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Frontiers in Molecular Neuroscience 2022Trigeminal ganglion (TG) is the first station of sensory pathways in the orofacial region. The TG neurons communicate with satellite glial cells (SGCs), macrophages and...
Trigeminal ganglion (TG) is the first station of sensory pathways in the orofacial region. The TG neurons communicate with satellite glial cells (SGCs), macrophages and other cells forming a functional unit that is responsible for processing of orofacial sensory information. Purinergic signaling, one of the most widespread autocrine and paracrine pathways, plays a crucial role in intercellular communication. The multidirectional action of purinergic signaling in different cell types contributes to the neuromodulation and orofacial sensation. To fully understand the purinergic signaling in these processes, it is essential to determine the shared and unique expression patterns of genes associated with purinergic signaling in different cell types. Here, we performed single-cell RNA sequencing of 22,969 cells isolated from normal mouse TGs. We identified 18 distinct cell populations, including 6 neuron subpopulations, 3 glial subpopulations, 7 immune cell subpopulations, fibroblasts, and endothelial cells. We also revealed the transcriptional features of genes associated with purinergic signaling, including purinergic receptors, extracellular adenosine triphosphate (eATP) release channels, eATP metabolism-associated enzymes, and eATP transporters in each cell type. Our results have important implications for understanding and predicting the cell type-specific roles of the purinergic signaling in orofacial signal processing in the trigeminal primary sensory system.
PubMed: 36311028
DOI: 10.3389/fnmol.2022.1038539 -
Frontiers in Endocrinology 2022Fatty liver disease is a spectrum of liver pathologies ranging from simple hepatic steatosis to non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis... (Review)
Review
Fatty liver disease is a spectrum of liver pathologies ranging from simple hepatic steatosis to non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and culminating with the development of cirrhosis or hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is complex and diverse, and there is a lack of effective treatment measures. In this review, we address hepatokines identified in the pathogenesis of NAFLD and NASH, including the signaling of FXR/RXR, PPARα/RXRα, adipogenesis, hepatic stellate cell activation/liver fibrosis, AMPK/NF-κB, and type 2 diabetes. We also highlight the interaction between hepatokines, and cytokines or peptides secreted from muscle (myokines), adipose tissue (adipokines), and hepatic stellate cells (stellakines) in response to certain nutritional and physical activity. Cytokines exert autocrine, paracrine, or endocrine effects on the pathogenesis of NAFLD and NASH. Characterizing signaling pathways and crosstalk amongst muscle, adipose tissue, hepatic stellate cells and other liver cells will enhance our understanding of interorgan communication and potentially serve to accelerate the development of treatments for NAFLD and NASH.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Adipokines; Carcinoma, Hepatocellular; NF-kappa B; PPAR alpha; Diabetes Mellitus, Type 2; AMP-Activated Protein Kinases; Liver Neoplasms; Liver Cirrhosis; Cytokines
PubMed: 36267567
DOI: 10.3389/fendo.2022.1007944 -
Advances in Biological Regulation Jan 2023Pancreatic islets are micro-organs composed of a mixture of endocrine and non-endocrine cells, where the former secrete hormones and peptides necessary for metabolic... (Review)
Review
Pancreatic islets are micro-organs composed of a mixture of endocrine and non-endocrine cells, where the former secrete hormones and peptides necessary for metabolic homeostasis. Through vasculature and innervation the cells within the islets are in communication with the rest of the body, while they interact with each other through juxtacrine, paracrine and autocrine signals, resulting in fine-tuned sensing and response to stimuli. In this context, cellular protrusion in islet cells, such as primary cilia and filopodia, have gained attention as potential signaling hubs. During the last decade, several pieces of evidence have shown how the primary cilium is required for islet vascularization, function and homeostasis. These findings have been possible thanks to the development of ciliary/basal body specific knockout models and technological advances in microscopy, which allow longitudinal monitoring of engrafted islets transplanted in the anterior chamber of the eye in living animals. Using this technique in combination with optogenetics, new potential paracrine interactions have been suggested. For example, reshaping and active movement of filopodia-like protrusions of δ-cells were visualized in vivo, suggesting a continuous cell remodeling to increase intercellular contacts. In this review, we discuss these recent discoveries regarding primary cilia and filopodia and their role in islet homeostasis and intercellular islet communication.
Topics: Animals; Pseudopodia; Cilia; Islets of Langerhans; Cell Communication; Signal Transduction
PubMed: 36266190
DOI: 10.1016/j.jbior.2022.100919 -
Science Signaling Oct 2022The tumor microbiome is increasingly implicated in cancer progression and resistance to chemotherapy. In pancreatic ductal adenocarcinoma (PDAC), high intratumoral loads...
The tumor microbiome is increasingly implicated in cancer progression and resistance to chemotherapy. In pancreatic ductal adenocarcinoma (PDAC), high intratumoral loads of correlate with shorter survival in patients. Here, we investigated the potential mechanisms underlying this association. We found that infection induced both normal pancreatic epithelial cells and PDAC cells to secrete increased amounts of the cytokines GM-CSF, CXCL1, IL-8, and MIP-3α. These cytokines increased proliferation, migration, and invasive cell motility in both infected and noninfected PDAC cells but not in noncancerous pancreatic epithelial cells, suggesting autocrine and paracrine signaling to PDAC cells. This phenomenon occurred in response to infection regardless of the strain and in the absence of immune and other stromal cells. Blocking GM-CSF signaling markedly limited proliferative gains after infection. Thus, infection in the pancreas elicits cytokine secretion from both normal and cancerous cells that promotes phenotypes in PDAC cells associated with tumor progression. The findings support the importance of exploring host-microbe interactions in pancreatic cancer to guide future therapeutic interventions.
Topics: Humans; Fusobacterium nucleatum; Granulocyte-Macrophage Colony-Stimulating Factor; Paracrine Communication; Interleukin-8; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Cell Proliferation; Pancreas
PubMed: 36256708
DOI: 10.1126/scisignal.abn4948 -
Frontiers in Cell and Developmental... 2022A primary reason behind the high level of complexity we embody as multicellular organisms is a highly complex intracellular and intercellular communication system. As a... (Review)
Review
A primary reason behind the high level of complexity we embody as multicellular organisms is a highly complex intracellular and intercellular communication system. As a result, the activities of multiple cell types and tissues can be modulated resulting in a specific physiological function. One of the key players in this communication process is extracellular signaling molecules that can act in autocrine, paracrine, and endocrine fashion to regulate distinct physiological responses. Neurotransmitters and neuropeptides are signaling molecules that renders long-range communication possible. In normal conditions, neurotransmitters are involved in normal responses such as development and normal physiological aspects; however, the dysregulation of neurotransmitters mediated signaling has been associated with several pathologies such as neurodegenerative, neurological, psychiatric disorders, and other pathologies. One of the interesting topics that is not yet fully explored is the connection between neuronal signaling and physiological changes during oocyte maturation and fertilization. Knowing the importance of Ca signaling in these reproductive processes, our objective in this review is to highlight the link between the neuronal signals and the intracellular changes in calcium during oocyte maturation and embryogenesis. Calcium (Ca) is a ubiquitous intracellular mediator involved in various cellular functions such as releasing neurotransmitters from neurons, contraction of muscle cells, fertilization, and cell differentiation and morphogenesis. The multiple roles played by this ion in mediating signals can be primarily explained by its spatiotemporal dynamics that are kept tightly checked by mechanisms that control its entry through plasma membrane and its storage on intracellular stores. Given the large electrochemical gradient of the ion across the plasma membrane and intracellular stores, signals that can modulate Ca entry channels or Ca receptors in the stores will cause Ca to be elevated in the cytosol and consequently activating downstream Ca-responsive proteins resulting in specific cellular responses. This review aims to provide an overview of the reported neurotransmitters and neuropeptides that participate in early stages of development and their association with Ca signaling.
PubMed: 36211465
DOI: 10.3389/fcell.2022.980219 -
International Journal of Molecular... Sep 2022Sphingosine-1-phosphate (S1P) is a versatile signaling lipid involved in the regulation of numerous cellular processes. S1P regulates cellular proliferation, migration,... (Review)
Review
Sphingosine-1-phosphate (S1P) is a versatile signaling lipid involved in the regulation of numerous cellular processes. S1P regulates cellular proliferation, migration, and apoptosis as well as the function of immune cells. S1P is generated from sphingosine (Sph), which derives from the ceramide metabolism. In particular, high concentrations of S1P are present in the blood. This originates mainly from erythrocytes, endothelial cells (ECs), and platelets. While erythrocytes function as a storage pool for circulating S1P, platelets can rapidly generate S1P de novo, store it in large quantities, and release it when the platelet is activated. Platelets can thus provide S1P in a short time when needed or in the case of an injury with subsequent platelet activation and thereby regulate local cellular responses. In addition, platelet-dependently generated and released S1P may also influence long-term immune cell functions in various disease processes, such as inflammation-driven vascular diseases. In this review, the metabolism and release of platelet S1P are presented, and the autocrine versus paracrine functions of platelet-derived S1P and its relevance in various disease processes are discussed. New pharmacological approaches that target the auto- or paracrine effects of S1P may be therapeutically helpful in the future for pathological processes involving S1P.
Topics: Blood Platelets; Cell Communication; Ceramides; Endothelial Cells; Humans; Lysophospholipids; Sphingosine
PubMed: 36142188
DOI: 10.3390/ijms231810278 -
Neuroendocrinology 2023Extracellular vesicles (EVs) are membrane-enclosed nanoparticles that contain various biomolecules, including nucleic acids, proteins and lipids, and are manufactured... (Review)
Review
Extracellular vesicles (EVs) are membrane-enclosed nanoparticles that contain various biomolecules, including nucleic acids, proteins and lipids, and are manufactured and released by virtually all cell types. There is evidence that EVs are involved in intercellular communication, acting in an autocrine, paracrine or/and endocrine manner. EVs are released by the cells of the central nervous system (CNS), including neurons, astrocytes, oligodendrocytes and microglia, and have the ability to cross the blood-brain barrier (BBB) and enter the systemic circulation. Neuroendocrine cells are specialized neurons that secrete hormones directly into blood vessels, such as the hypophyseal portal system or the systemic circulation, a process that allows neuroendocrine integration to take place. In mammals, neuroendocrine cells are widely distributed throughout various anatomic compartments, with the hypothalamus being a central neuroendocrine integrator. The hypothalamus is a key part of the stress system (SS), a highly conserved neuronal/neuroendocrine system aiming at maintaining systemic homeostasis when the latter is threatened by various stressors. The central parts of the SS are the interconnected hypothalamic corticotropin-releasing hormone (CRH) and the brainstem locus caeruleus-norepinephrine (LC-NE) systems, while their peripheral parts are, respectively, the pituitary-adrenal axis and the sympathetic nervous/sympatho-adrenomedullary systems (SNS-SAM) as well as components of the parasympathetic nervous system (PSNS). During stress, multiple CNS loci show plasticity and undergo remodeling, partly mediated by increased glutamatergic and noradrenergic activity, and the actions of cytokines and glucocorticoids, all regulated by the interaction of the hypothalamic-pituitary-adrenal (HPA) axis and the LC-NE/SNS-SAM systems. In addition, there are peripheral changes due to the increased secretion of stress hormones and pro-inflammatory cytokines in the context of stress-related systemic (para)inflammation. We speculate that during stress, central and peripheral, cellular and molecular alterations take place, with some of them generated, communicated, and spread via the release of stress-induced neural/neuroendocrine cell-derived EVs.
Topics: Animals; Hypothalamo-Hypophyseal System; Neurosecretory Systems; Adrenocorticotropic Hormone; Norepinephrine; Extracellular Vesicles; Cytokines; Pituitary-Adrenal System; Stress, Physiological; Corticotropin-Releasing Hormone; Mammals
PubMed: 36137504
DOI: 10.1159/000527182 -
Biomedicine & Pharmacotherapy =... Sep 2022Tumor cells can secret various cytokines and chemokines, which affect the tumor cells themselves and the neighboring cells. Here, we observed that human ovarian cancer...
Tumor cells can secret various cytokines and chemokines, which affect the tumor cells themselves and the neighboring cells. Here, we observed that human ovarian cancer (OC) cells developed resistance to paclitaxel treatment following culture with the conditioned medium (CM) derived from paclitaxel-resistant OC (OC) cells. A cytokine array revealed that both OC cells secreted large amounts of CC chemokine ligand 2 (CCL2). CCL2 and its receptor, CCR2, were overexpressed in OC cells. CCL2 expression was associated with worse progression-free survival in patients with ovarian cancer. The inhibition of the CCL2/CCR2 axis suppressed the chemoresistance induced by OC-CM. The enhanced expression and production of CCL2 in OC cells were mediated via the NF-κB pathway, and stimulated the activation of the PI3K/Akt pathway, which resulted in the development of paclitaxel resistance in OC cells. Additionally, the OC cells significantly increased the migration of macrophages, which was also associated with the overproduction of CCL2 in chemoresistant cancer cells. The macrophages stimulated by OC cells expressed high levels of markers of M2 phenotype, and their CM significantly decreased the paclitaxel responsiveness of OC cells. The administration of a CCR2 inhibitor to a murine model significantly improved the paclitaxel sensitivity. These data suggested that apart from inducing chemoresistance in OC cells by acting as an autocrine factor, CCL2 also functions as a chemokine that induces the chemotaxis of macrophages, which may contribute to chemoresistance. Therefore, targeting the CCL2/CCR2 signaling axis may improve the therapeutic response of patients with ovarian cancer to paclitaxel.
Topics: Animals; Autocrine Communication; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Chemokine CCL2; Chemokines; Cytokines; Female; Humans; Ligands; Macrophages; Mice; Ovarian Neoplasms; Paclitaxel; Phosphatidylinositol 3-Kinases
PubMed: 36076499
DOI: 10.1016/j.biopha.2022.113474