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Intercellular and Intracellular Communication in Human Health and Disease 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 May 2023) | Viewed by 63611

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Dr. Henrique Girao

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Faculty of Medicine, University of Coimbra, iCBR, 3000-548 Coimbra, Portugal
Interests: gap junctions; extracellular vesicles; TNTs; autophagy; endocytosis; intercellular communication
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Special Issue Information

Dear Colleagues,

A fine-tuned flow of information is essential to maintain the homeostasis and function of living organisms. This communication can occur between adjacent cells, through intercellular junctions or structures such as tunneling nanotubes (TNT), or physically separated cells via extracellular vesicles or soluble factors, including hormones, growth factors, cytokines and second messengers. These strategies are used by both unicellular and multicellular organisms to mount an integrative response that allows rapid and efficient adaptation to environmental stressors or external changes. For example, single-celled organisms, such as bacteria and yeasts, use both chemical molecules and physical structures to exchange information, allowing cell colonies to behave in a synchronized manner, like a multicellular entity. In multicellular organisms, an intricate meshwork of communication processes is essential to not only maintain the functions of tissues and organs but also to ensure an orchestrated interorgan crosstalk, required for a coordinated systemic response of the organism. Very often, intercellular communication mediated by extracellular signals elicits a stepwise intracellular cascade of reactions that imply highly regulated communication mechanisms, including interorganelle interplay.

This Special Issue intends to bring together, in a comprehensive and holistic overview, new advances concerning intercellular and intracellular communication strategies, used by either unicellular or multicellular organisms.

You are welcome to read all the publications in our first volume "Intercellular and Intracellular Communication in Human Health and Disease":

https://www.mdpi.com/journal/ijms/special_issues/Intercellular_Intracellular_Communication

Dr. Henrique Girao
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Intercellular and Intracellular Communication in Human Health and Disease in International Journal of Molecular Sciences (12 articles)

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Research

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28 pages, 6294 KiB

Open AccessArticle

A Comparative Study of the Antiemetic Effects of α₂-Adrenergic Receptor Agonists Clonidine and Dexmedetomidine against Diverse Emetogens in the Least Shrew (Cryptotis parva) Model of Emesis

by Yina Sun and Nissar A. Darmani

Int. J. Mol. Sci. 2024, 25(9), 4603; https://doi.org/10.3390/ijms25094603 - 23 Apr 2024

Cited by 1 | Viewed by 1024

Abstract

In contrast to cats and dogs, here we report that the α₂-adrenergic receptor antagonist yohimbine is emetic and corresponding agonists clonidine and dexmedetomidine behave as antiemetics in the least shrew model of vomiting. Yohimbine (0, 0.5, 0.75, 1, 1.5, 2, and 3 mg/kg, i.p.) caused vomiting in shrews in a bell-shaped and dose-dependent manner, with a maximum frequency (0.85 ± 0.22) at 1 mg/kg, which was accompanied by a key central contribution as indicated by increased expression of c-fos, serotonin and substance P release in the shrew brainstem emetic nuclei. Our comparative study in shrews demonstrates that clonidine (0, 0.1, 1, 5, and 10 mg/kg, i.p.) and dexmedetomidine (0, 0.01, 0.05, and 0.1 mg/kg, i.p.) not only suppress yohimbine (1 mg/kg, i.p.)-evoked vomiting in a dose-dependent manner, but also display broad-spectrum antiemetic effects against diverse well-known emetogens, including 2-Methyl-5-HT, GR73632, McN-A-343, quinpirole, FPL64176, SR141716A, thapsigargin, rolipram, and ZD7288. The antiemetic inhibitory ID₅₀ values of dexmedetomidine against the evoked emetogens are much lower than those of clonidine. At its antiemetic doses, clonidine decreased shrews’ locomotor activity parameters (distance moved and rearing), whereas dexmedetomidine did not do so. The results suggest that dexmedetomidine represents a better candidate for antiemetic potential with advantages over clonidine. Full article

(This article belongs to the Special Issue Intercellular and Intracellular Communication in Human Health and Disease 2.0)

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17 pages, 3667 KiB

Open AccessArticle

The Role of Extracellular Vesicles (EVs) in Chronic Graft vs. Host Disease, and the Potential Function of Placental Cell-Derived EVs as a Therapeutic Tool

by Mor Zavaro, Ayelet Dangot, Tali Hana Bar-Lev, Odelia Amit, Irit Avivi, Ron Ram and Anat Aharon

Int. J. Mol. Sci. 2023, 24(9), 8126; https://doi.org/10.3390/ijms24098126 - 1 May 2023

Cited by 1 | Viewed by 1979

Abstract

Chronic graft-versus-host disease (cGVHD) presents with dermal inflammation and fibrosis. We investigated the characteristics of extracellular vesicles (EVs) obtained from cGVHD patients, and their potential effects on human dermal fibroblast (NHDF) cells. The anti-inflammatory and anti-fibrotic effects of placental EVs were also explored given their known anti-inflammatory properties. Fourteen cGVHD patients’ EVs contained higher levels of fibrosis-related proteins, TGFβ and α-smooth muscle actin (αSMA), compared to EVs from thirteen healthy subjects. The exposure of NHDF cells to the patients’ EVs increased the NHDF cells’ TGFβ and αSMA expressions. Placental EVs derived from placental-expanded cells (PLX) (Pluri Inc.) and human villous trophoblast (HVT) cells expressing the mesenchymal markers CD29, CD73, and CD105, penetrated into both the epidermal keratinocytes (HACATs) and NHDF cells. Stimulation of the HACAT cells with cytokine TNFα/INFγ (0.01–0.1 ng/µL) reduced cell proliferation, while the addition of placental EVs attenuated this effect, increasing and normalizing cell proliferation. The treatment of NHDF cells with a combination of TGFβ and placental HVT EVs reduced the stimulatory effects of TGFβ on αSMA production by over 40% (p = 0.0286). In summary, EVs from patients with cGVHD can serve as a biomarker for the cGVHD state. Placental EVs may be used to regulate dermal inflammation and fibrosis, warranting further investigation of their therapeutic potential. Full article

(This article belongs to the Special Issue Intercellular and Intracellular Communication in Human Health and Disease 2.0)

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15 pages, 1491 KiB

Open AccessArticle

Upregulation of Inflammatory Mediators in Peripheral Blood CD40⁺ Cells in Children with Autism Spectrum Disorder

by Abdullah A. Aldossari, Mushtaq A. Ansari, Ahmed Nadeem, Sabry M. Attia, Saleh A. Bakheet, Laila Y. Al-Ayadhi, Mohammed M. Alanazi, Mudassar Shahid, Mohammad Y. Alwetaid, Marwa H. Hussein and Sheikh F. Ahmad

Int. J. Mol. Sci. 2023, 24(8), 7475; https://doi.org/10.3390/ijms24087475 - 19 Apr 2023

Cited by 5 | Viewed by 2048

Abstract

Autism spectrum disorder (ASD) is a common and severe neurodevelopmental disorder in early childhood, defined as social and communication deficits and repetitive and stereotypic behaviours. The aetiology is unknown in most cases. However, several studies have identified immune dysregulation as potentially promoting ASD. Among the numerous immunological findings in ASD, reports of increased pro-inflammatory markers remain the most consistently observed. C-C chemokine receptor type 1 (CCR1) activation is pro-inflammatory in several neurological disorders. Previous evidence has implied that the expression of chemokine receptors, inflammatory mediators, and transcription factors play a pivotal role in several neuroinflammatory disorders. There have also been reports on the association between increased levels of proinflammatory cytokines and ASD. In this study, we aimed to investigate the possible involvement of CCR1, inflammatory mediators, and transcription factor expression in CD40⁺ cells in ASD compared to typically developing controls (TDC). Flow cytometry analysis was used to determine the levels of CCR1-, IFN-γ-, T-box transcription factor (T-bet-), IL-17A-, retinoid-related orphan receptor gamma t (RORγt-), IL-22- and TNF-α-expressing CD40 cells in PBMCs in children with ASD and the TDC group. We further examined the mRNA and protein expression levels of CCR1 using real-time PCR and western blot analysis. Our results revealed that children with ASD had significantly increased numbers of CD40⁺CCR1⁺, CD40⁺IFN-γ⁺, CD40⁺T-bet⁺, CD40⁺IL-17A⁺, CD40⁺RORγt⁺, CD4⁺IL-22⁺, and CD40⁺TNF-α⁺ cells compared with the TDC group. Furthermore, children with ASD had higher CCR1 mRNA and protein expression levels than those in the TDC group. These results indicate that CCR1, inflammatory mediators, and transcription factors expressed in CD40 cells play vital roles in disease progression. Full article

(This article belongs to the Special Issue Intercellular and Intracellular Communication in Human Health and Disease 2.0)

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13 pages, 1045 KiB

Open AccessArticle

Circulating Interlukin-32 and Altered Blood Pressure Control in Individuals with Metabolic Dysfunction

by Melissa Tomasi, Alessandro Cherubini, Serena Pelusi, Sara Margarita, Cristiana Bianco, Francesco Malvestiti, Lorenzo Miano, Stefano Romeo, Daniele Prati and Luca Valenti

Int. J. Mol. Sci. 2023, 24(8), 7465; https://doi.org/10.3390/ijms24087465 - 18 Apr 2023

Cited by 5 | Viewed by 2180

Abstract

Fatty liver disease is most frequently related to metabolic dysfunction (MAFLD) and associated comorbidities, heightening the risk of cardiovascular disease, and is associated with higher hepatic production of IL32, a cytokine linked with lipotoxicity and endothelial activation. The aim of this study was to examine the relationship between circulating IL32 concentration and blood pressure control in individuals with metabolic dysfunction at high risk of MAFLD. IL32 plasma levels were measured by ELISA in 948 individuals with metabolic dysfunction enrolled in the Liver-Bible-2021 cohort. Higher circulating IL32 levels were independently associated with systolic blood pressure (estimate +0.008 log₁₀ per 1 mmHg increase, 95% c.i. 0.002–0.015; p = 0.016), and inversely correlated with antihypertensive medications (estimate −0.189, 95% c.i. −0.291–−0.088, p = 0.0002). Through multivariable analysis, IL32 levels predicted both systolic blood pressure (estimate 0.746, 95% c.i 0.173–1.318; p = 0.010) and impaired blood pressure control (OR 1.22, 95% c.i. 1.09–1.38; p = 0.0009) independently of demographic and metabolic confounders and of treatment. This study reveals that circulating IL32 levels are associated with impaired blood pressure control in individuals at risk of cardiovascular disease. Full article

(This article belongs to the Special Issue Intercellular and Intracellular Communication in Human Health and Disease 2.0)

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18 pages, 2243 KiB

Open AccessArticle

Extracellular Vesicles of COVID-19 Patients Reflect Inflammation, Thrombogenicity, and Disease Severity

by Anat Aharon, Ayelet Dangot, Fadi Kinaani, Mor Zavaro, Lian Bannon, Tali Bar-lev, Anat Keren-Politansky, Irit Avivi and Giris Jacob

Int. J. Mol. Sci. 2023, 24(6), 5918; https://doi.org/10.3390/ijms24065918 - 21 Mar 2023

Cited by 11 | Viewed by 2632

Abstract

Severe COVID-19 infections present with cytokine storms, hypercoagulation, and acute respiratory distress syndrome, with extracellular vesicles (EVs) being involved in coagulation and inflammation. This study aimed to determine whether coagulation profiles and EVs reflect COVID-19 disease severity. Thirty-six patients with symptomatic COVID-19 infection with mild/moderate/severe disease (12 in each group) were analyzed. Sixteen healthy individuals served as controls. Coagulation profiles and EV characteristics were tested by nanoparticle tracking analysis (NTA), flow cytometry, and Western blot. While coagulation factors VII, V, VIII, and vWF were comparable, significant differences were found in patients’ D-Dimer/fibrinogen/free protein S levels compared to controls. Severe patients’ EVs displayed higher percentages of small EVs (<150 nm) with increased expression of exosome marker CD63. Severe patients’ EVs displayed high levels of platelet markers (CD41) and coagulation factors (tissue factor activity, endothelial protein C receptor). EVs of patients with moderate/severe disease expressed significantly higher levels of immune cell markers (CD4/CD8/CD14) and contained higher levels of IL-6. We demonstrated that EVs, but not the coagulation profile, may serve as biomarkers for COVID-19 severity. EVs demonstrated elevated levels of immune- and vascular-related markers in patients with moderate/severe disease, and may play a role in disease pathogenesis. Full article

(This article belongs to the Special Issue Intercellular and Intracellular Communication in Human Health and Disease 2.0)

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15 pages, 2957 KiB

Open AccessArticle

Role of C-Terminal Domain and Membrane Potential in the Mobility of Kv1.3 Channels in Immune Synapse Forming T Cells

by Veronika Sebestyén, Éva Nagy, Gábor Mocsár, Julianna Volkó, Orsolya Szilágyi, Ádám Kenesei, György Panyi, Katalin Tóth, Péter Hajdu and György Vámosi

Int. J. Mol. Sci. 2022, 23(6), 3313; https://doi.org/10.3390/ijms23063313 - 18 Mar 2022

Cited by 2 | Viewed by 2252

Abstract

Voltage-gated Kv1.3 potassium channels are essential for maintaining negative membrane potential during T-cell activation. They interact with membrane-associated guanylate kinases (MAGUK-s) via their C-terminus and with TCR/CD3, leading to enrichment at the immunological synapse (IS). Molecular interactions and mobility may impact each other and the function of these proteins. We aimed to identify molecular determinants of Kv1.3 mobility, applying fluorescence correlation spectroscopy on human Jurkat T-cells expressing WT, C-terminally truncated (ΔC), and non-conducting mutants of mGFP-Kv1.3. ΔC cannot interact with MAGUK-s and is not enriched at the IS, whereas cells expressing the non-conducting mutant are depolarized. Here, we found that in standalone cells, mobility of ΔC increased relative to the WT, likely due to abrogation of interactions, whereas mobility of the non-conducting mutant decreased, similar to our previous observations on other membrane proteins in depolarized cells. At the IS formed with Raji B-cells, mobility of WT and non-conducting channels, unlike ΔC, was lower than outside the IS. The Kv1.3 variants possessing an intact C-terminus had lower mobility in standalone cells than in IS-engaged cells. This may be related to the observed segregation of F-actin into a ring-like structure at the periphery of the IS, leaving much of the cell almost void of F-actin. Upon depolarizing treatment, mobility of WT and ΔC channels decreased both in standalone and IS-engaged cells, contrary to non-conducting channels, which themselves caused depolarization. Our results support that Kv1.3 is enriched at the IS via its C-terminal region regardless of conductivity, and that depolarization decreases channel mobility. Full article

(This article belongs to the Special Issue Intercellular and Intracellular Communication in Human Health and Disease 2.0)

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25 pages, 2650 KiB

Open AccessArticle

Overexpression of miR-124 in Motor Neurons Plays a Key Role in ALS Pathological Processes

by Ana Rita Vaz, Daniela Vizinha, Hermes Morais, Ana Rita Colaço, Gecioni Loch-Neckel, Marta Barbosa and Dora Brites

Int. J. Mol. Sci. 2021, 22(11), 6128; https://doi.org/10.3390/ijms22116128 - 7 Jun 2021

Cited by 29 | Viewed by 4001

Abstract

miRNA(miR)-124 is an important regulator of neurogenesis, but its upregulation in SOD1G93A motor neurons (mSOD1 MNs) was shown to associate with neurodegeneration and microglia activation. We used pre-miR-124 in wild-type (WT) MNs and anti-miR-124 in mSOD1 MNs to characterize the miR-124 pathological role. miR-124 overexpression in WT MNs produced a miRNA profile like that of mSOD1 MNs (high miR-125b; low miR-146a and miR-21), and similarly led to early apoptosis. Alterations in mSOD1 MNs were abrogated with anti-miR-124 and changes in their miRNAs mostly recapitulated by their secretome. Normalization of miR-124 levels in mSOD1 MNs prevented the dysregulation of neurite network, mitochondria dynamics, axonal transport, and synaptic signaling. Same alterations were observed in WT MNs after pre-miR-124 transfection. Secretome from mSOD1 MNs triggered spinal microglia activation, which was unno-ticed with that from anti-miR-124-modulated cells. Secretome from such modulated MNs, when added to SC organotypic cultures from mSOD1 mice in the early symptomatic stage, also coun-teracted the pathology associated to GFAP decrease, PSD-95 and CX3CL1-CX3CR1 signaling im-pairment, neuro-immune homeostatic imbalance, and enhanced miR-124 expression levels. Data suggest that miR-124 is implicated in MN degeneration and paracrine-mediated pathogenicity. We propose miR-124 as a new therapeutic target and a promising ALS biomarker in patient sub-populations. Full article

(This article belongs to the Special Issue Intercellular and Intracellular Communication in Human Health and Disease 2.0)

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20 pages, 2631 KiB

Open AccessReview

Mitochondrial Connexins and Mitochondrial Contact Sites with Gap Junction Structure

by Selma Cetin-Ferra, Sharon C. Francis, Anthonya T. Cooper, Kit Neikirk, Andrea G. Marshall, Antentor Hinton, Jr. and Sandra A. Murray

Int. J. Mol. Sci. 2023, 24(10), 9036; https://doi.org/10.3390/ijms24109036 - 20 May 2023

Cited by 5 | Viewed by 2278

Abstract

Mitochondria contain connexins, a family of proteins that is known to form gap junction channels. Connexins are synthesized in the endoplasmic reticulum and oligomerized in the Golgi to form hemichannels. Hemichannels from adjacent cells dock with one another to form gap junction channels that aggregate into plaques and allow cell–cell communication. Cell–cell communication was once thought to be the only function of connexins and their gap junction channels. In the mitochondria, however, connexins have been identified as monomers and assembled into hemichannels, thus questioning their role solely as cell–cell communication channels. Accordingly, mitochondrial connexins have been suggested to play critical roles in the regulation of mitochondrial functions, including potassium fluxes and respiration. However, while much is known about plasma membrane gap junction channel connexins, the presence and function of mitochondrial connexins remain poorly understood. In this review, the presence and role of mitochondrial connexins and mitochondrial/connexin-containing structure contact sites will be discussed. An understanding of the significance of mitochondrial connexins and their connexin contact sites is essential to our knowledge of connexins’ functions in normal and pathological conditions, and this information may aid in the development of therapeutic interventions in diseases linked to mitochondria. Full article

(This article belongs to the Special Issue Intercellular and Intracellular Communication in Human Health and Disease 2.0)

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28 pages, 2175 KiB

Open AccessReview

Non-Classical Intercellular Communications: Basic Mechanisms and Roles in Biology and Medicine

by Natalia Polyakova, Maria Kalashnikova and Alexander Belyavsky

Int. J. Mol. Sci. 2023, 24(7), 6455; https://doi.org/10.3390/ijms24076455 - 29 Mar 2023

Cited by 10 | Viewed by 2837

Abstract

In multicellular organisms, interactions between cells and intercellular communications form the very basis of the organism’s survival, the functioning of its systems, the maintenance of homeostasis and adequate response to the environment. The accumulated experimental data point to the particular importance of intercellular communications in determining the fate of cells, as well as their differentiation and plasticity. For a long time, it was believed that the properties and behavior of cells were primarily governed by the interactions of secreted or membrane-bound ligands with corresponding receptors, as well as direct intercellular adhesion contacts. In this review, we describe various types of other, non-classical intercellular interactions and communications that have recently come into the limelight—in particular, the broad repertoire of extracellular vesicles and membrane protrusions. These communications are mediated by large macromolecular structural and functional ensembles, and we explore here the mechanisms underlying their formation and present current data that reveal their roles in multiple biological processes. The effects mediated by these new types of intercellular communications in normal and pathological states, as well as therapeutic applications, are also discussed. The in-depth study of novel intercellular interaction mechanisms is required for the establishment of effective approaches for the control and modification of cell properties both for basic research and the development of radically new therapeutic strategies. Full article

(This article belongs to the Special Issue Intercellular and Intracellular Communication in Human Health and Disease 2.0)

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33 pages, 1144 KiB

Open AccessReview

Mechanisms of Nausea and Vomiting: Current Knowledge and Recent Advances in Intracellular Emetic Signaling Systems

by Weixia Zhong, Omar Shahbaz, Garrett Teskey, Abrianna Beever, Nala Kachour, Vishwanath Venketaraman and Nissar A. Darmani

Int. J. Mol. Sci. 2021, 22(11), 5797; https://doi.org/10.3390/ijms22115797 - 28 May 2021

Cited by 86 | Viewed by 40451

Abstract

Nausea and vomiting are common gastrointestinal complaints that can be triggered by diverse emetic stimuli through central and/or peripheral nervous systems. Both nausea and vomiting are considered as defense mechanisms when threatening toxins/drugs/bacteria/viruses/fungi enter the body either via the enteral (e.g., the gastrointestinal tract) or parenteral routes, including the blood, skin, and respiratory systems. While vomiting is the act of forceful removal of gastrointestinal contents, nausea is believed to be a subjective sensation that is more difficult to study in nonhuman species. In this review, the authors discuss the anatomical structures, neurotransmitters/mediators, and corresponding receptors, as well as intracellular emetic signaling pathways involved in the processes of nausea and vomiting in diverse animal models as well as humans. While blockade of emetic receptors in the prevention of vomiting is fairly well understood, the potential of new classes of antiemetics altering postreceptor signal transduction mechanisms is currently evolving, which is also reviewed. Finally, future directions within the field will be discussed in terms of important questions that remain to be resolved and advances in technology that may help provide potential answers. Full article

(This article belongs to the Special Issue Intercellular and Intracellular Communication in Human Health and Disease 2.0)

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