Microglia promote autoimmune inflammation via the noncanonical NF-κB pathway.
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ABSTRACT:
SUBMITTER: Jie Z
PROVIDER: S-EPMC8442891 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:NF-κB signaling is a central pathway of immunity and integrates signal transduction upon a wide array of inflammatory stimuli. Noncanonical NF-κB signaling is activated by a small subset of TNF family receptors and characterized by NF-κB2/p52 transcriptional activity. The medical relevance of this pathway has recently re-emerged from the discovery of primary immunodeficiency patients that have loss-of-function mutations in the MAP3K14 gene encoding NIK. Nevertheless, knowledge of protein interactions that regulate noncanonical NF-κB signaling is sparse. Here we report a detailed state-of-the-art mass spectrometry-based protein-protein interaction network including the noncanonical NF-κB signaling nodes TRAF2, TRAF3, IKKα, NIK, and NF-κB2/p100. The value of the data set was confirmed by the identification of interactions already known to regulate this pathway. In addition, a remarkable number of novel interactors were identified. We provide validation of the novel NIK and IKKα interactor FKBP8, which may regulate processes downstream of noncanonical NF-κB signaling. To understand perturbed noncanonical NF-κB signaling in the context of misregulated NIK in disease, we also provide a differential interactome of NIK mutants that cause immunodeficiency. Altogether, this data set not only provides critical insight into how protein-protein interactions can regulate immune signaling but also offers a novel resource on noncanonical NF-κB signaling.
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Project description:NOTCH-dependent signaling pathways are critical for normal bone remodeling; however, it is unclear if dysfunctional NOTCH activation contributes to inflammation-mediated bone loss, as observed in rheumatoid arthritis (RA) patients. We performed RNA sequencing and pathway analyses in mesenchymal stem cells (MSCs) isolated from transgenic TNF-expressing mice, a model of RA, to identify pathways responsible for decreased osteoblast differentiation. 53 pathways were dysregulated in MSCs from RA mice, among which expression of genes encoding NOTCH pathway members and members of the noncanonical NF-κB pathway were markedly elevated. Administration of NOTCH inhibitors to RA mice prevented bone loss and osteoblast inhibition, and CFU-fibroblasts from RA mice treated with NOTCH inhibitors formed more new bone in recipient mice with tibial defects. Overexpression of the noncanonical NF-κB subunit p52 and RELB in a murine pluripotent stem cell line increased NOTCH intracellular domain-dependent (NICD-dependent) activation of an RBPjκ reporter and levels of the transcription factor HES1. TNF promoted p52/RELB binding to NICD, which enhanced binding at the RBPjκ site within the Hes1 promoter. Furthermore, MSC-enriched cells from RA patients exhibited elevated levels of HES1, p52, and RELB. Together, these data indicate that persistent NOTCH activation in MSCs contributes to decreased osteoblast differentiation associated with RA and suggest that NOTCH inhibitors could prevent inflammation-mediated bone loss.
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Project description:Uveitis, a vision-threatening inflammatory disease worldwide, is closely related to resident microglia. Retinal microglia are the main immune effector cells with strong plasticity, but their role in uveitis remains unclear. N6-methyladenosine (m6A) modification has been proven to be involved in the immune response. Therefore, we in this work aimed to identify the potentially crucial m6A regulators of microglia in uveitis. Through the single-cell sequencing (scRNA-seq) analysis and experimental verification, we found a significant decrease in the expression of fat mass and obesity-associated protein (FTO) in retinal microglia of uveitis mice and human microglia clone 3 (HMC3) cells with inflammation. Additionally, FTO knockdown was found to aggravate the secretion of inflammatory factors and the mobility/chemotaxis of microglia. Mechanistically, the RNA-seq data and rescue experiments showed that glypican 4 (GPC4) was the target of FTO, which regulated microglial inflammation mediated by the TLR4/NF-κB pathway. Moreover, RNA stability assays indicated that GPC4 upregulation was mainly regulated by the downregulation of the m6A "reader" YTH domain family protein 3 (YTHDF3). Finally, the FTO inhibitor FB23-2 further exacerbated experimental autoimmune uveitis (EAU) inflammation by promoting the GPC4/TLR4/NF-κB signaling axis, and this could be attenuated by the TLR4 inhibitor TAK-242. Collectively, a decreased FTO could facilitate microglial inflammation in EAU, suggesting that the restoration or activation of FTO function may be a potential therapeutic strategy for uveitis.
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Project description:Multiple human polyomaviruses (HPyV) can infect the skin, but only Merkel cell polyomavirus (MCPyV) has been implicated in the development of a cancer, Merkel cell carcinoma (MCC). While expression of HPyV6, HPyV7, and MCPyV small T antigens (sT), all induced a senescence-associated secretory phenotype (SASP), MCPyV sT uniquely activated noncanonical NF-κB (ncNF-κB), instead of canonical NF-κB signaling, to evade p53-mediated cellular senescence. Through its large T stabilization domain, MCPyV sT activated ncNF-κB signaling both by inducing H3K4 trimethylation-mediated increases of NFKB2 and RELB transcription and also by promoting NFKB2 stabilization and activation through FBXW7 inhibition. Noncanonical NF-κB signaling was required for SASP cytokine secretion, which promoted the proliferation of MCPyV sT-expressing cells through autocrine signaling. Virus-positive MCC cell lines and tumors showed ncNF-κB pathway activation and SASP gene expression, and the inhibition of ncNF-κB signaling prevented VP-MCC cell growth in vitro and in xenografts. We identify MCPyV sT-induced ncNF-κB signaling as an essential tumorigenic pathway in MCC. IMPLICATIONS: This work is the first to identify the activation of ncNF-κB signaling by any polyomavirus and its critical role in MCC tumorigenesis.
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Project description:Brain inflammation generally accompanies and accelerates neurodegeneration. Here we report a microglial mechanism in which polyglutamine binding protein 1 (PQBP1) senses extrinsic tau 3R/4R proteins by direct interaction and triggers an innate immune response by activating a cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) pathway. Tamoxifen-inducible and microglia-specific depletion of PQBP1 in primary culture in vitro and mouse brain in vivo shows that PQBP1 is essential for sensing-tau to induce nuclear translocation of nuclear factor κB (NFκB), NFκB-dependent transcription of inflammation genes, brain inflammation in vivo, and eventually mouse cognitive impairment. Collectively, PQBP1 is an intracellular receptor in the cGAS-STING pathway not only for cDNA of human immunodeficiency virus (HIV) but also for the transmissible neurodegenerative disease protein tau. This study characterises a mechanism of brain inflammation that is common to virus infection and neurodegenerative disorders.
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Project description:Stiffening of large arteries is increasingly used as an independent predictor of risk and therapeutic outcome for small artery dysfunction in many diseases including pulmonary hypertension. The molecular mechanisms mediating downstream vascular cell responses to large artery stiffening remain unclear. We hypothesize that high pulsatility flow, induced by large artery stiffening, causes inflammatory responses in downstream pulmonary artery endothelial cells (PAECs) through toll-like receptor (TLR) pathways. To recapitulate the stiffening effect of large pulmonary arteries that occurs in pulmonary hypertension, ultrathin silicone tubes of variable mechanical stiffness were formulated and were placed in a flow circulatory system. These tubes modulated the simulated cardiac output into pulsatile flows with different pulsatility indices, 0.5 (normal) or 1.5 (high). PAECs placed downstream of the tubes were evaluated for their expression of proinflammatory molecules (ICAM-1, VCAM-1, E-selectin and MCP-1), TLR receptors and intracellular NF-κB following flow exposure. Results showed that compared to flow with normal pulsatility, high pulsatility flow induced proinflammatory responses in PAECs, enhanced TLR2 expression but not TLR4, and caused NF-κB activation. Pharmacologic (OxPAPC) and siRNA inhibition of TLR2 attenuated high pulsatility flow-induced pro-inflammatory responses and NF-κB activation in PAECs. We also observed that PAECs isolated from small pulmonary arteries of hypertensive animals exhibiting proximal vascular stiffening demonstrated a durable ex-vivo proinflammatory phenotype (increased TLR2, TLR4 and MCP-1 expression). Intralobar PAECs isolated from vessels of IPAH patients also showed increased TLR2. In conclusion, this study demonstrates for the first time that TLR2/NF-κB signaling mediates endothelial inflammation under high pulsatility flow caused by upstream stiffening, but the role of TLR4 in flow pulsatility-mediated endothelial mechanotransduction remains unclear.
| S-EPMC4100881 | biostudies-literature
Project description:Background & aimsThe progression of hepatosteatosis to non-alcoholic steatohepatitis (NASH) is a critical step in the pathogenesis of hepatocellular cancer. However, the underlying mechanism(s) for this progression is essentially unknown. This study was designed to determine the role of miR-378 in regulating NASH progression.MethodsWe used immunohistochemistry, luciferase assays and immunoblotting to study the role of miR-378 in modulating an inflammatory pathway. Wild-type mice kept on a high-fat diet (HFD) were injected with miR-378 inhibitors or a mini-circle expression system containing miR-378, to study loss and gain-of functions of miR-378.ResultsMiR-378 expression is increased in livers of dietary obese mice and patients with NASH. Further studies revealed that miR-378 directly targeted Prkag2 that encodes AMP-activated protein kinase γ 2 (AMPKγ2). AMPK signaling negatively regulates the NF-κB-TNFα inflammatory axis by increasing deacetylase activity of sirtuin 1. By targeting Prkag2, miR-378 reduced sirtuin 1 activity and facilitated an inflammatory pathway involving NF-κB-TNFα. In contrast, miR-378 knockdown induced expression of Prkag2, increased sirtuin 1 activity and blocked the NF-κB-TNFα axis. Additionally, knockdown of increased Prkag2 offset the inhibitory effects of miR-378 inhibitor on the NF-κB-TNFα axis, suggesting that AMPK signaling mediates the role of miR-378 in facilitating this inflammatory pathway. Liver-specific expression of miR-378 triggered the development of NASH and fibrosis by activating TNFα signaling. Ablation of TNFα in miR-378-treated mice impaired the ability of miR-378 to facilitate hepatic inflammation and fibrosis, suggesting that TNFα signaling is required for miR-378 to promote NASH.ConclusionMiR-378 plays a key role in the development of hepatic inflammation and fibrosis by positively regulating the NF-κB-TNFα axis. MiR-378 is a potential therapeutic target for the treatment of NASH.Lay summaryThe recent epidemic of obesity has been associated with a sharp rise in the incidence of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism(s) remains poorly described and effective therapeutic approaches against NAFLD are lacking. The results establish that microRNA-378 facilitates the development of hepatic inflammation and fibrosis and suggests the therapeutic potential of microRNA-378 inhibitor for the treatment of NAFLD.
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Project description:BackgroundMicroglia-mediated neuroinflammation is important in Alzheimer's disease (AD) pathogenesis. Extracellular deposition of β-amyloid (Aβ), a major pathological hallmark of AD, can induce microglia activation. Adiponectin (APN), an adipocyte-derived adipokine, exerts anti-inflammatory effects in the periphery and brain. Chronic APN deficiency leads to cognitive impairment and AD-like pathologies in aged mice. Here, we aim to study the role of APN in regulating microglia-mediated neuroinflammation in AD.MethodsInflammatory response of cultured microglia (BV2 cells) to AβO and effects of APN were studied by measuring levels of proinflammatory cytokines (tumor necrosis factor α [TNFα] and interleukin-1β [IL-1β]) in cultured medium before and after exposure to AβO, with and without APN pretreatment. Adiponectin receptor 1 (AdipoR1) and receptor 2 (AdipoR2) were targeted by small interference RNA. To study the neuroprotective effect of APN, cultured HT-22 hippocampal cells were treated with conditioned medium of AβO-exposed BV2 cells or were co-cultured with BV2 cells in transwells. The cytotoxicity of HT-22 hippocampal cells was assessed by MTT reduction. We generated APN-deficient AD mice (APN-/-5xFAD) by crossing APN-knockout mice with 5xFAD mice to determine the effects of APN deficiency on microglia-mediated neuroinflammation in AD.ResultsAdipoR1 and AdipoR2 were expressed in BV2 cells and microglia of mice. Pretreatment with APN for 2 h suppressed TNFα and IL-1β release induced by AβO in BV2 cells. Additionally, APN rescued the decrease of AMPK phosphorylation and suppressed nuclear translocation of nuclear factor kappa B (NF-κB) induced by AβO. Compound C, an inhibitor of AMPK, abolished these effects of APN. Knockdown of AdipoR1, but not AdipoR2 in BV2 cells, inhibited the ability of APN to suppress proinflammatory cytokine release induced by AβO. Moreover, pretreatment with APN inhibited the cytotoxicity of HT-22 cells co-cultured with AβO-exposed BV2 cells. Lastly, APN deficiency exacerbated microglia activation in 9-month-old APN-/-5xFAD mice associated with upregulation of TNFα and IL-1β in the cortex and hippocampus.ConclusionsOur findings demonstrate that APN inhibits inflammatory response of microglia to AβO via AdipoR1-AMPK-NF-κB signaling, and APN deficiency aggravates microglia activation and neuroinflammation in AD mice. APN may be a novel therapeutic agent for inhibiting neuroinflammation in AD.
| S-EPMC6535190 | biostudies-literature
Project description:miR-19a/b belong to the miR-17-92 family. We have demonstrated previously that miR-19a/b are overexpressed in glioma and glioma cell lines. However, the role of miR-19a/b in glioma remains unclear. In the present study, we aim to identify the biological function and molecular mechanism of miR-19a/b in glioma cell proliferation and epithelial-mesenchymal transition (EMT). Knocking down miR-19a/b in LN308 glioblastoma (GBM) cells with higher expression of miR-19a/b inhibits cell proliferation and invasion, induces apoptosis, and suppresses EMT by downregulating the expression of Akt, phosphorylated p-Akt, nuclear factor κB (NF-κB), Snail, N-cadherin, and Vimentin and upregulating E-cadherin in vitro and in vivo. Enhanced proliferation and EMT are also observed when miR-19a/b are transfected into SNB19 GBM cells, with lowered expression of miR-19a/b. miR-19a is more effective than miR-19b in the regulation of biological behavior of glioma cells. miR-19a/b modulate molecular events for the promotion of EMT via the Akt-NF-κB pathway. SEPT7 has been confirmed as the target gene of miR-19a/b. The effect of miR-19a/b on proliferation and EMT of glioma cells and the Akt-NF-κB pathway could be reversed by transfection with SEPT7. Our study strongly suggests that miR-19a/b play a significant role in glioma progression and EMT through regulating target gene-SEPT7 and the SEPT7-Akt-NF-κB pathway.
| S-EPMC7868923 | biostudies-literature
Project description:BackgroundIrradiation has emerged as a valid tool for nasopharyngeal carcinoma (NPC) in situ treatment; however, NPC derived from tissues treated with irradiation is a main cause cancer-related death. The purpose of this study is to uncover the underlying mechanism regarding tumor growth after irradiation and provided potential therapeutic strategy.MethodsFibroblasts were extracted from fresh NPC tissue and normal nasopharyngeal mucosa. Immunohistochemistry was conducted to measure the expression of α-SMA and FAP. Cytokines were detected by protein array chip and identified by real-time PCR. CCK-8 assay was used to detect cell proliferation. Radiation-resistant (IRR) 5-8F cell line was established and colony assay was performed to evaluate tumor cell growth after irradiation. Signaling pathways were acquired via gene set enrichment analysis (GSEA). Comet assay and γ-H2AX foci assay were used to measure DNA damage level. Protein expression was detected by western blot assay. In vivo experiment was performed subcutaneously.ResultsWe found that radiation-resistant NPC tissues were constantly infiltrated with a greater number of cancer-associated fibroblasts (CAFs) compared to radiosensitive NPC tissues. Further research revealed that CAFs induced the formation of radioresistance and promoted NPC cell survival following irradiation via the IL-8/NF-κB pathway to reduce irradiation-induced DNA damage. Treatment with Tranilast, a CAF inhibitor, restricted the survival of CAF-induced NPC cells and attenuated the of radioresistance properties.ConclusionsTogether, these data demonstrate that CAFs can promote the survival of irradiated NPC cells via the NF-κB pathway and induce radioresistance that can be interrupted by Tranilast, suggesting the potential value of Tranilast in sensitizing NPC cells to irradiation.
| S-EPMC7923322 | biostudies-literature