TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation.
Ontology highlight
ABSTRACT:
SUBMITTER: Magno L
PROVIDER: S-EPMC8022522 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Phospholipase C-gamma 2 (PLCγ2) is highly expressed in hematopoietic and immune cells, where it is a key signalling node enabling diverse cellular functions. Within the periphery, gain-of-function (GOF) PLCγ2 variants, such as the strongly hypermorphic S707Y, cause severe immune dysregulation. The milder hypermorphic mutation PLCγ2 P522R increases longevity and confers protection in central nervous system (CNS) neurodegenerative disorders, implicating PLCγ2 as a novel therapeutic target for treating these CNS indications. Currently, nothing is known about what consequences strong PLCγ2 GOF has on CNS functionality, and more precisely on the specific biological functions of microglia. Using the PLCγ2 S707Y variant as a model of chronic activation we investigated the functional consequences of strong PLCγ2 GOF on human microglia. PLCγ2 S707Y expressing human inducible pluripotent stem cells (hiPSC)-derived microglia exhibited hypermorphic enzymatic activity under both basal and stimulated conditions, compared to PLCγ2 wild type. Despite the increase in PLCγ2 enzymatic activity, the PLCγ2 S707Y hiPSC-derived microglia display diminished functionality for key microglial processes including phagocytosis and cytokine secretion upon inflammatory challenge. RNA sequencing revealed a downregulation of genes related to innate immunity and response, providing molecular support for the phenotype observed. Our data suggests that chronic activation of PLCγ2 elicits a detrimental phenotype that is contributing to unfavourable CNS functions, and informs on the therapeutic window for targeting PLCγ2 in the CNS. Drug candidates targeting PLCγ2 will need to precisely mimic the effects of the PLCγ2 P522R variant on microglial function, but not those of the PLCγ2 S707Y variant.
2023-12-06 | GSE227513 | GEO
Project description:Human genetic studies have linked rare coding variants in microglial genes, such as TREM2, and more recently PLCG2 to Alzheimer's disease (AD) pathology. The P522R variant in PLCG2 has been shown to confer protection for AD and to result in a subtle increase in enzymatic activity. PLCγ2 is a key component of intracellular signal transduction networks and induces Ca2+ signals downstream of many myeloid cell surface receptors, including TREM2. To explore the relationship between PLCγ2 and TREM2 and the role of PLCγ2 in regulating immune cell function, we generated human induced pluripotent stem cell (iPSC)- derived macrophages from isogenic lines with homozygous PLCG2 knockout (Ko). Stimulating TREM2 signalling using a polyclonal antibody revealed a complete lack of calcium flux and IP1 accumulation in PLCγ2 Ko cells, demonstrating a non-redundant role of PLCγ2 in calcium release downstream of TREM2. Loss of PLCγ2 led to broad changes in expression of several macrophage surface markers and phenotype, including reduced phagocytic activity and survival, while LPS-induced secretion of the inflammatory cytokines TNFα and IL-6 was unaffected. We identified additional deficits in PLCγ2- deficient cells that compromised cellular adhesion and migration. Thus, PLCγ2 is key in enabling divergent cellular functions and might be a promising target to increase beneficial microglial functions.
| S-EPMC8494732 | biostudies-literature
Project description:TRPV5 (transient receptor potential vanilloid 5) is a unique calcium-selective TRP channel essential for calcium homeostasis. Unlike other TRPV channels, TRPV5 and its close homolog, TRPV6, do not exhibit thermosensitivity or ligand-dependent activation but are constitutively open at physiological membrane potentials and modulated by calmodulin (CaM) in a calcium-dependent manner. Here we report high-resolution electron cryomicroscopy structures of truncated and full-length TRPV5 in lipid nanodiscs, as well as of a TRPV5 W583A mutant and TRPV5 in complex with CaM. These structures highlight the mechanism of calcium regulation and reveal a flexible stoichiometry of CaM binding to TRPV5.
| S-EPMC6500171 | biostudies-literature
Project description:Stroke is the second leading cause of death worldwide and a leading cause of disability. Most strokes are caused by occlusion of a major cerebral artery, and substantial advances have been made in elucidating how ischemia damages the brain. In particular, increasing evidence points to a double-edged role of the immune system in stroke pathophysiology. In the acute phase, innate immune cells invade brain and meninges and contribute to ischemic damage, but may also be protective. At the same time, danger signals released into the circulation by damaged brain cells lead to activation of systemic immunity, followed by profound immunodepression that promotes life-threatening infections. In the chronic phase, antigen presentation initiates an adaptive immune response targeted to the brain, which may underlie neuropsychiatric sequelae, a considerable cause of poststroke morbidity. Here, we briefly review these pathogenic processes and assess the potential therapeutic value of targeting immunity in human stroke.
| S-EPMC7260029 | biostudies-literature
Project description:We discuss here some of the key immunological elements that are at the crossroads and need to be combined to develop a potent therapeutic HIV-1 vaccine. Therapeutic vaccines have been commonly used to enhance and/or recall pre-existing HIV-1-specific cell-mediated immune responses aiming to suppress virus replication. The current success of immune checkpoint blockers in cancer therapy renders them very attractive to use in HIV-1 infected individuals with the objective to preserve the function of HIV-1-specific T cells from exhaustion and presumably target the persistent cellular reservoir. The major latest advances in our understanding of the mechanisms responsible for virus reactivation during therapy-suppressed individuals provide the scientific basis for future combinatorial therapeutic vaccine development.
| S-EPMC7565497 | biostudies-literature
Project description:Allosteric modulation of G protein-coupled receptors (GPCRs) represents a novel approach to the development of probes and therapeutics that is expected to enable subtype-specific regulation of central nervous system target receptors. The metabotropic glutamate receptors (mGlus) are class C GPCRs that play important neuromodulatory roles throughout the brain, as such they are attractive targets for therapeutic intervention for a number of psychiatric and neurological disorders including anxiety, depression, Fragile X Syndrome, Parkinson's disease and schizophrenia. Over the last fifteen years, selective allosteric modulators have been identified for many members of the mGlu family. The vast majority of these allosteric modulators are thought to bind within the transmembrane-spanning domains of the receptors to enhance or inhibit functional responses. A combination of mutagenesis-based studies and pharmacological approaches are beginning to provide a better understanding of mGlu allosteric sites. Collectively, when mapped onto a homology model of the different mGlu subtypes based on the ?(2)-adrenergic receptor, the previous mutagenesis studies suggest commonalities in the location of allosteric sites across different members of the mGlu family. In addition, there is evidence for multiple allosteric binding pockets within the transmembrane region that can interact to modulate one another. In the absence of a class C GPCR crystal structure, this approach has shown promise with respect to the interpretation of mutagenesis data and understanding structure-activity relationships of allosteric modulator pharmacophores.
| S-EPMC2981682 | biostudies-literature
Project description:Vitamin D is widely reported to inhibit innate immune signalling and dendritic cell (DC) maturation, leading to attenuation of DC mediated T cell activation as a potential immunoregulatory mechanism to guard against autoimmunity and immmunopathology. It is not known whether vitamin D has global or gene specific effects on transcriptional responses downstream of innate immune stimulation. In order to address this question, we used genome-wide transcriptional profiling of monocyte derived DC differentiated in the presence and absence of vitamin D, and then stimulated with and without lipopolysaccharide for four hours.
2016-10-03 | E-MTAB-4883 | biostudies-arrayexpress
Project description:Autophagy is a multistep catabolic process through which misfolded, aggregated or mutated proteins and damaged organelles are internalized in membrane vesicles called autophagosomes and ultimately fused to lysosomes for degradation of sequestered components. The multistep nature of the process offers multiple regulation points prone to be deregulated and cause different human diseases but also offers multiple targetable points for designing therapeutic strategies. Cancer cells have evolved to use autophagy as an adaptive mechanism to survive under extremely stressful conditions within the tumor microenvironment, but also to increase invasiveness and resistance to anticancer drugs such as chemotherapy. This review collects clinical evidence of autophagy deregulation during cholangiocarcinogenesis together with preclinical reports evaluating compounds that modulate autophagy to induce cholangiocarcinoma (CCA) cell death. Altogether, experimental data suggest an impairment of autophagy during initial steps of CCA development and increased expression of autophagy markers on established tumors and in invasive phenotypes. Preclinical efficacy of autophagy modulators promoting CCA cell death, reducing invasiveness capacity and resensitizing CCA cells to chemotherapy open novel therapeutic avenues to design more specific and efficient strategies to treat this aggressive cancer.
| S-EPMC7140412 | biostudies-literature
Project description:Inflammatory monocyte-derived effector cells play an important role in the pathogenesis of numerous inflammatory diseases. However, no treatment option exists that is capable of modulating these cells specifically. We show that infused negatively charged, immune-modifying microparticles (IMPs), derived from polystyrene, microdiamonds, or biodegradable poly(lactic-co-glycolic) acid, were taken up by inflammatory monocytes, in an opsonin-independent fashion, via the macrophage receptor with collagenous structure (MARCO). Subsequently, these monocytes no longer trafficked to sites of inflammation; rather, IMP infusion caused their sequestration in the spleen through apoptotic cell clearance mechanisms and, ultimately, caspase-3-mediated apoptosis. Administration of IMPs in mouse models of myocardial infarction, experimental autoimmune encephalomyelitis, dextran sodium sulfate-induced colitis, thioglycollate-induced peritonitis, and lethal flavivirus encephalitis markedly reduced monocyte accumulation at inflammatory foci, reduced disease symptoms, and promoted tissue repair. Together, these data highlight the intricate interplay between scavenger receptors, the spleen, and inflammatory monocyte function and support the translation of IMPs for therapeutic use in diseases caused or potentiated by inflammatory monocytes.
| S-EPMC3973033 | biostudies-literature
Project description:BACKGROUND:Inflammation is a prominent feature of arrhythmogenic cardiomyopathy (ACM), but whether it contributes to the disease phenotype is not known. METHODS:To define the role of inflammation in the pathogenesis of ACM, we characterized nuclear factor-?B signaling in ACM models in vitro and in vivo and in cardiac myocytes from patient induced pluripotent stem cells. RESULTS:Activation of nuclear factor-?B signaling, indicated by increased expression and nuclear accumulation of phospho-RelA/p65, occurred in both an in vitro model of ACM (expression of JUP2157del2 in neonatal rat ventricular myocytes) and a robust murine model of ACM (homozygous knock-in of mutant desmoglein-2 [Dsg2mut/mut]) that recapitulates the cardiac manifestations seen in patients with ACM. Bay 11-7082, a small-molecule inhibitor of nuclear factor-?B signaling, prevented the development of ACM disease features in vitro (abnormal redistribution of intercalated disk proteins, myocyte apoptosis, release of inflammatory cytokines) and in vivo (myocardial necrosis and fibrosis, left ventricular contractile dysfunction, electrocardiographic abnormalities). Hearts of Dsg2mut/mut mice expressed markedly increased levels of inflammatory cytokines and chemotactic molecules that were attenuated by Bay 11-7082. Salutary effects of Bay 11-7082 correlated with the extent to which production of selected cytokines had been blocked. Nuclear factor-?B signaling was also activated in cardiac myocytes derived from a patient with ACM. These cells produced and secreted abundant inflammatory cytokines under basal conditions, and this was also greatly reduced by Bay 11-7082. CONCLUSIONS:Inflammatory signaling is activated in ACM and drives key features of the disease. Targeting inflammatory pathways may be an effective new mechanism-based therapy for ACM.
| S-EPMC6817418 | biostudies-literature