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Gut Jun 2021Dysregulated immune responses are the cause of IBDs. Studies in mice and humans suggest a central role of interleukin (IL)-23-producing mononuclear phagocytes in disease...
OBJECTIVE
Dysregulated immune responses are the cause of IBDs. Studies in mice and humans suggest a central role of interleukin (IL)-23-producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for selective IL-23 targeting therapies as part of personalised medicine.
DESIGN
We performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA sequencing to derive a transcriptomic signature of hyperinflammatory monocytes. Using gene network correlation analysis, we deconvolved this signature into components associated with homeostasis and inflammation in patient biopsy samples.
RESULTS
We characterised monocyte subsets of healthy individuals and patients with IBD that express IL-23. We identified autosensing and paracrine sensing of IL-1α/IL-1β and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion after lipopolysaccharide stimulation, whole bacteria exposure induced IL-23 production in controls via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to antitumour necrosis factor (TNF) therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease.
CONCLUSION
Our work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyperinflammation-associated IL-23 production in patients with severe ulcerating active Crohn's disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with IBD that might benefit from IL-23p19 and/or IL-1α/IL-1β-targeting therapies upstream of IL-23.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autocrine Communication; Cells, Cultured; Drug Resistance; Female; Gene Expression; Gene Expression Regulation; Gene Regulatory Networks; Homeostasis; Humans; Inflammatory Bowel Diseases; Interleukin-10; Interleukin-1alpha; Interleukin-1beta; Interleukin-23 Subunit p19; Lipopolysaccharides; Male; Middle Aged; Monocytes; Paracrine Communication; Receptors, Interleukin-10; Signal Transduction; Transcriptome; Tumor Necrosis Factor-alpha; Young Adult
PubMed: 33037057
DOI: 10.1136/gutjnl-2020-321731 -
Frontiers in Endocrinology 2019G protein-coupled receptors (GPCRs) constitute the largest superfamily of integral membrane protein receptors. As signal detectors, the several 100 known GPCRs are... (Review)
Review
G protein-coupled receptors (GPCRs) constitute the largest superfamily of integral membrane protein receptors. As signal detectors, the several 100 known GPCRs are responsible for sensing the plethora of endogenous ligands that are critical for the functioning of our endocrine system. Although GPCRs are typically considered as detectors for first messengers in classical signal transduction pathways, they seldom operate in isolation in complex biological systems. Intercellular communication between identical or different cell types is often mediated by autocrine or paracrine signals that are generated upon activation of specific GPCRs. In the context of energy homeostasis, the distinct complement of GPCRs in each cell type bridges the autocrine and paracrine communication within an organ, and the various downstream signaling mechanisms regulated by GPCRs can be integrated in a cell to produce an ultimate output. GPCRs thus act as gatekeepers that coordinate and fine-tune a response. By examining the role of GPCRs in activating and receiving autocrine and paracrine signals, one may have a better understanding of endocrine diseases that are associated with GPCR mutations, thereby providing new insights for treatment regimes.
PubMed: 31354618
DOI: 10.3389/fendo.2019.00428 -
International Journal of Molecular... Jun 2020Somatostatin is a peptide hormone, which most commonly is produced by endocrine cells and the central nervous system. In mammals, somatostatin originates from... (Review)
Review
Somatostatin is a peptide hormone, which most commonly is produced by endocrine cells and the central nervous system. In mammals, somatostatin originates from pre-prosomatostatin and is processed to a shorter form, i.e., somatostatin-14, and a longer form, i.e., somatostatin-28. The two peptides repress growth hormone secretion and are involved in the regulation of glucagon and insulin synthesis in the pancreas. In recent years, the processing and secretion of somatostatin have been studied intensively. However, little attention has been paid to the regulatory mechanisms that control its expression. This review provides an up-to-date overview of these mechanisms. In particular, it focuses on the role of enhancers and silencers within the promoter region as well as on the binding of modulatory transcription factors to these elements. Moreover, it addresses extracellular factors, which trigger key signaling pathways, leading to an enhanced somatostatin expression in health and disease.
Topics: Animals; Autocrine Communication; Enhancer Elements, Genetic; Feedback, Physiological; Gene Expression Regulation; Humans; Promoter Regions, Genetic; Somatostatin; Transcription Factors
PubMed: 32545257
DOI: 10.3390/ijms21114170 -
Biological Reviews of the Cambridge... Jun 2020The nervous system communicates with peripheral tissues through nerve fibres and the systemic release of hypothalamic and pituitary neurohormones. Communication between... (Review)
Review
The nervous system communicates with peripheral tissues through nerve fibres and the systemic release of hypothalamic and pituitary neurohormones. Communication between the nervous system and the largest human organ, skin, has traditionally received little attention. In particular, the neuro-regulation of sebaceous glands (SGs), a major skin appendage, is rarely considered. Yet, it is clear that the SG is under stringent pituitary control, and forms a fascinating, clinically relevant peripheral target organ in which to study the neuroendocrine and neural regulation of epithelia. Sebum, the major secretory product of the SG, is composed of a complex mixture of lipids resulting from the holocrine secretion of specialised epithelial cells (sebocytes). It is indicative of a role of the neuroendocrine system in SG function that excess circulating levels of growth hormone, thyroxine or prolactin result in increased sebum production (seborrhoea). Conversely, growth hormone deficiency, hypothyroidism, and adrenal insufficiency result in reduced sebum production and dry skin. Furthermore, the androgen sensitivity of SGs appears to be under neuroendocrine control, as hypophysectomy (removal of the pituitary) renders SGs largely insensitive to stimulation by testosterone, which is crucial for maintaining SG homeostasis. However, several neurohormones, such as adrenocorticotropic hormone and α-melanocyte-stimulating hormone, can stimulate sebum production independently of either the testes or the adrenal glands, further underscoring the importance of neuroendocrine control in SG biology. Moreover, sebocytes synthesise several neurohormones and express their receptors, suggestive of the presence of neuro-autocrine mechanisms of sebocyte modulation. Aside from the neuroendocrine system, it is conceivable that secretion of neuropeptides and neurotransmitters from cutaneous nerve endings may also act on sebocytes or their progenitors, given that the skin is richly innervated. However, to date, the neural controls of SG development and function remain poorly investigated and incompletely understood. Botulinum toxin-mediated or facial paresis-associated reduction of human sebum secretion suggests that cutaneous nerve-derived substances modulate lipid and inflammatory cytokine synthesis by sebocytes, possibly implicating the nervous system in acne pathogenesis. Additionally, evidence suggests that cutaneous denervation in mice alters the expression of key regulators of SG homeostasis. In this review, we examine the current evidence regarding neuroendocrine and neurobiological regulation of human SG function in physiology and pathology. We further call attention to this line of research as an instructive model for probing and therapeutically manipulating the mechanistic links between the nervous system and mammalian skin.
Topics: Animals; Brain; Dopamine; Growth Hormone; Humans; Hypothalamo-Hypophyseal System; Neurosecretory Systems; Peripheral Nervous System; Prolactin; Sebaceous Glands; Sebum; Skin; Skin Physiological Phenomena; Somatomedins; Stem Cells; Thyroid Gland
PubMed: 31970855
DOI: 10.1111/brv.12579 -
Frontiers in Plant Science 2023Plant development and pattern formation depend on diffusible signals and location cues. These developmental signals and cues activate intracellular downstream components... (Review)
Review
Plant development and pattern formation depend on diffusible signals and location cues. These developmental signals and cues activate intracellular downstream components through cell surface receptors that direct cells to adopt specific fates for optimal function and establish biological fitness. There may be a single-pole dual-control competing mode in controlling plant development and microbial infection. In plant development, paracrine signaling molecules compete with autocrine signaling molecules to bind receptors or receptor complexes, turn on antagonistic molecular mechanisms, and precisely regulate developmental processes. In the process of microbial infection, two different signaling molecules, competing receptors or receptor complexes, form their respective signaling complexes, trigger opposite signaling pathways, establish symbiosis or immunity, and achieve biological adaptation. We reviewed several "single-pole dual-control" competing modes, focusing on analyzing the competitive commonality and characterization of "single-pole dual-control" molecular mechanisms. We suggest it might be an economical protective mechanism for plants' sequentially and iteratively programmed developmental events. This mechanism may also be a paradigm for reducing internal friction in the struggle and coexistence with microbes. It provides extraordinary insights into molecular recognition, cell-to-cell communication, and protein-protein interactions. A detailed understanding of the "single-pole dual-control" competing mode will contribute to the discovery of more receptors or antagonistic peptides, and lay the foundation for food, biofuel production, and crop improvement.
PubMed: 37457334
DOI: 10.3389/fpls.2023.1149522 -
International Journal of Molecular... Aug 2021Recent data demonstrate the anabolic effect of oxytocin on bone. Bone cells express oxytocin receptors. Oxytocin promotes osteoblasts differentiation and function,... (Review)
Review
Recent data demonstrate the anabolic effect of oxytocin on bone. Bone cells express oxytocin receptors. Oxytocin promotes osteoblasts differentiation and function, leading to an increased bone formation with no effect on bone resorption and an improvement of bone microarchitecture. Oxytocin is synthetized by osteoblasts, and this synthesis is stimulated by estrogen. Animal studies demonstrate a direct action of oxytocin on bone, as the systemic administration of oxytocin prevents and reverses the bone loss induced by estrogen deficiency. Although oxytocin is involved in bone formation in both sexes during development, oxytocin treatment has no effect on male osteoporosis, underlining the importance of estrogen that amplifies its local autocrine and paracrine secretion. There are few human data showing a decrease in the oxytocin serum level in anorexia nervosa independently of estrogen and in amenorrheic women associated with impaired bone microarchitecture; in post-menopausal women a higher oxytocin serum level is associated with higher bone density, but not in osteoporotic men. Oxytocin displays many effects that may be beneficial in the management of osteoporosis, cardiovascular diseases, cognitive disorders, breast cancer, diabetes and body fat gain, all age-related diseases affecting elderly women, opening exciting therapeutic perspectives, although the issue is to find a single route, dosage and schedule able to reach all these targets.
Topics: Amenorrhea; Animals; Anorexia Nervosa; Autocrine Communication; Bone Density; Bone and Bones; Breast Neoplasms; Cardiovascular Diseases; Cognitive Dysfunction; Diabetes Mellitus; Estrogens; Female; Humans; Male; Osteoporosis, Postmenopausal; Oxytocin; Paracrine Communication; Sex Characteristics
PubMed: 34445256
DOI: 10.3390/ijms22168551 -
Phytomedicine : International Journal... Jan 2024Traditional Chinese medicine prescription sini decoction (SND) can alleviate inflammation, improve microcirculation, and modulate immune status in sepsis patients....
BACKGROUND
Traditional Chinese medicine prescription sini decoction (SND) can alleviate inflammation, improve microcirculation, and modulate immune status in sepsis patients. However, its underlying mechanisms remain unclear, and therapeutic effects may vary among individuals.
PURPOSE
Through a comprehensive and systematic network pharmacology analysis, the purpose of this study is to investigate the therapeutic mechanisms of SND in treating sepsis.
METHODS
An analysis of WGCNA identified CX3CR1 as a key gene influencing sepsis prognosis. A drug-active component-target network for SND was created using the traditional Chinese medicine systems pharmacology (TCMSP) database and Cytoscape software. Shared targets between SND and CX3CR1 high-expression gene modules were found through the GEO database. Gene module functionality was analyzed using GO, KEGG, GSEA, and GSVA. Unsupervised clustering of sepsis patients was performed based on the ferroptosis gene set, and immune cell interactions and mechanisms were explored using CIBERSORT, single-cell sequencing, and intercellular communication analysis.
RESULTS
This study demonstrates that high expression of CX3CR1 improves survival rates in sepsis patients and is associated with immune cell signaling pathways. SND contains 116 active components involved in oxidative stress and lipid metabolism pathways. HMOX1, a co-expressed gene in SND and CX3CR1 high-expression gene module, plays a crucial role in sepsis survival. Unsupervised clustering analysis classified sepsis patients into three clusters based on the ferroptosis gene set, revealing differences in immune cell expression and involvement in heme metabolism pathways. Notably, intercellular interactions among immune cells primarily occur through paracrine and autocrine mechanisms in MIF, GALECTIN, and IL16 signaling pathways, modulating the immune-inflammatory microenvironment in sepsis.
CONCLUSIONS
This study identifies CX3CR1 as a crucial molecule impacting sepsis prognosis through WGCNA analysis. It reveals that SND's active component, quercetin and kaempferol, target HMOX1 via related pathways to regulate heme metabolism, reduce inflammation, inhibit ferroptosis, and improve immune function, ultimately improving sepsis prognosis. These findings offer a solid pharmacological foundation and potential therapeutic targets for SND in treating sepsis.
Topics: Humans; Network Pharmacology; Multiomics; Drugs, Chinese Herbal; Sepsis; Inflammation; Heme; Molecular Docking Simulation
PubMed: 38029626
DOI: 10.1016/j.phymed.2023.155212 -
International Journal of Molecular... Aug 2023Myocardial infarction (MI) causes massive loss of cardiac myocytes and injury to the coronary microcirculation, overwhelming the limited capacity of cardiac... (Review)
Review
Myocardial infarction (MI) causes massive loss of cardiac myocytes and injury to the coronary microcirculation, overwhelming the limited capacity of cardiac regeneration. Cardiac repair after MI is finely organized by complex series of procedures involving a robust angiogenic response that begins in the peri-infarcted border area of the infarcted heart, concluding with fibroblast proliferation and scar formation. Efficient neovascularization after MI limits hypertrophied myocytes and scar extent by the reduction in collagen deposition and sustains the improvement in cardiac function. Compelling evidence from animal models and classical in vitro angiogenic approaches demonstrate that a plethora of well-orchestrated signaling pathways involving Notch, Wnt, PI3K, and the modulation of intracellular Ca concentration through ion channels, regulate angiogenesis from existing endothelial cells (ECs) and endothelial progenitor cells (EPCs) in the infarcted heart. Moreover, cardiac repair after MI involves cell-to-cell communication by paracrine/autocrine signals, mainly through the delivery of extracellular vesicles hosting pro-angiogenic proteins and non-coding RNAs, as microRNAs (miRNAs). This review highlights some general insights into signaling pathways activated under MI, focusing on the role of Ca influx, Notch activated pathway, and miRNAs in EC activation and angiogenesis after MI.
Topics: Animals; Cicatrix; Neovascularization, Physiologic; Myocardial Infarction; Myocytes, Cardiac; MicroRNAs; Endothelial Progenitor Cells
PubMed: 37569674
DOI: 10.3390/ijms241512298 -
Science Advances Aug 2023The insulin superfamily of peptides is essential for homeostasis as well as neuronal plasticity, learning, and memory. Here, we show that insulin-like growth factors 1...
The insulin superfamily of peptides is essential for homeostasis as well as neuronal plasticity, learning, and memory. Here, we show that insulin-like growth factors 1 and 2 (IGF1 and IGF2) are differentially expressed in hippocampal neurons and released in an activity-dependent manner. Using a new fluorescence resonance energy transfer sensor for IGF1 receptor (IGF1R) with two-photon fluorescence lifetime imaging, we find that the release of IGF1 triggers rapid local autocrine IGF1R activation on the same spine and more than several micrometers along the stimulated dendrite, regulating the plasticity of the activated spine in CA1 pyramidal neurons. In CA3 neurons, IGF2, instead of IGF1, is responsible for IGF1R autocrine activation and synaptic plasticity. Thus, our study demonstrates the cell type-specific roles of IGF1 and IGF2 in hippocampal plasticity and a plasticity mechanism mediated by the synthesis and autocrine signaling of IGF peptides in pyramidal neurons.
Topics: Autocrine Communication; Dendritic Spines; Hippocampus; Neuronal Plasticity; Pyramidal Cells
PubMed: 37531435
DOI: 10.1126/sciadv.adg0666