scholarly journals Immunoregulatory Property of C-Type Lectin-Like Receptors in Fibrosing Interstitial Lung Diseases

2020 ◽  
Vol 21 (10) ◽  
pp. 3665
Author(s):  
Wiwin Is Effendi ◽  
Tatsuya Nagano ◽  
Helmia Hasan ◽  
Resti Yudhawati
Keyword(s):  
Immune System ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Lung Diseases ◽  
Wound Repair ◽  
Tissue Injury ◽  
Interstitial Lung Diseases ◽  
Downstream Signaling ◽  
Cytokine Activation ◽  
Immune Impairment

The innate immune system identifies exogenous threats or endogenous stress through germline-encoded receptors called pattern recognition receptors (PRRs) that initiate consecutive downstream signaling pathways to control immune responses. However, the contribution of the immune system and inflammation to fibrosing interstitial lung diseases (ILD) remains poorly understood. Immunoreceptor tyrosine-based motif-bearing C-type lectin-like receptors (CTLRs) may interact with various immune cells during tissue injury and wound repair processes. Dectin-1 is a CTLR with dominant mechanisms manifested through its intracellular signaling cascades, which regulate fibrosis-promoting properties through gene transcription and cytokine activation. Additionally, immune impairment in ILD facilitates microbiome colonization; hence, Dectin-1 is the master protector in host pulmonary defense against fungal invasion. Recent progress in determining the signaling pathways that control the balance of fibrosis has implicated immunoreceptor tyrosine-based motif-bearing CTLRs as being involved, either directly or indirectly, in the pathogenesis of fibrosing ILD.

scholarly journals Structural aspects of molecular recognition in the immune system. Part II: Pattern recognition receptors (IUPAC Technical Report)

2014 ◽  
Vol 86 (10) ◽  
pp. 1483-1538 ◽  
Author(s):  
John A. Robinson ◽  
Kerstin Moehle
Keyword(s):  
Pattern Recognition ◽  
Immune System ◽  
Immune Responses ◽  
Signaling Pathways ◽  
Innate Immune System ◽  
Pattern Recognition Receptors ◽  
Innate Immune ◽  
Helicase Domain ◽  
Downstream Signaling ◽  
Adaptive Immune

Abstract The vertebrate immune system uses pattern recognition receptors (PRRs) to detect a large variety of molecular signatures (pathogen-associated molecular patterns, PAMPs) from a broad range of different invading pathogens. The PAMPs range in size from relatively small molecules, to others of intermediate size such as bacterial lipopolysaccharide, lipopeptides, and oligosaccharides, to macromolecules such as viral DNA, RNA, and pathogen-derived proteins such as flagellin. Underlying this functional diversity of PRRs is a surprisingly small number of structurally distinct protein folds that include leucine-rich repeats in Toll-like receptors (TLRs) and NOD-like receptors (NLRs), the DExH box helicase domain in RIG-like receptors (RLRs), and C-type lectin domains (CTLDs) in the C-type lectins. Following PAMP recognition by the PRRs, downstream signaling pathways activate the innate immune system to respond to invading pathogenic organisms. The resulting stimulatory response is also vital for a balanced adaptive immune response to the pathogen, mediated by circulating antibodies and/or cytotoxic T cells. However, an aberrant stimulation of the innate immune system can also lead to excessive inflammatory and toxic stress responses. Exciting opportunities are now arising for the design of small synthetic molecules that bind to PRRs and influence downstream signaling pathways. Such molecules can be useful tools to modulate immune responses, for example, as adjuvants to stimulate adaptive immune responses to a vaccine, or as therapeutic agents to dampen aberrant immune responses, such as inflammation. The design of agonists or antagonists of PRRs can now benefit from a surge in knowledge of the 3D structures of PRRs, many in complexes with their natural ligands. This review article describes recent progress in structural studies of PRRs (TLRs, NLRs, CTLs, and RLRs), which is required for an understanding of how they specifically recognize structurally diverse “foreign” PAMPs amongst a background of other “self” molecules, sometimes closely related in structure, that are present in the human body.

scholarly journals Role of α7 nicotinic receptor in the immune system and intracellular signaling pathways

2015 ◽  
Vol 3 ◽  
pp. 373-379 ◽  
Author(s):  
Robert Zdanowski ◽  
Małgorzata Krzyżowska ◽  
Dominika Ujazdowska ◽  
Aneta Lewicka ◽  
Sławomir Lewicki
Keyword(s):  
Immune System ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Nicotinic Receptor ◽  
Intracellular Signaling Pathways

scholarly journals Helicobacter pylori-Mediated Immunity and Signaling Transduction in Gastric Cancer

2020 ◽  
Vol 9 (11) ◽  
pp. 3699
Author(s):  
Nozomi Ito ◽  
Hironori Tsujimoto ◽  
Hideki Ueno ◽  
Qian Xie ◽  
Nariyoshi Shinomiya
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Intracellular Signaling ◽  
Cellular Proliferation ◽  
Gastric Cancer Cells ◽  
Downstream Signaling ◽  
H Pylori

Helicobacter pylori infection is a leading cause of gastric cancer, which is the second-most common cancer-related death in the world. The chronic inflammatory environment in the gastric mucosal epithelia during H. pylori infection stimulates intracellular signaling pathways, namely inflammatory signals, which may lead to the promotion and progression of cancer cells. We herein report two important signal transduction pathways, the LPS-TLR4 and CagA-MET pathways. Upon H. pylori stimulation, lipopolysaccharide (LPS) binds to toll-like receptor 4 (TLR4) mainly on macrophages and gastric epithelial cells. This induces an inflammatory response in the gastric epithelia to upregulate transcription factors, such as NF-κB, AP-1, and IRFs, all of which contribute to the initiation and progression of gastric cancer cells. Compared with other bacterial LPSs, H. pylori LPS has a unique function of inhibiting the mononuclear cell (MNC)-based production of IL-12 and IFN-γ. While this mechanism reduces the degree of inflammatory reaction of immune cells, it also promotes the survival of gastric cancer cells. The HGF/SF-MET signaling plays a major role in promoting cellular proliferation, motility, migration, survival, and angiogenesis, all of which are essential factors for cancer progression. H. pylori infection may facilitate MET downstream signaling in gastric cancer cells through its CagA protein via phosphorylation-dependent and/or phosphorylation-independent pathways. Other signaling pathways involved in H. pylori infection include EGFR, FAK, and Wnt/β-Catenin. These pathways function in the inflammatory process of gastric epithelial mucosa, as well as the progression of gastric cancer cells. Thus, H. pylori infection-mediated chronic inflammation plays an important role in the development and progression of gastric cancer.

Changes in Osmolality Sensitize the Response to Capsaicin in Trigeminal Sensory Neurons

2007 ◽  
Vol 97 (3) ◽  
pp. 2001-2015 ◽  
Author(s):  
Lieju Liu ◽  
Lei Chen ◽  
Wolfgang Liedtke ◽  
S. A. Simon
Keyword(s):  
Nervous System ◽  
Signaling Pathways ◽  
Sensory Neurons ◽  
Calcium Imaging ◽  
Intracellular Signaling ◽  
Trpv1 Receptor ◽  
Downstream Signaling ◽  
Intracellular Signaling Pathways ◽  
Inflammatory Conditions ◽  
Whole Cell Patch Clamp

Changes in tonicity in the peripheral nervous system can activate nociceptors and produce pain. Under local inflammatory conditions the peripheral terminals of nociceptors are subject to deviations from isotonicity. Previously it was shown that several members of the TRP(V) family of ion channels are responsive to changes in tonicity. Here we explore how changes in tonicity affect TRPV1 receptor-mediated responses to capsaicin in dissociated rat trigeminal ganglion (TG) neurons. Using whole cell patch-clamp and calcium imaging, we found that mild anisotonicity (260 and 348 mOsm/kg for hypotonicity and hypertonicity, respectively) strikingly sensitized the capsaicin-evoked current, Icaps. Confocal immunolocalization studies also revealed a modest anisotonicity-mediated redistribution of TRPV1 toward the plasma membrane of TG neurons. With respect to downstream signaling pathways, tonicity-induced sensitization of Icaps was dependent on whether hypo- or hypertonic stimuli were applied. Specifically, antagonism of PKA- and PI3K-activated pathways appreciably reduced the hypertonicity-induced sensitization of Icaps, whereas inhibition of PKC-mediated pathways selectively reduced the sensitization produced by hypotonic solutions. In summary, whereas the overall effects of hypo- and hypertonicity resulted in a similar pattern of potentiation of Icaps, intracellular signaling pathways were selective for hypo- versus hypertonicity-induced tuning of capsaicin-activated currents.

scholarly journals Signaling pathways of heat- and hypersalinity-induced polyp bailout in Pocillopora acuta

Coral Reefs ◽  
2021 ◽  
Author(s):  
Fabian Gösser ◽  
Arne Raulf ◽  
Axel Mosig ◽  
Ralph Tollrian ◽  
Maximilian Schweinsberg
Keyword(s):  
Gene Expression ◽  
Heat Stress ◽  
Immune System ◽  
Signaling Pathways ◽  
Acute Stress ◽  
Qpcr Assay ◽  
Growth Factor Signaling ◽  
Downstream Signaling ◽  
Genes Encoding ◽  
General Response

AbstractPolyp bailout is a drastic response to acute stress where coral coloniality breaks down and polyps detach. We induced polyp bailout in Pocillopora acuta with heat stress and tested for differential gene expression using RNAseq and a qPCR assay. Furthermore, we induced polyp bailout with hypersalinity and compared the results to identify stressor-independent signals and pathways active during polyp bailout. Both stressors led to the onset of polyp bailout and the detachment of vital polyps. We observed activation of microbe-associated molecular pattern receptors and downstream signaling pathways of the innate immune system. Further, we detected growth factors and genes active during Wnt-signaling potentially contributing to wound healing, regeneration, and proliferation. Upregulation of several genes encoding for matrix metalloproteinases and the fibroblast growth factor signaling pathway are the most likely involved in the remodeling of the extracellular matrix, as well as in the detachment of polyps from the calcareous skeleton during polyp bailout. Expression of genes of interest in our qPCR assay of vital polyps from our heat-stress experiment, showed a trend for a normalization of gene expression after polyp bailout. Our results provide new insights into the signaling cascades leading to the observed physiological responses during polyp bailout. Comparison between the two stressors showed that certain signaling pathways are independent of the stressor and suggested that polyp bailout is a general response of corals to acute stress. Furthermore, immune system responses during polyp bailout indicate that microbe-associated partners of corals may lead to the polyp bailout response.

scholarly journals The Role of Mitochondria in Immune-Cell-Mediated Tissue Regeneration and Ageing

2021 ◽  
Vol 22 (5) ◽  
pp. 2668
Author(s):  
Yu-Jih Su ◽  
Pei-Wen Wang ◽  
Shao-Wen Weng
Keyword(s):  
Mitochondrial Dna ◽  
Immune System ◽  
Tissue Regeneration ◽  
Intracellular Signaling ◽  
Immune Cell ◽  
Tissue Injury ◽  
Energy Requirement ◽  
Human Mesenchymal Stem Cells ◽  
Adaptive Immune System

During tissue injury events, the innate immune system responds immediately to alarms sent from the injured cells, and the adaptive immune system subsequently joins in the inflammatory reaction. The control mechanism of each immune reaction relies on the orchestration of different types of T cells and the activators, antigen-presenting cells, co-stimulatory molecules, and cytokines. Mitochondria are an intracellular signaling organelle and energy plant, which supply the energy requirement of the immune system and maintain the system activation with the production of reactive oxygen species (ROS). Extracellular mitochondria can elicit regenerative effects or serve as an activator of the immune cells to eliminate the damaged cells. Recent clarification of the cytosolic escape of mitochondrial DNA triggering innate immunity underscores the pivotal role of mitochondria in inflammation-related diseases. Human mesenchymal stem cells could transfer mitochondria through nanotubular structures to defective mitochondrial DNA cells. In recent years, mitochondrial therapy has shown promise in treating heart ischemic events, Parkinson’s disease, and fulminating hepatitis. Taken together, these results emphasize the emerging role of mitochondria in immune-cell-mediated tissue regeneration and ageing.

Improving the therapeutic window of conventional opioids: novel differential signaling modulators

2019 ◽  
Vol 44 (1) ◽  
pp. 32-37 ◽  
Author(s):  
Eugene R Viscusi
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Unmet Need ◽  
Therapeutic Window ◽  
Primary Concern ◽  
Receptor Ligands ◽  
Downstream Signaling ◽  
Differential Signaling ◽  
Postoperative Setting ◽  
Clinical Potential

Conventional opioids are widely used for acute pain management in the postoperative setting. However, a primary concern with conventional opioids is their therapeutic window—the range between doses that produce the desired therapeutic effect (analgesia) and doses that produce unwanted opioid-related adverse events (ORAEs). Conventional µ receptor opioids have a narrow therapeutic window in part because of their mechanism of action (MoA): they bind to µ receptors and non-selectively activate two intracellular signaling pathways, leading to analgesia and to ORAEs. This review explores the clinical potential of µ receptor ligands with differential signaling. Agents with a ‘differential signaling” MoA represent an innovative approach that may enhance the therapeutic window. These agents modulate µ receptor activity to selectively engage downstream signaling pathways associated with analgesia while limiting activity in downstream signaling pathways that lead to ORAEs. Differential signaling may fulfill an unmet need in the management of postoperative pain.

scholarly journals EGFR-dependent tyrosine phosphorylation of integrin β4 is not required for downstream signaling events in cancer cell lines

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lisa te Molder ◽  
Maaike Kreft ◽  
Niels Heemskerk ◽  
Joyce Schuring ◽  
Jose M. de Pereda ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Signaling Pathways ◽  
Tyrosine Phosphorylation ◽  
Intracellular Signaling ◽  
Growth Factor Receptor ◽  
Carcinoma Cells ◽  
Integrin Subunit ◽  
A431 Cells ◽  
Promote Cell Proliferation ◽  
Downstream Signaling

AbstractIn epithelial cancers, the epidermal growth factor receptor (EGFR) and integrin α6β4 are frequently overexpressed and found to synergistically activate intracellular signaling pathways that promote cell proliferation and migration. In cancer cells, the β4 subunit is phosphorylated at tyrosine residues not normally recognized as kinase substrates; however, the function of these phosphotyrosine residues in cancer cells is a subject of much debate. In EGFR-overexpressing carcinoma cells, we found that the Src family kinase (SFK) inhibitor PP2 reduces β4 tyrosine phosphorylation following the activation of EGFR. However, siRNA mediated knockdown of the SFKs Src, Fyn, Yes and Lyn, individually or in combination, did not affect the EGF-induced phosphorylation of β4. Using phospho-peptide affinity chromatography and mass spectrometry, we found that PLCγ1 binds β4 at the phosphorylated residues Y1422/Y1440, but were unable to verify this interaction in A431 carcinoma cells that overexpress the EGFR. Furthermore, using A431 cells devoid of β4 or reconstituted with phenylalanine specific mutants of β4, the activation of several downstream signaling pathways, including PLCγ/PKC, MAPK and PI3K/Akt, were not substantially affected. We conclude that tyrosine-phosphorylated β4 does not enhance EGFR-mediated signaling in EGFR-overexpressing cells, despite the fact that this integrin subunit is highly tyrosine phosphorylated in these cells.

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