not recommended for routine clinical practice but remain valuable research methods. ().
GUIDELINE 6
When resource constraints prevent the use of routine tests, consideration of membrane function should still be part of the clinical management and may be inferred from the daily UF in response to the prescription. ().
Topics: Adult; Dialysis Solutions; Glucans; Glucose; Humans; Icodextrin; Peritoneal Dialysis; Peritoneum; Sodium; Ultrafiltration
PubMed: 33563110
DOI: 10.1177/0896860820982218 -
Current Opinion in Gastroenterology Mar 2015The intestinal immune system is constantly exposed to foreign antigens, which for the most part should be tolerated, but the immune system retains the ability to react... (Review)
Review
PURPOSE OF REVIEW
The intestinal immune system is constantly exposed to foreign antigens, which for the most part should be tolerated, but the immune system retains the ability to react rapidly and effectively to eliminate pathogens. Dendritic cells are at the front line in maintaining intestinal integrity as they are widely distributed within the intestinal lamina propria, Peyer's patches and mesenteric lymph nodes.
RECENT FINDINGS
The identification of dendritic cell subsets and phenotypic markers within the healthy and diseased intestine has progressed significantly, including improved identification of dendritic cell subsets within the human intestine. Recently, the role for dietary factors and the microbiome in modulating the intestinal dendritic cell functions has begun to be better investigated, resulting in a number of new findings relating to retinoic acid metabolism, pattern recognition receptor triggering and G-protein-coupled receptor activation. In addition, the interactions between goblet cells and mucin with intestinal dendritic cells are being better defined.
SUMMARY
In this review, we discuss the recent findings relating to intestinal dendritic cells, in particular the importance of dendritic cells in sensing the intestinal microenvironment and the consequences for health and disease.
Topics: Antigens; Dendritic Cells; Gastric Mucins; Goblet Cells; Humans; Immune Tolerance; Immunity, Mucosal; Inflammatory Bowel Diseases; Intestinal Mucosa; Phenotype
PubMed: 25651073
DOI: 10.1097/MOG.0000000000000155 -
Molecules (Basel, Switzerland) Aug 2022This review is an attempt to incorporate water as a structural and thermodynamic component of biomembranes. With this purpose, the consideration of the membrane... (Review)
Review
This review is an attempt to incorporate water as a structural and thermodynamic component of biomembranes. With this purpose, the consideration of the membrane interphase as a bidimensional hydrated polar head group solution, coupled to the hydrocarbon region allows for the reconciliation of two theories on cells in dispute today: one considering the membrane as an essential part in terms of compartmentalization, and another in which lipid membranes are not necessary and cells can be treated as a colloidal system. The criterium followed is to describe the membrane state as an open, non-autonomous and responsive system using the approach of Thermodynamic of Irreversible Processes. The concept of an open/non-autonomous membrane system allows for the visualization of the interrelationship between metabolic events and membrane polymorphic changes. Therefore, the Association Induction Hypothesis (AIH) and lipid properties interplay should consider hydration in terms of free energy modulated by water activity and surface (lateral) pressure. Water in restricted regions at the lipid interphase has thermodynamic properties that explain the role of H-bonding networks in the propagation of events between membrane and cytoplasm that appears to be relevant in the context of crowded systems.
Topics: Lipid Bilayers; Lipids; Membranes; Thermodynamics; Water
PubMed: 35956945
DOI: 10.3390/molecules27154994 -
Trends in Molecular Medicine Mar 2018Organismal fitness demands proper response to neutralize the threat from infection or injury. At the mammalian intestinal epithelium barrier, the inflammasome... (Review)
Review
Organismal fitness demands proper response to neutralize the threat from infection or injury. At the mammalian intestinal epithelium barrier, the inflammasome coordinates an elaborate tissue repair response marked by the induction of antimicrobial peptides, wound-healing cytokines, and reparative proliferation of epithelial stem cells. The inflammasome in myeloid and intestinal epithelial compartments exerts these effects in part through maintenance of a healthy microbiota. Disease-associated mutations and elevated expression of certain inflammasome sensors have been identified. In many cases, inhibition of inflammasome activity has dramatic effects on disease outcome in mouse models of experimental colitis. Here, we discuss recent studies on the role of distinct inflammasome sensors in intestinal homeostasis and how this knowledge may be translated into a therapeutic setting.
Topics: Animals; Colitis; Gastrointestinal Microbiome; Homeostasis; Humans; Inflammasomes; Inflammation; Intestinal Mucosa; Intestines; Pyroptosis; Wound Healing
PubMed: 29433944
DOI: 10.1016/j.molmed.2018.01.004 -
Biochimica Et Biophysica Acta.... Oct 2018In this article we review current understanding of basic principles for the folding of membrane proteins, focusing on the more abundant alpha-helical class. Membrane... (Review)
Review
In this article we review current understanding of basic principles for the folding of membrane proteins, focusing on the more abundant alpha-helical class. Membrane proteins, vital to many biological functions and implicated in numerous diseases, fold into their active conformations in the complex environment of the cell bilayer membrane. While many membrane proteins rely on the translocon and chaperone proteins to fold correctly, others can achieve their functional form in the absence of any translation apparatus or other aides. Nevertheless, the spontaneous folding process is not well understood at the molecular level. Recent findings suggest that helix fraying and loop formation may be important for overall structure, dynamics and regulation of function. Several types of membrane helices with ionizable amino acids change their topology with pH. Additionally we note that some peptides, including many that are rich in arginine, and a particular analogue of gramicidin, are able passively to translocate across cell membranes. The findings indicate that a final protein structure in a lipid-bilayer membrane is sequence-based, with lipids contributing to stability and regulation. While much progress has been made toward understanding the folding process for alpha-helical membrane proteins, it remains a work in progress. This article is part of a Special Issue entitled: Emergence of Complex Behavior in Biomembranes edited by Marjorie Longo.
Topics: Amino Acid Sequence; Amino Acids; Cell Membrane; Hydrogen-Ion Concentration; Lipid Bilayers; Membrane Proteins; Membranes; Models, Molecular; Peptides; Protein Conformation; Protein Conformation, alpha-Helical; Protein Folding; Protein Structure, Secondary
PubMed: 29447916
DOI: 10.1016/j.bbamem.2018.02.010 -
Cell and Tissue Research Jul 2017The last 5 years have witnessed tremendous advances in both light- and electron-microscopic techniques in the biomedical sciences. Application of these new cutting-edge... (Review)
Review
The last 5 years have witnessed tremendous advances in both light- and electron-microscopic techniques in the biomedical sciences. Application of these new cutting-edge methods to glomerular biology has advanced considerably and, in part, completed our endeavor to draw a detailed map of the glomerular tuft. The scope of this review is to illustrate these new insights within both the morphometry of podocyte cells and the architecture of the glomerular filtration barrier and to assess whether these findings have indeed had an impact on our biological understanding of glomerular function.
Topics: Animals; Glomerular Basement Membrane; Humans; Podocytes
PubMed: 28283912
DOI: 10.1007/s00441-017-2590-3 -
Tissue & Cell Feb 2019The interactions between cells and the extracellular matrix (ECM) play a major role in normal and pathological conditions. The ECM can modulate several biological... (Review)
Review
The interactions between cells and the extracellular matrix (ECM) play a major role in normal and pathological conditions. The ECM can modulate several biological functions including cell proliferation, adhesion, differentiation and survival through its interactions with cell receptors. Laminins are one of the most important glycoproteins present in basement membranes, a type of ECM. The pattern of expression of its different isoforms depends on the spatiotemporal organization of each tissue. While integrins are the most studied laminin receptors, other non-integrin laminin receptors are also involved. This review focuses on two particular non-integrin laminin receptors in the epithelial context: dystroglycan and 37/67 laminin receptor (37/67LR). Dystroglycan is a two-subunit protein discovered in the muscle as part of the dystrophin-associated glycoprotein complex. This protein can also be found in many epithelia where its roles are variable. The 37/67LR is a still incompletely understood laminin receptor that is important to regulate intestinal epithelial cell function and could be involved in various pathological conditions.
Topics: Basement Membrane; Cell Differentiation; Cell Proliferation; Dystroglycans; Epithelial Cells; Epithelium; Extracellular Matrix; Humans; Integrins; Laminin; Receptors, Laminin
PubMed: 30736907
DOI: 10.1016/j.tice.2018.12.005