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Internal and Emergency Medicine Mar 2024The intestine is the largest interface between the internal body and the external environment. The intestinal barrier is a dynamic system influenced by the composition... (Review)
Review
The intestine is the largest interface between the internal body and the external environment. The intestinal barrier is a dynamic system influenced by the composition of the intestinal microbiome and the activity of intercellular connections, regulated by hormones, dietary components, inflammatory mediators, and the enteric nervous system (ENS). Over the years, it has become increasingly evident that maintaining a stable intestinal barrier is crucial to prevent various potentially harmful substances and pathogens from entering the internal environment. Disruption of the barrier is referred to as 'leaky gut' or leaky gut wall syndrome and seems to be characterized by the release of bacterial metabolites and endotoxins, such as lipopolysaccharide (LPS), into the circulation. This condition, mainly caused by bacterial infections, oxidative stress, high-fat diet, exposure to alcohol or chronic allergens, and dysbiosis, appear to be highly connected with the development and/or progression of several metabolic and autoimmune systemic diseases, including obesity, non-alcoholic fatty liver disease (NAFLD), neurodegeneration, cardiovascular disease, inflammatory bowel disease, and type 1 diabetes mellitus (T1D). In this review, starting from a description of the mechanisms that enable barrier homeostasis and analyzing the relationship between this complex ecosystem and various pathological conditions, we explore the role of the gut barrier in driving systemic inflammation, also shedding light on current and future therapeutic interventions.
Topics: Humans; Autoimmune Diseases; Gastrointestinal Microbiome; Inflammation; Intestinal Barrier Function; Intestinal Mucosa; Non-alcoholic Fatty Liver Disease
PubMed: 37505311
DOI: 10.1007/s11739-023-03374-w -
Annual Review of Genomics and Human... Aug 2023The subcellular localization of a biopolymer often informs its function. RNA is traditionally confined to the cytosolic and nuclear spaces, where it plays critical and... (Review)
Review
The subcellular localization of a biopolymer often informs its function. RNA is traditionally confined to the cytosolic and nuclear spaces, where it plays critical and conserved roles across nearly all biochemical processes. Our recent observation of cell surface glycoRNAs may further explain the extracellular role of RNA. While cellular membranes are efficient gatekeepers of charged polymers such as RNAs, a large body of research has demonstrated the accumulation of specific RNA species outside of the cell, termed extracellular RNAs (exRNAs). Across various species and forms of life, protein pores have evolved to transport RNA across membranes, thus providing a mechanistic path for exRNAs to achieve their extracellular topology. Here, we review types of exRNAs and the pores capable of RNA transport to provide a logical and testable path toward understanding the biogenesis and regulation of cell surface glycoRNAs.
Topics: Humans; RNA; Cell Membrane; Membranes; Cytosol; Polymers
PubMed: 37068783
DOI: 10.1146/annurev-genom-101722-101224 -
The Journal of Experimental Medicine Oct 2023Mast cells (MCs) are tissue-resident immune cells that exhibit homeostatic and neuron-associated functions. Here, we combined whole-tissue imaging and single-cell RNA...
Mast cells (MCs) are tissue-resident immune cells that exhibit homeostatic and neuron-associated functions. Here, we combined whole-tissue imaging and single-cell RNA sequencing datasets to generate a pan-organ analysis of MCs in mice and humans at steady state. In mice, we identify two mutually exclusive MC populations, MrgprB2+ connective tissue-type MCs and MrgprB2neg mucosal-type MCs, with specific transcriptomic core signatures. While MrgprB2+ MCs develop in utero independently of the bone marrow, MrgprB2neg MCs develop after birth and are renewed by bone marrow progenitors. In humans, we unbiasedly identify seven MC subsets (MC1-7) distributed across 12 organs with different transcriptomic core signatures. MC1 are preferentially enriched in the bladder, MC2 in the lungs, and MC4, MC6, and MC7 in the skin. Conversely, MC3 and MC5 are shared by most organs but not skin. This comprehensive analysis offers valuable insights into the natural diversity of MC subtypes in both mice and humans.
Topics: Humans; Mice; Animals; Mast Cells; Mucous Membrane; Transcriptome
PubMed: 37462672
DOI: 10.1084/jem.20230570 -
Nature Immunology Sep 2023Omnivorous animals, including mice and humans, tend to prefer energy-dense nutrients rich in fat over plant-based diets, especially for short periods of time, but the...
Omnivorous animals, including mice and humans, tend to prefer energy-dense nutrients rich in fat over plant-based diets, especially for short periods of time, but the health consequences of this short-term consumption of energy-dense nutrients are unclear. Here, we show that short-term reiterative switching to 'feast diets', mimicking our social eating behavior, breaches the potential buffering effect of the intestinal microbiota and reorganizes the immunological architecture of mucosa-associated lymphoid tissues. The first dietary switch was sufficient to induce transient mucosal immune depression and suppress systemic immunity, leading to higher susceptibility to Salmonella enterica serovar Typhimurium and Listeria monocytogenes infections. The ability to respond to antigenic challenges with a model antigen was also impaired. These observations could be explained by a reduction of CD4 T cell metabolic fitness and cytokine production due to impaired mTOR activity in response to reduced microbial provision of fiber metabolites. Reintroducing dietary fiber rewired T cell metabolism and restored mucosal and systemic CD4 T cell functions and immunity. Finally, dietary intervention with human volunteers confirmed the effect of short-term dietary switches on human CD4 T cell functionality. Therefore, short-term nutritional changes cause a transient depression of mucosal and systemic immunity, creating a window of opportunity for pathogenic infection.
Topics: Humans; Mice; Animals; Mucous Membrane; Salmonella typhimurium; T-Lymphocytes; Immunity, Mucosal
PubMed: 37580603
DOI: 10.1038/s41590-023-01587-x -
Progress in Retinal and Eye Research Nov 2023The pre-Descemet's layer/Dua's layer, also termed the Dua-Fine layer and the pre-posterior limiting lamina layer, lies anterior to the Descemet's membrane in the cornea,... (Review)
Review
The pre-Descemet's layer (Dua's layer, also known as the Dua-Fine layer and the pre-posterior limiting lamina layer): Discovery, characterisation, clinical and surgical applications, and the controversy.
The pre-Descemet's layer/Dua's layer, also termed the Dua-Fine layer and the pre-posterior limiting lamina layer, lies anterior to the Descemet's membrane in the cornea, is 10 μm (range 6-16) thick, made predominantly of type I and some type VI collagen with abundant elastin, more than any other layer of the cornea. It has high tensile strength (bursting pressure up to 700 mm of Hg), is impervious to air and almost acellular. At the periphery it demonstrates fenestrations and ramifies to become the core of the trabecular meshwork, with implications for intraocular pressure and glaucoma. It has been demonstrated in some species of animals. The layer has assumed considerable importance in anterior and posterior lamellar corneal transplant surgery by improving our understanding of the behaviour of corneal tissue during these procedures, improved techniques and made the surgery safer with better outcomes. It has led to the innovation of new surgical procedures namely, pre-Descemet's endothelial keratoplasty, suture management of acute hydrops, DALK-triple and Fogla's mini DALK. The discovery and knowledge of the layer has introduced paradigm shifts in our age old concepts of Descemet's membrane detachment, acute corneal hydrops in keratoconus and Descemetoceles, with impact on management approaches. It has been shown to contribute to the pathology and clinical signs observed in corneal infections and some corneal dystrophies. Early evidence suggests that it may have a role in the pathogenesis of keratoconus in relation to its elastin content. Its contribution to corneal biomechanics and glaucoma are subjects of current investigations.
Topics: Humans; Descemet Membrane; Keratoconus; Elastin; Corneal Transplantation; Edema; Glaucoma
PubMed: 36642673
DOI: 10.1016/j.preteyeres.2022.101161 -
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 -
Advanced Science (Weinheim,... Sep 2023The interaction between trophoblasts, stroma cells, and immune cells at the maternal-fetal interface constitutes the functional units of the placenta, which is crucial...
The interaction between trophoblasts, stroma cells, and immune cells at the maternal-fetal interface constitutes the functional units of the placenta, which is crucial for successful pregnancy outcomes. However, the investigation of this intricate interplay is restricted due to the absence of efficient experimental models. To address this challenge, a robust, reliable methodology for generating placenta villi organoids (PVOs) from early, late, or diseased pregnancies using air-liquid surface culture is developed. PVOs contain cytotrophoblasts that can self-renew and differentiate directly, along with stromal elements that retain native immune cells. Analysis of scRNA sequencing and WES data reveals that PVOs faithfully recapitulate the cellular components and genetic alterations of the corresponding source tissue. Additionally, PVOs derived from patients with preeclampsia exhibit specific pathological features such as inflammation, antiangiogenic imbalance, and decreased syncytin expression. The PVO-based propagation of primary placenta villi should enable a deeper investigation of placenta development and exploration of the underlying pathogenesis and therapeutics of placenta-originated diseases.
Topics: Pregnancy; Female; Humans; Placenta; Chorionic Villi; Placentation; Trophoblasts; Organoids
PubMed: 37438660
DOI: 10.1002/advs.202301565 -
Proceedings of the National Academy of... Jun 2023Gut microbiota imbalance (dysbiosis) is increasingly associated with pathological conditions, both within and outside the gastrointestinal tract. Intestinal Paneth cells...
Gut microbiota imbalance (dysbiosis) is increasingly associated with pathological conditions, both within and outside the gastrointestinal tract. Intestinal Paneth cells are considered to be guardians of the gut microbiota, but the events linking Paneth cell dysfunction with dysbiosis remain unclear. We report a three-step mechanism for dysbiosis initiation. Initial alterations in Paneth cells, as frequently observed in obese and inflammatorybowel diseases patients, cause a mild remodeling of microbiota, with amplification of succinate-producing species. SucnR1-dependent activation of epithelial tuft cells triggers a type 2 immune response that, in turn, aggravates the Paneth cell defaults, promoting dysbiosis and chronic inflammation. We thus reveal a function of tuft cells in promoting dysbiosis following Paneth cell deficiency and an unappreciated essential role of Paneth cells in maintaining a balanced microbiota to prevent inappropriate activation of tuft cells and deleterious dysbiosis. This succinate-tuft cell inflammation circuit may also contribute to the chronic dysbiosis observed in patients.
Topics: Humans; Dysbiosis; Mucous Membrane; Inflammation; Paneth Cells; Succinates; Succinic Acid
PubMed: 37307458
DOI: 10.1073/pnas.2219431120 -
Kidney International Dec 2023Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the...
Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.
Topics: Humans; Glomerulonephritis, Membranous; Consensus; Autoantibodies; Nephrectomy; Glomerular Basement Membrane; Receptors, Phospholipase A2
PubMed: 37795587
DOI: 10.1016/j.kint.2023.06.032 -
Current Opinion in Microbiology Aug 2023The formation of lateral microdomains is emerging as a central organizing principle in bacterial membranes. These microdomains are targets of antibiotic development and... (Review)
Review
The formation of lateral microdomains is emerging as a central organizing principle in bacterial membranes. These microdomains are targets of antibiotic development and have the potential to enhance natural product synthesis, but the rules governing their assembly are unclear. Previous studies have suggested that microdomain formation is promoted by lipid phase separation, particularly by cardiolipin (CL) and isoprenoid lipids, and there is strong evidence that CL biosynthesis is required for recruitment of membrane proteins to cell poles and division sites. New work demonstrates that additional bacterial lipids may mediate membrane protein localization and function, opening the field for mechanistic evaluation of lipid-driven membrane organization in vivo.
Topics: Membrane Proteins; Membranes; Bacteria; Cardiolipins; Biophysics; Cell Membrane
PubMed: 37058914
DOI: 10.1016/j.mib.2023.102315