scholarly journals PON1 Deficiency Promotes TREM2 Pathway-Mediated Microglial Phagocytosis and Inhibits Pro-Inflammatory Cytokines Release in Vitro and in Vivo

2021 ◽  
Author(s):  
Li Zhang ◽  
Wei Dong ◽  
Yuanwu Ma ◽  
Lin Bai ◽  
Xu Zhang ◽  
...  
Keyword(s):  
Rat Brain ◽  
Inflammatory Cytokines ◽  
Paraoxonase 1 ◽  
Primary Microglia ◽  
Microglial Phagocytosis ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines ◽  
Brain Tissues

Abstract Paraoxonase 1 (PON1) plays an anti-inflammatory role in the cardiovascular system. Levels of serum PON1 and polymorphisms in this gene were linked to Alzheimer disease (AD) and Parkinson disease (PD), but its function in the neuroimmune system and AD are not clear. To address this issue, we used PON1 knockout rats previously generated by our lab to investigate the role of PON1 in microglia. Knockout of PON1 in rat brain tissues protected against LPS-induced microglia activation. PON1 deficiency in rat primary microglia increased TREM2 (triggering receptor expressed in myeloid cells 2) expression, phagocytosis and IL-10 (M2-phenotype marker) release, but decreased production of pro-inflammatory cytokines such as IL-1β, IL-6, IL-12, IL-18 especially TNF-α (M1-phenotype markers) induced by LPS. PON1 deficiency in rat primary microglia activated TREM2 pathway but decreased LPS-induced ERK activation. The phagocytosis promoting effect of PON1 knockout could be reversed by administration of recombinant PON1 protein. The interaction between PON1 and TREM2 was verified by co-immunoprecipitation (co-IP) using rat brain tissues or over-expressed BV2 cell lysates, which might be involved in lysosomal degradation of TREM2. Furthermore, PON1 knockout may also enhance microglial phagocytosis and clearance of exogenous Aβ by an intrahippocampal injection and decrease the transcription of cytokines such as IL-1β, IL-6 and TNF-α in vivo. These results suggest an inhibitory role of PON1 in microglial phagocytosis dependent on its interaction with TREM2. These findings provide novel insights into the role of PON1 in neuroinflammation and highlight TREM2 as a potential target for Alzheimer’s disease therapy.

scholarly journals PON1 Deficiency Promotes TREM2 Pathway-Mediated Microglial Phagocytosis and Inhibits Pro-Inflammatory Cytokines Release in Vitro and in Vivo

2021 ◽  
Author(s):  
Li Zhang ◽  
Wei Dong ◽  
Yuanwu Ma ◽  
Lin Bai ◽  
Xu Zhang ◽  
...  
Keyword(s):  
Rat Brain ◽  
Inflammatory Cytokines ◽  
Paraoxonase 1 ◽  
Primary Microglia ◽  
Microglial Phagocytosis ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines ◽  
Brain Tissues

Abstract Background: Paraoxonase 1 (PON1), an HDL-associated enzyme, plays an anti-inflammatory role in the cardiovascular system. Levels of serum PON1 and polymorphisms in this gene were linked to Alzheimer disease (AD) and Parkinson disease (PD), but its function in the neuroimmune system and AD are not clear.Methods: PON1 knockout rats previously generated by our lab were used to investigate the role of PON1 in microglia. Wild type (WT) rats and PON1 knockout (KO) rats were injected with lipopolysaccharide (LPS, 5 or 20 mg/kg) and the survival rates were compared. Microglia on the sections of rat brain tissues were immunostained with anti-Iba1 antibody and the microglia morphology was compared. The phagocytosis, cytokines release and transcriptome of rat primary microglia cells treated with or without LPS were analyzed. The interactions between PON1 and TREM2 were detected by co-immunoprecipitation (co-IP) using rat brain tissues or over-expressed BV2 cell lysates. The effects of PON1 on microglial phagocytosis in vivo were investigated in a rat model of AD produced by an intrahippocampal injection of Aβ1-42.Results: The expression of PON1 was detected in human and rat brain tissues and rat primary microglia. Knockout of PON1 in rat brain tissues protected against LPS-induced lethality by decreasing TNF-α expression. PON1 knockout in microglia increased TREM2 (triggering receptor expressed in myeloid cells 2) expressing and phagocytosis, but decreased production of pro-inflammatory cytokines such as IL-1β, IL-6, IL-12, IL-18 especially TNF-α (M1-phenotype markers) and increased IL-10 (M2-phenotype marker) release induced by LPS. PON1 knockout activated TREM2 pathway but decreased LPS-induced ERK activation. The phagocytosis promoting effect was reversed by administration of recombinant PON1 protein. The interaction between PON1 and TREM2 was verified and might be involved in lysosomal degradation of TREM2. Further, PON1 knockout may also enhance microglial phagocytosis and clearance of exogenous Aβ and decrease the transcription of cytokines such as IL-1β, IL-6 and TNF-α in vivo.Conclusions: These results suggest an inhibitory role of PON1 in microglial phagocytosis dependent on its interaction with TREM2. These findings provide novel insights into the role of PON1 in neuroinflammation and highlight TREM2 as a potential target for Alzheimer’s disease therapy.

scholarly journals PON1 deficiency promotes TREM2 pathway-mediated microglial phagocytosis and inhibits LPS-induced pro-inflammatory cytokines release

2020 ◽  
Author(s):  
lianfeng zhang ◽  
Li Zhang ◽  
Wei Dong ◽  
Yuanwu Ma ◽  
Lin Bai ◽  
...  
Keyword(s):  
Rat Brain ◽  
Inflammatory Cytokines ◽  
Paraoxonase 1 ◽  
Primary Microglia ◽  
Promoting Effect ◽  
Microglial Phagocytosis ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines ◽  
Brain Tissues

Abstract Background Paraoxonase 1 (PON1), an HDL-associated enzyme, plays an anti-inflammatory role in the cardiovascular system. Levels of serum PON1 and polymorphisms in this gene were linked to Alzheimer disease (AD) and Parkinson disease (PD), but its function in the neuroimmune system and AD are not clear. Methods PON1 knockout rats previously generated by our lab were used to investigate the role of PON1 in microglia. Wild type (WT) rats and PON1 knockout (KO) rats were injected with lipopolysaccharide (LPS, 5 or 20 mg/kg) and the survival rates were compared. Microglia on the sections of rat brain tissues were immunostained with anti-Iba1 antibody and the microglia morphology was compared. The phagocytosis, cytokines release and transcriptome of primary microglia cells treated with or without LPS were analyzed. The interactions between PON1 and TREM2 were detected by co-immunoprecipitation (co-IP) using rat brain tissues or over-expressed BV2 cell lysates. Results The expression of PON1 was detected in human and rat brain tissues and rat primary microglia. Knockout of PON1 in rat brain tissues protected against LPS-induced lethality by decreasing TNF-α expression. PON1 knockout in microglia increased TREM2 (triggering receptor expressed in myeloid cells 2) expressing and phagocytosis, but decreased production of pro-inflammatory cytokines such as IL-1β, IL-6, IL-12, IL-18 especially TNF-α (M1-phenotype markers) and increased IL-10 (M2-phenotype marker) release induced by LPS. PON1 knockout activated TREM2 pathway but decreased LPS-induced ERK activation. The phagocytosis promoting effect was reversed by administration of recombinant PON1 protein. The interaction between PON1 and TREM2 was verified and was associated with the localization of TREM2 in lysosomes. Conclusions These results suggest an inhibitory role of PON1 in microglial phagocytosis dependent on its interaction with TREM2. These findings provide novel insights into the role of PON1 in neuroinflammation and highlight TREM2 as a potential target for Alzheimer’s disease therapy.

scholarly journals Steroid Sulfates from Ophiuroids (Brittle Stars): Action on Some Factors of Innate and Adaptive Immunity

2016 ◽  
Vol 11 (6) ◽  
pp. 1934578X1601100
Author(s):  
Anna K Gazha ◽  
Lyudmila A. Ivanushko ◽  
Eleonora V. Levina ◽  
Sergey N. Fedorov ◽  
Tatyana S. Zaporozets ◽  
...  
Keyword(s):  
Adaptive Immunity ◽  
Inflammatory Cytokines ◽  
Brittle Stars ◽  
Innate And Adaptive Immunity ◽  
Functional Activities ◽  
In Vivo Experiments ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

The action of seven polyhydroxylated sterol mono- and disulfates (1-7), isolated from ophiuroids, on innate and adaptive immunity was examined in in vitro and in vivo experiments. At least, three of them (1, 2 and 4) increased the functional activities of neutrophils, including levels of oxygen-dependent metabolism, adhesive and phagocytic properties, and induced the expression of pro-inflammatory cytokines TNF-α and IL-8. Compound 4 was the most active for enhancing the production of antibody forming cells in the mouse spleen.

scholarly journals IKK-2 inhibitor TPCA-1 represses nasal epithelial inflammation in vitro

2011 ◽  
Vol 49 (2) ◽  
pp. 168-173
Author(s):  
F. Sachse ◽  
K. Becker ◽  
T.J. Basel ◽  
D. Weiss ◽  
C. Rudack
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Disease ◽  
Inflammatory Process ◽  
Nasal Polyposis ◽  
Paraffin Sections ◽  
Tnf Α ◽  
Epithelial Inflammation ◽  
Pro Inflammatory Cytokines

BACKGROUND: Nasal polyposis (NP) is considered a subgroup within chronic rhinosinusitis. NP can be further subdivided into aspirin sensitive- and aspirin tolerant types (ASNP/ ATNP). Although the true etiology of NP has not been identified so far, it is agreed that NP represents an inflammatory disease of the nasal mucosa. Alterations of cellular kinase activities including that of IKK-2 might play a role in this inflammatory process. METHODS: Paraffin sections of ASNP, ATNP and controls were immunostained with Phospho-IkB-α antibody that detects the direct IKK-2 product (IkB-α. Intensity of epithelial staining was analysed semi-quantitatively by two independent observers. In cultured nasal polyp epithelial cells (NPECs) epithelial derived cytokines IL-8 and GRO α were induced by TNF-α or Staphylococcal supernatants and subsequently repressed by IKK-2 inhibitor TPCA-1. RESULTS: Significant Phospho-IkB-α staining was observed in the nasal epithelium of ASNP compared to ATNP and controls suggesting strong IKK-2 activation in patients with ASNP in vivo. In vitro, pro-inflammatory cytokines IL-8 and GRO-α in NPECs were significantly repressed by TPCA-1. CONCLUSION: IKK-2 activity is increased in the subgroup of ASNP. IL-8 and GRO-α responses were repressed by IKK-2 inhibitor TPCA-1 in vitro. IKK-2 inhibitors might represent a potential target for anti-inflammatory intervention in ASNP.

Over-expression of PTEN attenuates the inflammation of fibroblast-like synoviocytes in rheumatoid arthritis

2020 ◽  
Author(s):  
Xiao-Feng Li ◽  
Qing-Qing Xu ◽  
Man-Wen Yang ◽  
He Chen ◽  
Su-Qin Yin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Dna Methylation ◽  
Inflammatory Cytokines ◽  
Pten Expression ◽  
Over Expression ◽  
Tnf Α ◽  
And Migration ◽  
Fibroblast Like Synoviocytes ◽  
Pro Inflammatory Cytokines

Abstract Background: Rheumatoid arthritis (RA) is characterized by a tumor-like expansion of the synovium and the subsequent destruction of adjacent articular cartilage and bone. Recent studies have shown that phosphatase and tension homolog deleted on chromosome 10 (PTEN) might contribute to the survival of fibroblast-like synoviocytes (FLS) and the production of pro-inflammatory cytokines in RA.Methods : The expression was determined in RA and adjuvant-induced arthritis (AIA) synovial tissues by immunohistochemistry. FLSs were treatment with bpv, PTEN-RNAi or over-expression plasmid in RA and AIA. FLSs migration was assessed. The ad-PTEN was also injected into the knee of AIA in vivo. Chromatin Immunoprecipitation (ChIP) and Methylation-special PCR (MSP) assay were used to study the expression of PTEN mRNA in DNA methylation.Results : Down-regulated level of PTEN expression was observed in RA and AIA. Inhibition PTEN expression by bpv or PTEN-RNAi could promote the expression of pro-inflammatory cytokines, chemokines and migration of FLS with TNF-α in RA and AIA. Consistently, over-expression of PTEN reduced their low-expression of pro-inflammatory cytokines, chemokines and migration. Intra-articular injection of ad-PTEN in AIA knees dramatically reduced inflammatory and paw swelling in vivo. The ChIP and MSP assay has clearly detected the DNA methylation of PTEN was increased in FLS with TNF-α. Moreover, intraperitoneally injected 5-Aza in AIA also suppressed the inflammatory and paws swelling in vivo.Conclusions: Our findings suggest that over-expression PTEN attenuates the formation of pro-inflammatory cytokines, chemokines and migration of FLS, and it may be regulated by DNA methylation in the pathogenesis of RA.

Upregulated Long Non-coding RNA ALMS1-IT1 Promotes Neuroinflammation by Activating NF-κB Signaling in Ischemic Cerebral Injury

2021 ◽  
Vol 27 ◽  
Author(s):  
Peng Lu ◽  
Ye Zhang ◽  
Huanjiang Niu ◽  
Yirong Wang
Keyword(s):  
Inflammatory Cytokines ◽  
Nuclear Translocation ◽  
Cell Model ◽  
Intrathecal Injection ◽  
Cerebral Injury ◽  
Aberrant Expression ◽  
Tnf Α ◽  
Neuro Inflammation ◽  
Pro Inflammatory Cytokines ◽  
Brain Tissues

Background: ALMS1-IT1, a recently identified lncRNA, has been proven to play a crucial role in regulating tumor progression and predicting the survival time of tumor patients. Data analysis from the Human Body Map (HBM) revealed that ALMS1-IT1 is expressed mainly in brain tissues. Methods: In this study, the role of ALMS1-IT in regulating neuro-inflammation and functional recovery was investigated after ischemic cerebral damage. To this end, the rat model of transient middle cerebral artery occlusion (tMCAO) was constructed, the cell model of oxygen-glucose deprivation (OGD) was established using BV2 microglial cells, and the aberrant expression of ALMS1-IT1 was assessed in brain tissues. After ALMS1-IT1 knockdown through intrathecal injection of Lv-shALMS1-IT1, neuro-inflammatory response and functional tests including a modified neurological severity score (mNSS) and a foot-fault test were assessed. Results: The level of ALMS1-IT1 was promptly enhanced at 12 hours (h) following MCAO, peaking at 48 h, and remaining high at day 14 compared to the sham group. Pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) were increased after MCAO, whereas ALMS1-IT1 inhibition suppressed the expression of IL-1β, IL-6 and TNF-α in MCAO rats. The results from mNSS and foot-fault test showed that ALMS1-IT1 knockdown significantly improved spatial learning and sensorimotor function of MCAO rats. Mechanistically, ALMS1-IT1 knockdown suppressed the activation of NF-κB signaling in vitro and in vivo, as evidenced by decreased p65 expression and p65 nuclear translocation. ALMS1-IT1 overexpression facilitated pro-inflammatory cytokines expression in microglia, whereas the effect was blocked by treatment with JSH-23 (a specific NF-κB inhibitor). Conclusions: These data demonstrated that ALMS1-IT1 inhibition improved neurological function of MCAO rats, at least in part by repressing NF-κB-dependent neuro-inflammation.

scholarly journals ROLE OF MONOCYTES IN PATHOGENESIS OF GENERALIZED PERITONITIS

2020 ◽  
pp. 455-460
Author(s):  
A.R. SARAEV ◽  
◽  
SH.K. NAZAROV ◽  
S.G. ALI-ZADE ◽  
◽  
...  
Keyword(s):  
Septic Shock ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Inflammatory Cytokines ◽  
Abdominal Sepsis ◽  
Endothelial Progenitor ◽  
Generalized Peritonitis ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Objective: To study the sepsis markers informativeness to assess the role of monocytes in the pathogenesis of generalized peritonitis (GP). Methods: The study included 160 patients with GP, who were divided into 3 groups, according to the stages of the disease. To establish the activity of monocytes was made a determination of the level of cytokine TNF-α and presepsin in the blood. Results: Studies showed that the level of TNF-α in patient with septic shock was reliably lower (24.5±13.3 pg/ml) than in patients with endogenous intoxication and abdominal sepsis. The value of TNF-α in deceased patients also was low – 4.8±0.9 pg/ml. This indicates a decrease in the ability of monocytes in GP at the stage of septic shock to exude a sufficient amount of pro-inflammatory cytokines in response to endotoxin aggression. The level of presepsin increased by stages and amounted to 355.6±8.6, 783.4±24.0 and 1587.7±70.5 pg/ml, respectively. This indicates the circulation in the blood of the CD14 receptor, which is able to express on monocytes, converting them into endothelial progenitor cells. Conclusions: Monocytes as endothelial progenitor cells contribute to the regeneration and restoration of endothelial function in its dysfunction that develops in GP and abdominal sepsis. In consequence of developing immunosuppression and suppression of monocyte function in the stage of septic shock, the process of renewal of endothelial cells is weakened, the secretion of pro-inflammatory cytokines, in particular TNF-α, decreases, which can contribute to an increase in mortality in septic shock. Keywords: Monocytes, abdominal sepsis, septic shock, endothelial dysfunction, progenitor cells.

scholarly journals Lactobacillus ruminis Alleviates DSS-Induced Colitis by Inflammatory Cytokines and Gut Microbiota Modulation

Foods ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1349
Author(s):  
Bo Yang ◽  
Mingjie Li ◽  
Shuo Wang ◽  
R. Paul Ross ◽  
Catherine Stanton ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Inflammatory Cytokines ◽  
Short Chain Fatty Acids ◽  
Colon Tissue ◽  
Tnf Α ◽  
Lactobacillus Ruminis ◽  
Immune Response In Vitro ◽  
Pro Inflammatory Cytokines

Lactobacillus ruminis can stimulate the immune response in vitro, but previous studies were only carried out in vitro and the anti-inflammatory effects of L. ruminis needs more in vivo evidences. In this study, the immune regulation and potential mechanisms of L. ruminis was investigated in DSS-induced colitis mice. L. ruminis FXJWS27L3 and L. ruminis FXJSW17L1 relieved the symptoms of colitis, including inhibition of colon shortening and colon tissue damage. L. ruminis FXJWS27L3 significantly reduced the pro-inflammatory cytokines IL-1β, TNF-α, and IL-17, while L. ruminis FXJSW17L1 significantly increased short chain fatty acids in mice feces. Moreover, L. ruminis FXJWS27L3 and L. ruminis FXJSW17L1 treatments significantly increased the gut microbiota diversity and balance the intestine microbiota profiles, which improved the imbalance of intestine microbiota composition to a certain extent. The results showed that L. ruminis can alleviate DSS-induced colitis, which possibly was related to promoting the expression of pro-inflammatory cytokines, up-regulating SCFAs and restoring the imbalance of gut microbiota.

IL-17 regulates expression of cytokines in human osteoblasts rather than bone-specific genes

2020 ◽  
Author(s):  
Susanne Drynda ◽  
Andreas Drynda ◽  
Christoph H. Lohmann ◽  
Jessica Bertrand ◽  
Jörn Kekow
Keyword(s):  
Bone Resorption ◽  
Inflammatory Cytokines ◽  
Osteoclast Differentiation ◽  
Inflammatory Rheumatic Diseases ◽  
Transcriptional Level ◽  
Culture Model ◽  
Tnf Α ◽  
Primary Osteoblasts ◽  
Pro Inflammatory Cytokines

Abstract Objective The cytokine IL-17 plays a crucial role in the development and promoting of inflammatory rheumatic diseases, such as psoriasis arthritis and ankylosing spondylitis. The influence of IL-17 on the osteoblast differentiation from mesenchymal stem cells has already been well studied. However, the effect of IL-17 on mature osteoblasts is not yet fully understood. Methods In this study, the influence of IL-17 on the expression of osteogenic markers and pro-inflammatory cytokines was analyzed on mRNA and protein level in an osteoblast cell culture model. Results Our data indicate that IL-17 alone has no significant influence on the expression of osteoblast-specific genes. However, a significant upregulation of pro-inflammatory cytokines at the transcriptional level by IL-17 was observed in primary osteoblasts. This effect on the regulation of pro-inflammatory cytokines was abolished completely by administration of a therapeutic anti-IL-17 antibody. Co-stimulation with TNF-α and IL-17 led to an upregulation of pro-inflammatory cytokines, which significantly exceeded the additive effect of both cytokines. In this co-stimulation, the anti-IL-17 antibody could not completely reverse the IL-17 effect. The same IL-17 and TNF-α effect was observed in osteoblast-like cells (MG63), whereas IL-17 alone did not induce the expression of pro-inflammatory cytokines. Conclusion The upregulation of the pro-inflammatory cytokines IL-1, IL-6, and IL-8 in primary osteoblasts by IL-17 indicates an indirect regulatory effect on osteoclastogenesis and activation of bone resorption. The therapeutic IL-17 antibody reduced the IL-17 induced release of pro-inflammatory cytokines by osteoblasts and this, in turn, could also reduce the effect on osteoclast differentiation and bone resorption. Our study underlines the important role of osteoblasts as major players in the osteoimmunologic network.

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