Family Of Intracellular Receptors Research Articles

NLRP3 Inflammasome Involvement in Heart, Liver, and Lung Diseases—A Lesson from Cytokine Storm Syndrome

Inflammation and inflammasomes have been proposed as important regulators of the host–microorganism interaction, playing a key role in morbidity and mortality due to the coronavirus disease 2019 (COVID-19) in subjects with chronic conditions and compromised immune system. The inflammasome consists of a multiprotein complex that finely regulates the activation of caspase-1 and the production and secretion of potent pro-inflammatory cytokines such as IL-1β and IL-18. The pyrin containing NOD (nucleotide-binding oligomerization domain) like receptor (NLRP) is a family of intracellular receptors, sensing patterns associated to pathogens or danger signals and NLRP3 inflammasome is the most deeply analyzed for its involvement in the innate and adaptive immune system as well as its contribution to several autoinflammatory and autoimmune diseases. It is highly expressed in leukocytes and up-regulated in sentinel cells upon inflammatory stimuli. NLRP3 expression has also been reported in B and T lymphocytes, in epithelial cells of oral and genital mucosa, in specific parenchymal cells as cardiomyocytes, and keratinocytes, and chondrocytes. It is well known that a dysregulated activation of the inflammasome is involved in the pathogenesis of different disorders that share the common red line of inflammation in their pathogenetic fingerprint. Here, we review the potential roles of the NLRP3 inflammasome in cardiovascular events, liver damage, pulmonary diseases, and in that wide range of systemic inflammatory syndromes named as a cytokine storm.

Multi-Omics Analysis of the Expression and Prognosis for FKBP Gene Family in Renal Cancer.

BackgroundThe FK506-binding protein (FKBP) is a family of intracellular receptors that can bind specifically to the immunosuppressant FK506 and rapamycin. Although FKBPs play crucial roles in biological processes and carcinogenesis, their prognostic value and molecular mechanism in clear cell renal cell carcinoma (ccRCC) remain unclear.MethodsUsing pan-cancer data from The Cancer Genome Atlas (TCGA) and public databases, we analyzed the expression and correlation of FKBPs in 33 tumor types. Survival and Cox regression analyses were employed to explore the prognostic value of FKBPs. The relationship with tumor microenvironment and stemness indices was taken into account to evaluate the function of FKBPs. We constructed a risk score model to predict the prognosis of patients with ccRCC. The receiver operating characteristic (ROC) curve was performed to further test the prognostic ability of our model. Nomogram, joint effects analysis, and clinical relevance were performed to assist the clinician. Gene set enrichment analysis (GSEA) and cell line experiments were performed to investigate the function and molecular mechanisms of FKBPs in patients with ccRCC. Paired clinical specimens and multi-omics analysis were used to further validate and explore the factors affecting gene expression in ccRCC patients.ResultsThe expression levels of FKBP10 and FKBP11 were higher in ccRCC tissues than in normal tissues. The alteration in expression may be because of the degree of DNA methylation. Increased expression levels of FKBP10 and FKBP11 were associated with worse overall survival (OS). More importantly, GSEA revealed that FKBP10 is mainly involved in cell metabolism and autophagy, whereas FKBP11 is mainly associated with immune-related biological processes and autophagy. Cell Counting Kit 8 (CCK-8) and Transwell assays revealed that knockdown of FKBP10 and FKBP11 inhibits proliferation, migration, and invasion of the ccRCC cell line.ConclusionFKBP10 and FKBP11 play important roles in ccRCC phenotypes and are potential prognostic markers as well as new therapeutic targets for patients with ccRCC.

Co-opting the cell-cycle machinery for plant immunity.

Plant effector-triggered immunity is a robust cellular defense response activated by a family of intracellular receptors. In this issue of Cell Host & Microbe, Wang etal. (2014) show that receptor-activated defense pathways utilize several core cell-cycle regulatory components to induce resistance and programmed cell death against pathogens.

Varicella-Zoster Virus Infection Triggers Formation of an Interleukin-1β (IL-1β)-processing Inflammasome Complex

Innate cellular immunity is the immediate host response against pathogens, and activation of innate immunity also modulates the induction of adaptive immunity. The nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a family of intracellular receptors that recognize conserved patterns associated with intracellular pathogens, but information about their role in the host defense against DNA viruses is limited. Here we report that varicella-zoster virus (VZV), an alphaherpesvirus that is the causative agent of varicella and herpes zoster, induces formation of the NLRP3 inflammasome and the associated processing of the proinflammatory cytokine IL-1β by activated caspase-1 in infected cells. NLRP3 inflammasome formation was induced in VZV-infected human THP-1 cells, which are a transformed monocyte cell line, primary lung fibroblasts, and melanoma cells. Absent in melanoma gene-2 (AIM2) is an interferon-inducible protein that can form an alternative inflammasome complex with caspase-1 in virus-infected cells. Experiments in VZV-infected melanoma cells showed that NLRP3 protein recruits the adaptor protein ASC and caspase-1 to form an NLRP3 inflammasome complex independent of AIM2 protein and in the absence of free radical reactive oxygen species release. NLRP3 was also expressed extensively in infected skin xenografts in the severe combined immunodeficiency mouse model of VZV pathogenesis in vivo. We conclude that NLRP3 inflammasome formation is an innate cellular response to infection with this common pathogenic human herpesvirus.

NOD2 receptors in adenopituitary folliculostellate cells: expression and function

Folliculostellate cells (FS cells) are non-endocrine cells from the pituitary gland that respond to bacterial endotoxins by producing cytokines. In immune cells, an important component of bacterial recognition are the toll-like receptors (TLRs). Previously, we showed that FS cells express TLR4. The TLR4 ligand lipopolysaccharide (LPS) stimulates interleukin-6 (IL6) production through nuclear factor kappaB (NFKB) induction. Binding of IL6 to gp130 receptor activates signal transducer and activator of transcription 3 (STAT3), an important mediator of inflammatory response. Another family involved in innate immune response following bacterial infection is the nucleotide-binding oligomerisation domain (NOD) intracellular receptor family. Herein, we describe for the first time the expression and function of NOD receptors in human pituitary and FS TtT/GF cell line. The NOD2 agonist muramyl dipeptide (MDP) increased Nf kappa b1-transcriptional activity, -protein expression and IL6 secretion in TtT/GF cells. Furthermore, these effects were potentiated by the combination of MDP and LPS. Silencing NOD2 abolished the action of LPS on NFKB transcriptional activity and IL6 production, indicating that, in TtT/GF cells, TLR4 transduces its signal through NOD2 receptor. We show here that in TtT/GF cells, Nod2 overexpression or stimulation by MDP increased STAT3 transcriptional activity. Furthermore, silencing STAT3 inhibited basal, LPS and MDP stimulated NFKB protein expression and overexpression of protein inhibitor of activated STAT3 (Pias3) markedly decreased basal NFKB activity. These data suggest that in TtT/GF cells, STAT3 acting upstream to NFKB mediates NOD2 receptor signalling pathway. In conclusion, the present study demonstrates that NOD molecules play a modulatory role in the pituitary by regulating the function and activation of FS cells in response to bacterial components.

Drug discovery and the intracellular receptor family

Drug discovery using intracellular receptors (IRs) as targets presents its own set of unique complications and advantages. The natural ligands for these receptors are, in many cases, already used as drugs. To effectively exploit these targets, newer molecules must have either increased receptor selectivity or increased tissue or gene selectivity to reduce side effects. The search for these molecules will yield new therapeutics as well as new insights into the mechanism of action of these receptors and their ligands.