International Journal of Molecular Sciences

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18 pages, 4582 KiB

Open AccessArticle

Expression and Localization Profiles of Tight Junction Proteins in Immune Cells Depend on Their Activation Status

by Lena Voges, Franziska Weiß, Ana-Teresa Branco, Michael Fromm and Susanne M. Krug

Int. J. Mol. Sci. 2024, 25(9), 4861; https://doi.org/10.3390/ijms25094861 - 29 Apr 2024

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Abstract

The ability of the immune system to combat pathogens relies on processes like antigen sampling by dendritic cells and macrophages migrating through endo- and epithelia or penetrating them with their dendrites. In addition, other immune cell subtypes also migrate through the epithelium after [...] Read more.

The ability of the immune system to combat pathogens relies on processes like antigen sampling by dendritic cells and macrophages migrating through endo- and epithelia or penetrating them with their dendrites. In addition, other immune cell subtypes also migrate through the epithelium after activation. For paracellular migration, interactions with tight junctions (TJs) are necessary, and previous studies reported TJ protein expression in several immune cells. Our investigation aimed to characterize, in more detail, the expression profiles of TJ proteins in different immune cells in both naïve and activated states. The mRNA expression analysis revealed distinct expression patterns for TJ proteins, with notable changes, mainly increases, upon activation. At the protein level, LSR appeared predominant, being constitutively present in naïve cell membranes, suggesting roles as a crucial interaction partner. Binding experiments suggested the presence of claudins in the membrane only after stimulation, and claudin-8 translocation to the membrane occurred after stimulation. Our findings suggest a dynamic TJ protein expression in immune cells, implicating diverse functions in response to stimulation, like interaction with TJ proteins or regulatory roles. While further analysis is needed to elucidate the precise roles of TJ proteins, our findings indicate important non-canonical functions of TJ proteins in immune response. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: From Structure to Pathologies)

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16 pages, 9937 KiB

Open AccessArticle

Altered Sweat Composition Due to Changes in Tight Junction Expression of Sweat Glands in Cholinergic Urticaria Patients

by Denisa Daci, Sabine Altrichter, François Marie Grillet, Selma Dib, Ahmad Mouna, Sukashree Suresh Kumar, Dorothea Terhorst-Molawi, Marcus Maurer, Dorothee Günzel and Jörg Scheffel

Int. J. Mol. Sci. 2024, 25(9), 4658; https://doi.org/10.3390/ijms25094658 - 25 Apr 2024

Viewed by 1260

Abstract

In cholinergic urticaria (CholU), small, itchy wheals are induced by exercise or passive warming and reduced sweating has been reported. Despite the described reduced muscarinic receptor expression, sweat duct obstruction, or sweat allergy, the underlying pathomechanisms are not well understood. To gain further [...] Read more.

In cholinergic urticaria (CholU), small, itchy wheals are induced by exercise or passive warming and reduced sweating has been reported. Despite the described reduced muscarinic receptor expression, sweat duct obstruction, or sweat allergy, the underlying pathomechanisms are not well understood. To gain further insights, we collected skin biopsies before and after pulse-controlled ergometry and sweat after sauna provocation from CholU patients as well as healthy controls. CholU patients displayed partially severely reduced local sweating, yet total sweat volume was unaltered. However, sweat electrolyte composition was altered, with increased K⁺ concentration in CholU patients. Formalin-fixed, paraffin-embedded biopsies were stained to explore sweat leakage and tight junction protein expression. Dermcidin staining was not found outside the sweat glands. In the secretory coils of sweat glands, the distribution of claudin-3 and -10b as well as occludin was altered, but the zonula occludens-1 location was unchanged. In all, dermcidin and tight junction protein staining suggests an intact barrier with reduced sweat production capability in CholU patients. For future studies, an ex vivo skin model for quantification of sweat secretion was established, in which sweat secretion could be pharmacologically stimulated or blocked. This ex vivo model will be used to further investigate sweat gland function in CholU patients and decipher the underlying pathomechanism(s). Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: From Structure to Pathologies)

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16 pages, 5072 KiB

Open AccessArticle

Claudin-10 Expression and the Gene Expression Pattern of Thick Ascending Limb Cells

by Gaelle Brideau, Lydie Cheval, Camille Griveau, Wung-Man Evelyne Ling, Loïc Lievre, Gilles Crambert, Dominik Müller, Jovana Broćić, Emeline Cherchame, Pascal Houillier and Caroline Prot-Bertoye

Int. J. Mol. Sci. 2024, 25(7), 4008; https://doi.org/10.3390/ijms25074008 - 3 Apr 2024

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Abstract

Many genomic, anatomical and functional differences exist between the medullary (MTAL) and the cortical thick ascending limb of the loop of Henle (CTAL), including a higher expression of claudin-10 (CLDN10) in the MTAL than in the CTAL. Therefore, we assessed to what extent [...] Read more.

Many genomic, anatomical and functional differences exist between the medullary (MTAL) and the cortical thick ascending limb of the loop of Henle (CTAL), including a higher expression of claudin-10 (CLDN10) in the MTAL than in the CTAL. Therefore, we assessed to what extent the Cldn10 gene expression is a determinant of differential gene expression between MTAL and CTAL. RNAs extracted from CTAL and MTAL microdissected from wild type (WT) and Cldn10 knock out mice (cKO) were analyzed by RNAseq. Differential and enrichment analyses (GSEA) were performed with interactive R Shiny software. Between WT and cKO MTAL, 637 genes were differentially expressed, whereas only 76 were differentially expressed between WT and cKO CTAL. Gene expression patterns and GSEA analyses in all replicates showed that WT MTAL did not cluster with the other replicates; no hierarchical clustering could be found between WT CTAL, cKO CTAL and cKO MTAL. Compared to WT replicates, cKO replicates were enriched in Cldn16, Cldn19, Pth1r, (parathyroid hormone receptor type 1), Casr (calcium sensing receptor) and Vdr (Vitamin D Receptor) mRNA in both the cortex and medulla. Cldn10 is associated with gene expression patterns, including genes specifically involved in divalent cations reabsorption in the TAL. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: From Structure to Pathologies)

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25 pages, 17269 KiB

Open AccessArticle

Molecular Dynamics Simulations of Claudin-10a and -10b Ion Channels: With Similar Architecture, Different Pore Linings Determine the Opposite Charge Selectivity

by Santhosh Kumar Nagarajan and Jörg Piontek

Int. J. Mol. Sci. 2024, 25(6), 3161; https://doi.org/10.3390/ijms25063161 - 9 Mar 2024

Cited by 1 | Viewed by 1208

Abstract

Claudin polymers constitute the tight junction (TJ) backbone that forms paracellular barriers, at least for bigger solutes. While some claudins also seal the barrier for small electrolytes, others form ion channels. For cation-selective claudin-15 and claudin-10b, structural models of channels embedded in homo-polymeric [...] Read more.

Claudin polymers constitute the tight junction (TJ) backbone that forms paracellular barriers, at least for bigger solutes. While some claudins also seal the barrier for small electrolytes, others form ion channels. For cation-selective claudin-15 and claudin-10b, structural models of channels embedded in homo-polymeric strands have been suggested. Here, we generated a model for the prototypic anion-selective claudin-10a channel. Based on previously established claudin-10b models, dodecamer homology models of claudin-10a embedded in two membranes were analyzed by molecular dynamics simulations. The results indicate that both claudin-10 isoforms share the same strand and channel architecture: Sidewise unsealed tetrameric pore scaffolds are interlocked with adjacent pores via the β1β2 loop of extracellular segment 1. This leads to TJ-like strands with claudin subunits arranged in four joined rows in two opposing membranes. Several but not all cis- and trans-interaction modes are indicated to be conserved among claudin-10a, -10b, and -15. However, pore-lining residues that differ between claudin-10a and -10b (i.e., R33/I35, A34/D36, K69/A71, N54/D56, H60/N62, R62/K64) result in opposite charge selectivity of channels. This was supported by electric field simulations for both claudins and is consistent with previous electrophysiological studies. In summary, for the first time, a structural and mechanistic model of complete and prototypic paracellular anion channels is provided. This improves understanding of epithelial paracellular transport. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: From Structure to Pathologies)

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35 pages, 17518 KiB

Open AccessArticle

The Role of ZO-2 in Modulating JAM-A and γ-Actin Junctional Recruitment, Apical Membrane and Tight Junction Tension, and Cell Response to Substrate Stiffness and Topography

by Diana Cristina Pinto-Dueñas, Christian Hernández-Guzmán, Patrick Matthew Marsch, Anand Sunil Wadurkar, Dolores Martín-Tapia, Lourdes Alarcón, Genaro Vázquez-Victorio, Juan Vicente Méndez-Méndez, José Jorge Chanona-Pérez, Shikha Nangia and Lorenza González-Mariscal

Int. J. Mol. Sci. 2024, 25(5), 2453; https://doi.org/10.3390/ijms25052453 - 20 Feb 2024

Cited by 1 | Viewed by 2130

Abstract

This work analyzes the role of the tight junction (TJ) protein ZO-2 on mechanosensation. We found that the lack of ZO-2 reduced apical membrane rigidity measured with atomic force microscopy, inhibited the association of γ-actin and JAM-A to the cell border, and instead [...] Read more.

This work analyzes the role of the tight junction (TJ) protein ZO-2 on mechanosensation. We found that the lack of ZO-2 reduced apical membrane rigidity measured with atomic force microscopy, inhibited the association of γ-actin and JAM-A to the cell border, and instead facilitated p114RhoGEF and afadin accumulation at the junction, leading to an enhanced mechanical tension at the TJ measured by FRET, with a ZO-1 tension probe, and increased tricellular TJ tension. Simultaneously, adherens junction tension measured with an E-cadherin probe was unaltered. The stability of JAM-A and ZO-2 binding was assessed by a collaborative in silico study. The absence of ZO-2 also impacted the cell response to the substrate, as monolayers plated in 20 kPa hydrogels developed holes not seen in parental cultures and displayed a retarded elongation and formation of cell aggregates. The absence of ZO-2 was sufficient to induce YAP and Snail nuclear accumulation in cells cultured over glass, but when ZO-2 KD cells were plated in nanostructured ridge arrays, they displayed an increased abundance of nuclear Snail and conspicuous internalization of claudin-4. These results indicate that the absence of ZO-2 also impairs the response of cells to substrate stiffness and exacerbates transformation triggered by substrate topography. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: From Structure to Pathologies)

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13 pages, 2852 KiB

Open AccessArticle

Integrating Continuous Transepithelial Flux Measurements into an Ussing Chamber Set-Up

by Çlirim Alija, Lukas Knobe, Ioanna Pouyiourou, Mikio Furuse, Rita Rosenthal and Dorothee Günzel

Int. J. Mol. Sci. 2024, 25(4), 2252; https://doi.org/10.3390/ijms25042252 - 13 Feb 2024

Viewed by 1154

Abstract

Fluorescently labelled compounds are often employed to study the paracellular properties of epithelia. For flux measurements, these compounds are added to the donor compartment and samples collected from the acceptor compartment at regular intervals. However, this method fails to detect rapid changes in [...] Read more.

Fluorescently labelled compounds are often employed to study the paracellular properties of epithelia. For flux measurements, these compounds are added to the donor compartment and samples collected from the acceptor compartment at regular intervals. However, this method fails to detect rapid changes in permeability. For continuous transepithelial flux measurements in an Ussing chamber setting, a device was developed, consisting of a flow-through chamber with an attached LED, optical filter, and photodiode, all encased in a light-impermeable container. The photodiode output was amplified and recorded. Calibration with defined fluorescein concentration (range of 1 nM to 150 nM) resulted in a linear output. As proof of principle, flux measurements were performed on various cell lines. The results confirmed a linear dependence of the flux on the fluorescein concentration in the donor compartment. Flux depended on paracellular barrier function (expression of specific tight junction proteins, and EGTA application to induce barrier loss), whereas activation of transcellular chloride secretion had no effect on fluorescein flux. Manipulation of the lateral space by osmotic changes in the perfusion solution also affected transepithelial fluorescein flux. In summary, this device allows a continuous recording of transepithelial flux of fluorescent compounds in parallel with the electrical parameters recorded by the Ussing chamber. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: From Structure to Pathologies)

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10 pages, 1836 KiB

Open AccessArticle

Urinary Acidification Does Not Explain the Absence of Nephrocalcinosis in a Mouse Model of Familial Hypomagnesaemia with Hypercalciuria and Nephrocalcinosis (FHHNC)

by Amr Al-Shebel, Geert Michel, Tilman Breiderhoff and Dominik Müller

Int. J. Mol. Sci. 2024, 25(3), 1779; https://doi.org/10.3390/ijms25031779 - 1 Feb 2024

Cited by 2 | Viewed by 983

Abstract

Patients with mutations in Cldn16 suffer from familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) which can lead to renal insufficiency. Mice lacking claudin-16 show hypomagnesemia and hypercalciuria, but no nephrocalcinosis. Calcium oxalate and calcium phosphate are the most common insoluble calcium salts that [...] Read more.

Patients with mutations in Cldn16 suffer from familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) which can lead to renal insufficiency. Mice lacking claudin-16 show hypomagnesemia and hypercalciuria, but no nephrocalcinosis. Calcium oxalate and calcium phosphate are the most common insoluble calcium salts that accumulate in the kidney in the case of nephrocalcinosis, however, the formation of these salts is less favored in acidic conditions. Therefore, urine acidification has been suggested to limit the formation of calcium deposits in the kidney. Assuming that urine acidification is causative for the absence of nephrocalcinosis in the claudin-16-deficient mouse model, we aimed to alkalinize the urine of these mice by the ablation of the subunit B1 of the vesicular ATPase in addition to claudin-16. In spite of an increased urinary pH in mice lacking claudin-16 and the B1 subunit, nephrocalcinosis did not develop. Thus, urinary acidification is not the only factor preventing nephrocalcinosis in claudin-16 deficient mice. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: From Structure to Pathologies)

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15 pages, 3910 KiB

Open AccessArticle

Quercetin Improves Barrier Properties in Porcine Small Intestine but Not in Peyer’s Patches

by Valeria Cornelius, Linda Droessler and Salah Amasheh

Int. J. Mol. Sci. 2024, 25(3), 1530; https://doi.org/10.3390/ijms25031530 - 26 Jan 2024

Cited by 3 | Viewed by 1249

Abstract

Peyer’s patches (PPs) are part of the gut-associated lymphatic tissue (GALT) and represent the first line of the intestinal immunological defense. They consist of follicles with lymphocytes and an overlying subepithelial dome with dendritic cells and macrophages, and they are covered by the [...] Read more.

Peyer’s patches (PPs) are part of the gut-associated lymphatic tissue (GALT) and represent the first line of the intestinal immunological defense. They consist of follicles with lymphocytes and an overlying subepithelial dome with dendritic cells and macrophages, and they are covered by the follicle-associated epithelium (FAE). A sealed paracellular pathway in the FAE is crucial for the controlled uptake of luminal antigens. Quercetin is the most abundant plant flavonoid and has a barrier-strengthening effect on tight junctions (TJs), a protein complex that regulates the paracellular pathway. In this study, we aimed to analyze the effect of quercetin on porcine PPs and the surrounding villus epithelium (VE). We incubated both tissue types for 4 h in Ussing chambers, recorded the transepithelial electrical resistance (TEER), and measured the unidirectional tracer flux of [³H]-mannitol. Subsequently, we analyzed the expression, protein amount, and localization of three TJ proteins, claudin 1, claudin 2, and claudin 4. In the PPs, we could not detect an effect of quercetin after 4 h, neither on TEER nor on the [³H]-mannitol flux. In the VE, quercetin led to a higher TEER value, while the [³H]-mannitol flux was unchanged. The pore-forming claudin 2 was decreased while the barrier-forming claudin 4 was increased and the expression was upregulated. Claudin 1 was unchanged and all claudins could be located in the paracellular membrane by immunofluorescence microscopy. Our study shows the barrier-strengthening effect of quercetin in porcine VE by claudin 4 upregulation and a claudin 2 decrease. Moreover, it underlines the different barrier properties of PPs compared to the VE. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: From Structure to Pathologies)

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22 pages, 3817 KiB

Open AccessArticle

Canonical and Non-Canonical Localization of Tight Junction Proteins during Early Murine Cranial Development

by Shermin Mak and Annette Hammes

Int. J. Mol. Sci. 2024, 25(3), 1426; https://doi.org/10.3390/ijms25031426 - 24 Jan 2024

Cited by 1 | Viewed by 1376

Abstract

This study investigates the intricate composition and spatial distribution of tight junction complex proteins during early mouse neurulation. The analyses focused on the cranial neural tube, which gives rise to all head structures. Neurulation brings about significant changes in the neuronal and non-neuronal [...] Read more.

This study investigates the intricate composition and spatial distribution of tight junction complex proteins during early mouse neurulation. The analyses focused on the cranial neural tube, which gives rise to all head structures. Neurulation brings about significant changes in the neuronal and non-neuronal ectoderm at a cellular and tissue level. During this process, precise coordination of both epithelial integrity and epithelial dynamics is essential for accurate tissue morphogenesis. Tight junctions are pivotal for epithelial integrity, yet their complex composition in this context remains poorly understood. Our examination of various tight junction proteins in the forebrain region of mouse embryos revealed distinct patterns in the neuronal and non-neuronal ectoderm, as well as mesoderm-derived mesenchymal cells. While claudin-4 exhibited exclusive expression in the non-neuronal ectoderm, we demonstrated a neuronal ectoderm specific localization for claudin-12 in the developing cranial neural tube. Claudin-5 was uniquely present in mesenchymal cells. Regarding the subcellular localization, canonical tight junction localization in the apical junctions was predominant for most tight junction complex proteins. ZO-1 (zona occludens protein-1), claudin-1, claudin-4, claudin-12, and occludin were detected at the apical junction. However, claudin-1 and occludin also appeared in basolateral domains. Intriguingly, claudin-3 displayed a non-canonical localization, overlapping with a nuclear lamina marker. These findings highlight the diverse tissue and subcellular distribution of tight junction proteins and emphasize the need for their precise regulation during the dynamic processes of forebrain development. The study can thereby contribute to a better understanding of the role of tight junction complex proteins in forebrain development. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: From Structure to Pathologies)

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13 pages, 1239 KiB

Open AccessArticle

Association of Plasma Claudin-5 with Age and Alzheimer Disease

by Keisuke Tachibana, Ryuichi Hirayama, Naoyuki Sato, Kotaro Hattori, Takashi Kato, Hiroyuki Takeda and Masuo Kondoh

Int. J. Mol. Sci. 2024, 25(3), 1419; https://doi.org/10.3390/ijms25031419 - 24 Jan 2024

Cited by 3 | Viewed by 2024

Abstract

The blood–brain barrier (BBB) plays pivotal roles in synaptic and neuronal functioning by sealing the space between adjacent microvascular endothelial cells. BBB breakdown is present in patients with mild cognitive impairment (MCI) or Alzheimer disease (AD). Claudin-5 (CLDN-5) is a tetra-spanning protein essential [...] Read more.

The blood–brain barrier (BBB) plays pivotal roles in synaptic and neuronal functioning by sealing the space between adjacent microvascular endothelial cells. BBB breakdown is present in patients with mild cognitive impairment (MCI) or Alzheimer disease (AD). Claudin-5 (CLDN-5) is a tetra-spanning protein essential for sealing the intercellular space between adjacent endothelial cells in the BBB. In this study, we developed a blood-based assay for CLDN-5 and investigated its diagnostic utility using 100 cognitively normal (control) subjects, 100 patients with MCI, and 100 patients with AD. Plasma CLDN-5 levels were increased in patients with AD (3.08 ng/mL) compared with controls (2.77 ng/mL). Plasma levels of phosphorylated tau (pTau181), a biomarker of pathological tau, were elevated in patients with MCI or AD (2.86 and 4.20 pg/mL, respectively) compared with control subjects (1.81 pg/mL). In patients with MCI or AD, plasma levels of CLDN-5—but not pTau181—decreased with age, suggesting some age-dependent BBB changes in MCI and AD. These findings suggest that plasma CLDN-5 may a potential biochemical marker for the diagnosis of AD. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: From Structure to Pathologies)

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Review

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30 pages, 4612 KiB

Open AccessReview

Nanostructure-Mediated Transport of Therapeutics through Epithelial Barriers

by M. Eva Hansen, Yasmin Ibrahim, Tejal A. Desai and Michael Koval

Int. J. Mol. Sci. 2024, 25(13), 7098; https://doi.org/10.3390/ijms25137098 - 28 Jun 2024

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Abstract

The ability to precisely treat human disease is facilitated by the sophisticated design of pharmacologic agents. Nanotechnology has emerged as a valuable approach to creating vehicles that can specifically target organ systems, effectively traverse epithelial barriers, and protect agents from premature degradation. In [...] Read more.

The ability to precisely treat human disease is facilitated by the sophisticated design of pharmacologic agents. Nanotechnology has emerged as a valuable approach to creating vehicles that can specifically target organ systems, effectively traverse epithelial barriers, and protect agents from premature degradation. In this review, we discuss the molecular basis for epithelial barrier function, focusing on tight junctions, and describe different pathways that drugs can use to cross barrier-forming tissue, including the paracellular route and transcytosis. Unique features of drug delivery applied to different organ systems are addressed: transdermal, ocular, pulmonary, and oral delivery. We also discuss how design elements of different nanoscale systems, such as composition and nanostructured architecture, can be used to specifically enhance transepithelial delivery. The ability to tailor nanoscale drug delivery vehicles to leverage epithelial barrier biology is an emerging theme in the pursuit of facilitating the efficacious delivery of pharmacologic agents. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: From Structure to Pathologies)

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36 pages, 4044 KiB

Open AccessReview

The Basic Requirement of Tight Junction Proteins in Blood-Brain Barrier Function and Their Role in Pathologies

by Sophie Dithmer, Ingolf E. Blasig, Paul A. Fraser, Zhihai Qin and Reiner F. Haseloff

Int. J. Mol. Sci. 2024, 25(11), 5601; https://doi.org/10.3390/ijms25115601 - 21 May 2024

Cited by 3 | Viewed by 1914

Abstract

This review addresses the role of tight junction proteins at the blood-brain barrier (BBB). Their expression is described, and their role in physiological and pathological processes at the BBB is discussed. Based on this, new approaches are depicted for paracellular drug delivery and [...] Read more.

This review addresses the role of tight junction proteins at the blood-brain barrier (BBB). Their expression is described, and their role in physiological and pathological processes at the BBB is discussed. Based on this, new approaches are depicted for paracellular drug delivery and diagnostics in the treatment of cerebral diseases. Recent data provide convincing evidence that, in addition to its impairment in the course of diseases, the BBB could be involved in the aetiology of CNS disorders. Further progress will be expected based on new insights in tight junction protein structure and in their involvement in signalling pathways. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: From Structure to Pathologies)

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13 pages, 1653 KiB

Open AccessReview

Micronutrients at Supplemental Levels, Tight Junctions and Epithelial Barrier Function: A Narrative Review

by Katherine M. DiGuilio, Elizabeth A. Del Rio, Ronald N. Harty and James M. Mullin

Int. J. Mol. Sci. 2024, 25(6), 3452; https://doi.org/10.3390/ijms25063452 - 19 Mar 2024

Cited by 2 | Viewed by 1634

Abstract

Disease modifiers, whether from cancer, sepsis, systemic inflammation, or microbial pathogens, all appear to induce epithelial barrier leak, with induced changes of the Tight Junctional (TJ) complex being pivotal to the process. This leak—and the ensuant breakdown of compartmentation—plays a central role in [...] Read more.

Disease modifiers, whether from cancer, sepsis, systemic inflammation, or microbial pathogens, all appear to induce epithelial barrier leak, with induced changes of the Tight Junctional (TJ) complex being pivotal to the process. This leak—and the ensuant breakdown of compartmentation—plays a central role in disease morbidity on many levels. Accumulation of lung water in the luminal compartment of airways was a major driver of morbidity and mortality in COVID-19 and is an excellent example of the phenomenon. Increasing awareness of the ability of micronutrients to improve basal barrier function and reduce barrier compromise in pathophysiology may prove to be a low-cost, safe, and easily administered prophylactic and/or therapeutic option amenable to large populations. The growing appreciation of the clinical utility of supplemental doses of Vitamin D in COVID-19 is but one example. This narrative review is intended to propose a general theory on how and why micronutrients—at levels above normal dietary intake—successfully remodel TJs and improve barrier function. It discusses the key difference between dietary/Recommended Daily Allowance (RDA) levels of micronutrients versus supplemental levels, and why the latter are needed in disease situations. It advances a hypothesis for why signal transduction regulation of barrier function may require these higher supplemental doses to achieve the TJ remodeling and other barrier element changes that are clinically beneficial. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: From Structure to Pathologies)

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16 pages, 5123 KiB

Open AccessReview

Computational Models of Claudin Assembly in Tight Junctions and Strand Properties

by Sarah McGuinness, Samaneh Sajjadi, Christopher R. Weber and Fatemeh Khalili-Araghi

Int. J. Mol. Sci. 2024, 25(6), 3364; https://doi.org/10.3390/ijms25063364 - 16 Mar 2024

Cited by 2 | Viewed by 1502

Abstract

Claudins are one of the major components of tight junctions (TJs) that polymerize within the cell membrane and form interactions between cells. Some claudins seal the paracellular space, limiting paracellular flux, while others form selectively permeable ion channels that control the paracellular permeability [...] Read more.

Claudins are one of the major components of tight junctions (TJs) that polymerize within the cell membrane and form interactions between cells. Some claudins seal the paracellular space, limiting paracellular flux, while others form selectively permeable ion channels that control the paracellular permeability of small ions. Claudin strands are known to be dynamic and reshape within TJs to accommodate large-scale movements and rearrangements of epithelial tissues. Here, we summarize the recent computational and modeling studies on claudin assembly into tetrameric ion channels and their polymerization into μm long strands within the membrane. Computational studies ranging from all-atom molecular dynamics, coarse-grained simulations, and hybrid-resolution simulations elucidate the molecular nature of claudin assembly and function and provide a framework that describes the lateral flexibility of claudin strands. Full article

(This article belongs to the Special Issue The Tight Junction and Its Proteins: From Structure to Pathologies)

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