Expression of Concern: LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia.
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SUBMITTER: PLOS ONE Editors
PROVIDER: S-EPMC10718406 | biostudies-literature | 2023
REPOSITORIES: biostudies-literature
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Expression of Concern: LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia.
PloS one 20231213 12
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Project description:Long-term exposure to elevated levels of manganese (Mn) causes manganism, a neurodegenerative disorder with Parkinson's disease (PD)-like symptoms. Increasing evidence suggests that leucine-rich repeat kinase 2 (LRRK2), which is highly expressed in microglia and macrophages, contributes to the inflammation and neurotoxicity seen in autosomal dominant and sporadic PD. As gene-environment interactions have emerged as important modulators of PD-associated toxicity, LRRK2 may also mediate Mn-induced inflammation and pathogenesis. In this study, we investigated the role of LRRK2 in Mn-induced toxicity using human microglial cells (HMC3), LRRK2-wild-type (WT) and LRRK2-knockout (KO) RAW264.7 macrophage cells. Results showed that Mn activated LRRK2 kinase by phosphorylation of its serine residue at the 1292 position (S1292) as a marker of its kinase activity in macrophage and microglia, while inhibition with GSK2578215A (GSK) and MLi-2 abolished Mn-induced LRRK2 activation. LRRK2 deletion and its pharmacological inhibition attenuated Mn-induced apoptosis in macrophages and microglia, along with concomitant decreases in the pro-apoptotic Bcl-2-associated X (Bax) protein. LRRK2 deletion also attenuated Mn-induced production of reactive oxygen species (ROS) and the pro-inflammatory cytokine TNF-α. Mn-induced phosphorylation of mitogen-activated protein kinase (MAPK) p38 and ERK signaling proteins was significantly attenuated in LRRK2 KO cells and GSK-treated cells. Moreover, inhibition of MAPK p38 and ERK as well as LRRK2 attenuated Mn-induced oxidative stress and cytotoxicity. These findings suggest that LRRK2 kinase activity plays a critical role in Mn-induced toxicity via downstream activation of MAPK signaling in macrophage and microglia. Collectively, these results suggest that LRRK2 could be a potential molecular target for developing therapeutics to treat Mn-related neurodegenerative disorders.
| S-EPMC6333340 | biostudies-literature
Project description:Janus kinases (JAKs) and their downstream STAT proteins play key roles in cytokine signaling, tissue homeostasis, and cancer development. Using a breast cancer model that conditionally lacks Janus kinase 1, we show here that JAK1 is essential for IL-6-class inflammatory cytokine signaling and plays a critical role in metastatic cancer progression. JAK1 is indispensable for the oncogenic activation of STAT1, STAT3, and STAT6 in ERBB2-expressing cancer cells, suggesting that ERBB2 receptor tyrosine kinase complexes do not directly activate these STAT proteins in vivo. A genome-wide gene expression analysis revealed that JAK1 signaling has pleiotropic effects on several pathways associated with cancer progression. We established that FOS and MAP3K8 are targets of JAK1/STAT3 signaling, which promotes tumorsphere formation and cell migration. The results highlight the significance of JAK1 as a rational therapeutic target to block IL-6-class cytokines, which are master regulators of cancer-associated inflammation.
| S-EPMC6431084 | biostudies-literature
Project description:AimEvaluating and screening of genes related to colorectal inflammation of mice for finding critical ones in this disease was the aim of this study.BackgroundMany studies are shown direct relationship between inflammation and colorectal cancer onset and development. Several molecular aspects of inflammation are investigated to discover molecular mechanism of this disease.MethodsProfiles of differentially expressed genes (DEGs) of mice inflamed colorectal tissue in comparison with normal samples are obtained from Gene Expression Omnibus (GEO) database. The significant and characterized DEGs were screened via protein-protein interaction (PPI) network. Hubs of the network were determined and backbone network was constructed. Moreover, action network for the critical nodes was constructed and analyzed.ResultsEight central genes including IL6, ALB, PRDM10, AKT1, GAPDH, IL8, INS and TNF were determined as hub nodes. Findings indicate that insulin plays critical role in regulation of hub genes. This finding shows association between inflammation and metabolism dysregulation. Except PRDM10 and GAPDH, the other hubs show considerable regulatory effects on each other.ConclusionInflammation of colorectal tissue is strongly depended on metabolism especially to insulin function.
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Project description:Complement impacts innate and adaptive immunity. Using a model in which the human KEL glycoprotein is expressed on murine red blood cells (RBCs), we have shown that polyclonal immunoprophylaxis (KELIg) prevents alloimmunization to transfused RBCs when a recipient is in their baseline state of heath but with immunoprophylaxis failure occurring in the presence of a viral-like stimulus. As complement can be detected on antibody coated KEL RBCs following transfusion, we hypothesized that recipient complement synergizes with viral-like inflammation to reduce immunoprophylaxis efficacy. Indeed, we found recipient C3 and C1q were critical to immunoprophylaxis failure in the setting of a viral-like stimulus, with no anti-KEL IgG alloantibodies generated in C3-/- or C1q-/- mice following KELIg treatment and KEL RBC transfusion. Differences in RBC uptake were noted in mice lacking C3, with lower consumption by splenic and peripheral blood inflammatory monocytes. Finally, no alloantibodies were detected in the setting of a viral-like stimulus following KELIg treatment and KEL RBC transfusion in mice lacking complement receptors (CR1/2-/-), narrowing key cells for immunoprophylaxis failure to those expressing these complement receptors. In-vitro studies showed complement fixed opsonized RBCs were significantly less likely to bind to B-cells from CR1/2-/- than wild type mice, potentially implicating lowered B-cell activation threshold in the presence of complement as being responsible for these findings. We thus propose a two-hit model for inflammation-induced immunoprophylaxis failure, where the first "hit" is recipient inflammation and the second "hit" is complement production/sensing. These results may have translational relevance to antigen-antibody interactions in humans.
| S-EPMC8270673 | biostudies-literature
Project description:Janus kinases (JAKs) and their downstream STAT proteins play key roles in cytokine signaling, tissue homeostasis, and cancer development. Using a novel breast cancer model that conditionally lacks the Janus kinase 1, we show here that JAK1 is essential for IL-6 class inflammatory cytokine signaling and plays a critical role in metastatic cancer progression. JAK1 is indispensable for the oncogenic activation of STAT1, STAT3, and STAT6 in ERBB2-expressing cancer cells, suggesting that ERBB2 receptor tyrosine kinase complexes do not directly activate these STAT proteins in vivo. A genome-wide gene expression analysis revealed that JAK1 signaling has pleiotropic effects on several pathways associated with cancer progression. We established that FOS and MAP3K8 are targets of JAK1/STAT3 signaling that promote tumorsphere formation and cell migration. The results highlight the significance of JAK1 as a rational therapeutic target to block IL-6 class cytokines that are master regulators of cancer-associated inflammation.
2019-03-27 | GSE121064 | GEO
Project description:Mounting evidence supports a critical role for central nervous system (CNS) glial cells in neuroinflammation and neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's Disease (PD), Multiple Sclerosis (MS), as well as neurovascular ischemic stroke. Previously, we found that loss of the PD-associated gene leucine-rich repeat kinase 2 (Lrrk2) in macrophages, peripheral innate immune cells, induced mitochondrial stress and elevated basal expression of type I interferon (IFN) stimulated genes (ISGs) due to chronic mitochondrial DNA engagement with the cGAS/STING DNA sensing pathway. Here, we report that loss of LRRK2 results in a paradoxical response in microglial cells, a CNS-specific macrophage population. In primary murine microglia and microglial cell lines, loss of Lrrk2 reduces tonic IFN signaling leading to a reduction in ISG expression. Consistent with reduced type I IFN, mitochondria from Lrrk2 KO microglia are protected from stress and have elevated metabolism. These protective phenotypes involve upregulation of NRF2, an important transcription factor in the response to oxidative stress and are restricted by LRRK2 kinase activity. Collectively, these findings illustrate a dichotomous role for LRRK2 within different immune cell populations and give insight into the fundamental differences between immune regulation in the CNS and the periphery.
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Project description:Inflammatory cells contribute to the pathogenesis of renal ischemia-reperfusion injury (IRI). However, the signaling mechanisms underlying the infiltration of inflammatory cells into the kidney are not well understood. In this study, we examined the effects of phosphoinositide 3 kinase γ (PI3Kγ) on inflammatory cells infiltration into the kidney in response to ischemia-reperfusion injury. Compared with wild-type mice, PI3Kγ knockout mice displayed less IRI in the kidney with fewer tubular apoptotic cell. Furthermore, PI3Kγ deficiency decreased the number of infiltrated neutrophils, macrophages, and T cells in the kidney, which was accompanied by a decrease in the expression of pro-inflammatory cytokines in the kidney. Moreover, wild-type mice treated with AS-605240, a selective PI3Kγ inhibitor, displayed less tubular damage, accumulated fewer inflammatory cells, and expressed less proinflammatory molecules in the kidney following IRI. These results demonstrate that PI3Kγ has a critical role in the pathogenesis of kidney damage in IRI, indicating that PI3Kγ inhibition may serve as a potential therapeutic strategy for the prevention of ischemia-reperfusion-induced kidney injury.
| S-EPMC8909888 | biostudies-literature
Project description:BackgroundSilencing of normal gene expression occurs early in the apoptosis of neurons, well before the cell is committed to the death pathway, and has been extensively characterized in injured retinal ganglion cells. The causative mechanism of this widespread change in gene expression is unknown. We investigated whether an epigenetic change in active chromatin, specifically histone H4 deacetylation, was an underlying mechanism of gene silencing in apoptotic retinal ganglion cells (RGCs) following an acute injury to the optic nerve.ResultsHistone deacetylase 3 (HDAC3) translocates to the nuclei of dying cells shortly after lesion of the optic nerve and is associated with an increase in nuclear HDAC activity and widespread histone deacetylation. H4 in promoters of representative genes was rapidly and indiscriminately deacetylated, regardless of the gene examined. As apoptosis progressed, H4 of silenced genes remained deacetylated, while H4 of newly activated genes regained, or even increased, its acetylated state. Inhibition of retinal HDAC activity with trichostatin A (TSA) was able to both preserve the expression of a representative RGC-specific gene and attenuate cell loss in response to optic nerve damage.ConclusionsThese data indicate that histone deacetylation plays a central role in transcriptional dysregulation in dying RGCs. The data also suggests that HDAC3, in particular, may feature heavily in apoptotic gene silencing.
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Project description:Chronic manganese (Mn) exposure can lead to manganism, a neurological disorder sharing common symptoms with Parkinson's disease (PD). Studies have shown that Mn can increase the expression and activity of leucine-rich repeat kinase 2 (LRRK2), leading to inflammation and toxicity in microglia. LRRK2 G2019S mutation also elevates LRRK2 kinase activity. Thus, we tested if Mn-increased microglial LRRK2 kinase is responsible for Mn-induced toxicity, and exacerbated by G2019S mutation, using WT and LRRK2 G2019S knock-in mice and BV2 microglia. Mn (30 mg/kg, nostril instillation, daily for 3 weeks) caused motor deficits, cognitive impairments, and dopaminergic dysfunction in WT mice, which were exacerbated in G2019S mice. Mn induced proapoptotic Bax, NLRP3 inflammasome, IL-1β, and TNF-α in the striatum and midbrain of WT mice, and these effects were more pronounced in G2019S mice. BV2 microglia were transfected with human LRRK2 WT or G2019S, followed by Mn (250 μM) exposure to better characterize its mechanistic action. Mn increased TNF-α, IL-1β, and NLRP3 inflammasome activation in BV2 cells expressing WT LRRK2, which was elevated further in G2019S-expressing cells, while pharmacological inhibition of LRRK2 mitigated these effects in both genotypes. Moreover, the media from Mn-treated G2019S-expressing BV2 microglia caused greater toxicity to the cath.a-differentiated (CAD) neuronal cells compared to media from microglia expressing WT. Mn-LRRK2 activated RAB10 which was exacerbated in G2019S. RAB10 played a critical role in LRRK2-mediated Mn toxicity by dysregulating the autophagy-lysosome pathway and NLRP3 inflammasome in microglia. Our novel findings suggest that microglial LRRK2 via RAB10 plays a critical role in Mn-induced neuroinflammation.
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Project description:Neutrophilic inflammation is a prominent feature of chronic obstructive pulmonary disease (COPD). Developmental endothelial locus-1 (Del-1) has been reported to limit excessive neutrophilic inflammation by inhibiting neutrophil adhesion to the vascular endothelial cells. However, the effects of Del-1 in COPD are not known. We investigated the role of Del-1 in the pathogenesis of COPD. Del-1 protein expression was decreased in the lungs of COPD patients, especially in epithelial cells and alveolar macrophages. In contrast to human lung tissue, Del-1 expression was upregulated in lung tissue from mice treated with cigarette smoke extracts (CSE). Overexpression of Del-1 significantly suppressed IL-8 release and apoptosis in CSE-treated epithelial cells. In contrast, knockdown of Del-1 enhanced IL-8 release and apoptosis. In macrophages, overexpression of Del-1 significantly suppressed inflammatory cytokine release, and knockdown of Del-1 enhanced it. This anti-inflammatory effect was mediated by inhibiting the phosphorylation and acetylation of NF-κB p65. Nuclear factor erythroid 2-related factor 2 (Nrf2) activators, such as quercetin, resveratrol, and sulforaphane, increased Del-1 in both cell types. These results suggest that Del-1, mediated by Nrf2, plays a protective role against the pathogenesis of COPD, at least in part through anti-inflammatory and anti-apoptotic effects.
| S-EPMC10888117 | biostudies-literature