Drice restrains Diap2-mediated inflammatory signalling and intestinal inflammation.
Ontology highlight
ABSTRACT:
SUBMITTER: Kietz C
PROVIDER: S-EPMC8738736 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Balanced control of innate immune signaling in the intestine represents an important host defense mechanism to avoid inappropriate responses that may exacerbate mucosal injury in acute inflammation. In this study, we report that TRIM58, a RING E3-ubiquitin ligase, associates with TLR2. The interaction was found in a yeast two-hybrid screen (human leukocyte and mononuclear library) and confirmed by coimmunoprecipitation of tagged and endogenous proteins. TRIM58 was predominantly expressed by murine and human myeloid-derived cells. Stimulation with a TLR2 ligand modulated TRIM58 synthesis in myeloid cells. Overexpression of TRIM58, but only in presence of the RING domain, promoted proteasome-dependent degradation of TLR2, inhibiting its signaling activity. Genetic deletion of Trim58 in mice (Trim58 -/-) led to impaired resolution of acute dextran sodium sulfate-induced colitis, which was characterized by delayed recovery from colonic injury and associated with enhanced expression of TLR2 protein and proinflammatory cyto/chemokine production in inflamed colons. Using myeloid cell-specific deletion of Trim58 in mice, we demonstrated that the myeloid cell compartment was responsible for early colitis acceleration in Trim58 deficiency. In vitro studies revealed that Trim58 -/- myeloid cells, which showed constitutive upregulation of TLR2 protein, overreacted to a proinflammatory milieu (TNF-α and IFN-γ) with increased IL-1β protein production, which mechanistically depended on Tlr2 Finally, we found that TRIM58 mRNA and protein expression levels were reduced in colonic specimens from patients with ulcerative colitis. In conclusion, we identify TRIM58 as a novel negative mediator of innate immune control and mucosal homeostasis via TLR2 signaling. Dysfunction of TRIM58 in myeloid cells may contribute to ulcerative colitis pathogenesis.
| S-EPMC6731451 | biostudies-literature
Project description:Group 3 innate lymphoid cells (ILC3s), a subset of the innate lymphoid cells, are abundantly present in the intestine and are crucial regulators of intestinal inflammation. Brg1 (Brahma-related gene 1), a catalytic subunit of the mammalian SWI-SNF-like chromatin-remodeling BAF complex, regulates the development and function of various immune cells. Here, by genetic deletion of Brg1 in ILC3s (Smarca4ΔILC3), we prove that Brg1 supports the differentiation of NKp46+ILC3s by promoting the T-bet expression in NKp46-ILC3s, which facilitates the conversion of NKp46-ILC3s to NKp46+ILC3s. Strikingly, Smarca4ΔILC3 mice of the Rag1-/- background develop spontaneous colitis accompanied with increased GM-CSF production in ILC3s. By construction of a mixed bone marrow chimeric system, we demonstrate that Brg1 enhances T-bet and inhibits GM-CSF expression in ILC3s through a cell-intrinsic manner. Blockade of GM-CSF ameliorates colitis in Rag1-/-Smarca4ΔILC3 mice, suggesting that the suppression of GM-CSF production from ILC3s by Brg1 serves as a critical mechanism for Brg1 to restrain intestinal inflammation. We have further demonstrated that Brg1 binds to the Tbx21 and Csf2 gene locus in ILC3s, and favors the active and repressive histones modifications on gene locus of Tbx21 and Csf2 respectively. Our work reveals the essential role of Brg1 in intestinal immunity by regulating ILC3s.
| S-EPMC7790751 | biostudies-literature
Project description:The functional relevance and mechanistic basis of the effects of the pyroptosis executioner Gasdermin D (GSDMD) on colitis remain unclear. In this study, we observed that GSDMD protein was activated during intestinal inflammation in a model of chemically induced colitis. GSDMD deficiency exacerbated experimental colitis independent of changes in the microbiota and without affecting the production of antimicrobial peptides. GSDMD deficiency in macrophages, but not epithelial cells, was sufficient to drive this exacerbated experimental colitis. We further demonstrate that GSDMD functions in macrophages as a negative regulator to control cyclic GMP-AMP synthase (cGAS)-dependent inflammation, thereby protecting against colitis. Moreover, the administration of cGAS inhibitor can rescue the colitogenic phenotype in GSDMD-deficient mice. Collectively, these findings provide the first demonstration of GSDMD's role in controlling colitis and a detailed delineation of the underlying mechanism.
| S-EPMC7314554 | biostudies-literature
Project description:The transcriptional regulator STAT3 curbs pro-inflammatory cytokine production mediated by NF-κB signalling in innate immune cells, yet the mechanism by which this occurs has been unclear. Here we identify STAT3 as a pivotal negative regulator of Ubc13, an E2 ubiquitin-conjugating enzyme that facilitates TRAF6 K63-linked ubiquitination and NF-κB activation. Ubc13 accumulates intracellularly in the absence of STAT3. Depletion of Ubc13 in Stat3-deficient macrophages subdues excessive RANKL- or LPS-dependent gene expression, indicating that Ubc13 overexpression mediates enhanced transcriptional responses in the absence of STAT3. In RANKL-activated macrophages, STAT3 is stimulated by autocrine IL-6 and inhibits accrual of Ets-1, Set1 methyltransferase and trimethylation of histone H3 lysine 4 (H3K4me3) at the Ube2n (Ubc13) promoter. These results delineate a mechanism by which STAT3 operates as a transcriptional repressor on Ube2n, thus modulating NF-κB activity by regulation of Ubc13 abundance. Our data suggest that this pathway plays important roles in bone homeostasis and restraint of inflammation.
| S-EPMC4270087 | biostudies-literature
Project description:ObjectiveEosinophils reside in the colonic mucosa and increase significantly during disease. Although a number of studies have suggested that eosinophils contribute to the pathogenesis of GI inflammation, the expanding scope of eosinophil-mediated activities indicate that they also regulate local immune responses and modulate tissue inflammation. We sought to define the impact of eosinophils that respond to acute phases of colitis in mice.DesignAcute colitis was induced in mice by administration of dextran sulfate sodium, 2,4,6-trinitrobenzenesulfonic acid or oxazolone to C57BL/6J (control) or eosinophil deficient (PHIL) mice. Eosinophils were also depleted from mice using antibodies against interleukin (IL)-5 or by grafting bone marrow from PHIL mice into control mice. Colon tissues were collected and analysed by immunohistochemistry, flow cytometry and reverse transcription PCR; lipids were analysed by mass spectroscopy.ResultsEosinophil-deficient mice developed significantly more severe colitis, and their colon tissues contained a greater number of neutrophils, than controls. This compensatory increase in neutrophils was accompanied by increased levels of the chemokines CXCL1 and CXCL2, which attract neutrophils. Lipidomic analyses of colonic tissue from eosinophil-deficient mice identified a deficiency in the docosahexaenoic acid-derived anti-inflammatory mediator 10, 17- dihydroxydocosahexaenoic acid (diHDoHE), namely protectin D1 (PD1). Administration of an exogenous PD1-isomer (10S, 17S-DiHDoHE) reduced the severity of colitis in eosinophil-deficient mice. The PD1-isomer also attenuated neutrophil infiltration and reduced levels of tumour necrosis factor-α, IL-1β, IL-6 and inducible NO-synthase in colons of mice. Finally, in vitro assays identified a direct inhibitory effect of PD1-isomer on neutrophil transepithelial migration.ConclusionsEosinophils exert a protective effect in acute mouse colitis, via production of anti-inflammatory lipid mediators.
| S-EPMC4515997 | biostudies-literature
Project description:Background & aimsKPV is a tripeptide (Lys-Pro-Val), which possesses anti-inflammatory properties; however, its mechanisms of action still remain unknown. PepT1 is a di/tripeptide transporter normally expressed in the small intestine and induced in colon during inflammatory bowel disease (IBD). The aim of this study was to 1) investigate whether the KPV anti-inflammatory effect is PepT1-mediated in intestinal epithelian and immune cells, and 2) examine the anti-inflammatory effects in two models of mice colitis.MethodsHuman intestinal epithelial cells Caco2-BBE, HT29-Cl.19A, and human T cells (Jurkat) were stimulated with pro-inflammatory cytokines in the present or absence of KPV. KPV anti-inflammatory effect was assessed using a NF-kappaB luciferase gene reporter, Western blot, real-time RT-PCR and ELISA. Uptake experiments were performed using cold KPV as a competitor for PepT1 radiolabelled substrate or using [(3)H]KPV to determine kinetic characteristics of KPV uptake. Anti-inflammatory effect of KPV was also investigated in DSS- and TNBS-induced colitis in mice. KPV was added to drinking water and inflammation was assessed at the histologic level and by proinflammatory cytokine mRNA expression.ResultsNanomolar concentrations of KPV inhibit the activation of NF-kappaB and MAP kinase inflammatory signaling pathways, and reduce pro-inflammatory cytokine secretion. We found that KPV acts via PepT1 expressed in immune and intestinal epithelial cells. Furthermore, oral administration of KPV reduces the incidence of DSS- and TNBS-induced colitis indicated by a decrease in pro-inflammatory cytokine expression.ConclusionsThis study indicates tht KPV is transported into cells by PepT1 and might be a new therapeutic agent for IBD.
| S-EPMC2431115 | biostudies-literature
Project description:Aims: Mitochondrial stress and dysfunction within the intestinal epithelium are known to contribute to the pathogenesis of inflammatory bowel disease (IBD). However, the importance of mitophagy during intestinal inflammation remains poorly understood. The primary aim of this study was to investigate how the mitophagy protein BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L/NIX) mitigates mitochondrial damage during intestinal inflammation in the hopes that these data will allow us to target mitochondrial health in the intestinal epithelium as an adjunct to immune-based treatment strategies. Results: In the intestinal epithelium of patients with ulcerative colitis, we found that NIX was upregulated and targeted to the mitochondria. We obtained similar findings in wild-type mice undergoing experimental colitis. An increase in NIX expression was found to depend on stabilization of hypoxia-inducible factor-1 alpha (HIF1α), which binds to the Nix promoter region. Using the reactive oxygen species (ROS) scavenger MitoTEMPO, we were able to attenuate disease and inhibit both HIF1α stabilization and subsequent NIX expression, suggesting that mitochondrially derived ROS are crucial to initiating the mitophagic response during intestinal inflammation. We subjected a global Nix-/- mouse to dextran sodium sulfate colitis and found that these mice developed worse disease. In addition, Nix-/- mice were found to exhibit increased mitochondrial mass, likely due to the inability to clear damaged or dysfunctional mitochondria. Innovation: These results demonstrate the importance of mitophagy within the intestinal epithelium during IBD pathogenesis. Conclusion: NIX-mediated mitophagy is required to maintain intestinal homeostasis during inflammation, highlighting the impact of mitochondrial damage on IBD progression.
| S-EPMC7262642 | biostudies-literature
Project description:Macrophages are strategically distributed in mammalian tissues and play an essential role in priming immune response. However, macrophages need to constantly strike a balance between activation and inhibition state to avoid a futile inflammatory reaction. Herein, we identify the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as a potent repressor of macrophage pro-inflammatory activation. Gain- and loss-of-function studies revealed that CITED2 is required for optimal peroxisome proliferator-activated receptor gamma (PPAR?) activation and attendant select anti-inflammatory gene expression in macrophages. More importantly, deficiency of CITED2 resulted in significant attenuation in rosiglitazone-induced PPAR? activity, PPAR? recruitment to target gene promoters and anti-inflammatory target gene expression in macrophages. Interestingly, deficiency of Cited2 strikingly heightened pro-inflammatory gene expression through stabilization of hypoxia-inducible factor 1 alpha (HIF1?) protein in macrophages. Further, overexpression of Egln3 or inhibition of HIF1? in Cited2-deficient macrophages completely reversed elevated pro-inflammatory cytokine/chemokine gene expression. Importantly, mice bearing a myeloid-specific deletion of Cited2 were highly susceptible to endotoxin-induced sepsis symptomatology and mortality. Collectively, our observations identify CITED2 as a novel negative regulator of macrophage pro-inflammatory activation and protect the host from inflammatory insults.
| S-EPMC5809687 | biostudies-other
Project description:Inflammatory bone resorption mediated by osteoclasts is a major cause of morbidity and disability in many inflammatory disorders, including rheumatoid arthritis (RA). The mechanisms that regulate osteoclastogenesis and bone resorption in inflammatory settings are complex and have not been well elucidated. In this study, we identify the immunoregulator differentially expressed in FDCP 6 homolog (Def6) as a novel inhibitor of osteoclastogenesis in physiological and inflammatory conditions. Def6 deficiency in Def6-/- mice enhanced the sensitivity of osteoclast precursors to the physiological osteoclastogenic inducer receptor activator for NF-κB ligand, and Def6-/- osteoclasts formed actin rings. Furthermore, Def6 deficiency markedly increased TNF-α-induced osteoclastogenesis in vitro and in vivo and enhanced bone resorption in an inflammatory osteolysis mouse model. TNF-α serum levels correlated negatively with Def6 expression levels in osteoclast precursors obtained from RA patients, and the osteoclastogenic capacity of the osteoclast precursors was significantly inversely correlated with their Def6 expression levels, indicating that Def6 functions as an inhibitor of excessive osteoclast formation and bone destruction in RA. Mechanistically, Def6 suppressed osteoclastogenesis and the expression of key osteoclastogenic factors NFATc1, B lymphocyte-induced maturation protein-1, and c-Fos by regulating an endogenous IFN-β-mediated autocrine feedback loop. The Def6-dependent pathway may represent a novel therapeutic target to prevent pathological bone destruction.
| S-EPMC5425156 | biostudies-literature
Project description:ErbB-2/HER2 is an oncogenic tyrosine kinase that regulates a signalling network by forming ligand-induced heterodimers with several growth factor receptors of the ErbB family. Hsp90 and co-chaperones regulate degradation of ErbB-2 but not other ErbB members. Here, we report that the role of Hsp90 in modulating the ErbB network extends beyond regulation of protein stability. The capacity of ErbB-2 to recruit ligand-bound receptors into active heterodimers is limited by Hsp90, which is dissociated from ErbB-2 following ligand-induced heterodimerization. We show that Hsp90 binds a specific loop within the kinase domain of ErbB-2, thereby restraining heterodimer formation and catalytic function. These results define a role for Hsp90 as a molecular switch regulating the ErbB signalling network by limiting formation of ErbB-2-centred receptor complexes.
| S-EPMC1299195 | biostudies-literature