scholarly journals Modulation of Neuro-Inflammatory Signals in Microglia by Plasma Prekallikrein and Neuronal Cell Debris

2021 ◽  
Vol 12 ◽  
Author(s):  
Aneese A. Jaffa ◽  
Miran A. Jaffa ◽  
Mayssam Moussa ◽  
Ibrahim A. Ahmed ◽  
Mia Karam ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Microglial Activation ◽  
Neuronal Cell ◽  
Bioinformatic Analysis ◽  
Activation Process ◽  
Cell Debris ◽  
Enhanced Expression ◽  
Inflammatory Processes ◽  
Hoe 140

Microglia, the resident phagocytes of the central nervous system and one of the key modulators of the innate immune system, have been shown to play a major role in brain insults. Upon activation in response to neuroinflammation, microglia promote the release of inflammatory mediators as well as promote phagocytosis. Plasma prekallikrein (PKall) has been recently implicated as a mediator of neuroinflammation; nevertheless, its role in mediating microglial activation has not been investigated yet. In the current study, we evaluate the mechanisms through which PKall contributes to microglial activation and release of inflammatory cytokines assessing PKall-related receptors and their dynamics. Murine N9-microglial cells were exposed to PKall (2.5 ng/ml), lipopolysaccharide (100 ng/ml), bradykinin (BK, 0.1 μM), and neuronal cell debris (16.5 μg protein/ml). Gene expression of bradykinin 2 receptor (B2KR), protease-activated receptor 2 (PAR-2), along with cytokines and fibrotic mediators were studied. Bioinformatic analysis was conducted to correlate altered protein changes with microglial activation. To assess receptor dynamics, HOE-140 (1 μM) and GB-83 (2 μM) were used to antagonize the B2KR and PAR-2 receptors, respectively. Also, the role of autophagy in modulating microglial response was evaluated. Data from our work indicate that PKall, LPS, BK, and neuronal cell debris resulted in the activation of microglia and enhanced expression/secretion of inflammatory mediators. Elevated increase in inflammatory mediators was attenuated in the presence of HOE-140 and GB-83, implicating the engagement of these receptors in the activation process coupled with an increase in the expression of B2KR and PAR-2. Finally, the inhibition of autophagy significantly enhanced the release of the cytokine IL-6 which were validated via bioinformatics analysis demonstrating the role of PKall in systematic and brain inflammatory processes. Taken together, we demonstrated that PKall can modulate microglial activation via the engagement of PAR-2 and B2KR where PKall acts as a neuromodulator of inflammatory processes.

scholarly journals Inflammation and JNK's Role in Niacin-GPR109A Diminished Flushed Effect in Microglial and Neuronal Cells With Relevance to Schizophrenia

2021 ◽  
Vol 12 ◽  
Author(s):  
Sabrina H. Ansarey
Keyword(s):  
Inflammatory Mediators ◽  
Neuronal Death ◽  
Microglial Activation ◽  
Negative Symptoms ◽  
Genome Wide Association Study ◽  
Genetic Mutation ◽  
Genome Wide ◽  
Ultra High Risk ◽  
Altered Proteins

Schizophrenia is a neuropsychiatric illness with no single definitive aetiology, making its treatment difficult. Antipsychotics are not fully effective because they treat psychosis rather than the cognitive or negative symptoms. Antipsychotics fail to alleviate symptoms when patients enter the chronic stage of illness. Topical application of niacin showed diminished skin flush in the majority of patients with schizophrenia compared to the general population who showed flushing. The niacin skin flush test is useful for identifying patients with schizophrenia at their ultra-high-risk stage, and understanding this pathology may introduce an effective treatment. This review aims to understand the pathology behind the diminished skin flush response, while linking it back to neurons and microglia. First, it suggests that there are altered proteins in the GPR109A-COX-prostaglandin pathway, inflammatory imbalance, and kinase signalling pathway, c-Jun N-terminal kinase (JNK), which are associated with diminished flush. Second, genes from the GPR109A-COX-prostaglandin pathway were matched against the 128-loci genome wide association study (GWAS) for schizophrenia using GeneCards, suggesting that G-coupled receptor-109A (GPR109A) may have a genetic mutation, resulting in diminished flush. This review also suggests that there may be increased pro-inflammatory mediators in the GPR109A-COX-prostaglandin pathway, which contributes to the diminished flush pathology. Increased levels of pro-inflammatory markers may induce microglial-activated neuronal death. Lastly, this review explores the role of JNK on pro-inflammatory mediators, proteins in the GPR109A-COX-prostaglandin pathway, microglial activation, and neuronal death. Inhibiting JNK may reverse the changes observed in the diminished flush response, which might make it a good therapeutic target.

scholarly journals Microglial TonEBP mediates LPS-induced inflammation and memory loss as transcriptional cofactor for NF-κB and AP-1

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Gyu Won Jeong ◽  
Hwan Hee Lee ◽  
Whaseon Lee-Kwon ◽  
Hyug Moo Kwon
Keyword(s):  
Microglial Activation ◽  
Neuronal Damage ◽  
Neuronal Cell Death ◽  
Myeloid Cells ◽  
Memory Loss ◽  
Neuronal Cell ◽  
Microglial Cell Line ◽  
Bv2 Cells ◽  
Pro Inflammatory Cytokines

Abstract Background Microglia are brain-resident myeloid cells involved in the innate immune response and a variety of neurodegenerative diseases. In macrophages, TonEBP is a transcriptional cofactor of NF-κB which stimulates the transcription of pro-inflammatory genes in response to LPS. Here, we examined the role of microglial TonEBP. Methods We used microglial cell line, BV2 cells. TonEBP was knocked down using lentiviral transduction of shRNA. In animals, TonEBP was deleted from myeloid cells using a line of mouse with floxed TonEBP. Cerulenin was used to block the NF-κB cofactor function of TonEBP. Results TonEBP deficiency blocked the LPS-induced expression of pro-inflammatory cytokines and enzymes in association with decreased activity of NF-κB in BV2 cells. We found that there was also a decreased activity of AP-1 and that TonEBP was a transcriptional cofactor of AP-1 as well as NF-κB. Interestingly, we found that myeloid-specific TonEBP deletion blocked the LPS-induced microglia activation and subsequent neuronal cell death and memory loss. Cerulenin disrupted the assembly of the TonEBP/NF-κB/AP-1/p300 complex and suppressed the LPS-induced microglial activation and the neuronal damages in animals. Conclusions TonEBP is a key mediator of microglial activation and neuroinflammation relevant to neuronal damage. Cerulenin is an effective blocker of the TonEBP actions.

scholarly journals The Role of Inflammation in the Pathogenesis of Macular Edema Secondary to Retinal Vascular Diseases

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Francisco J. Ascaso ◽  
Valentín Huerva ◽  
Andrzej Grzybowski
Keyword(s):  
Macular Edema ◽  
Adhesion Molecules ◽  
Retinal Vein Occlusion ◽  
Diabetic Macular Edema ◽  
Inflammatory Mediators ◽  
Vascular Diseases ◽  
Vein Occlusion ◽  
Inflammatory Processes ◽  
Nonspecific Sign

Macular edema (ME) is a nonspecific sign of numerous retinal vascular diseases. This paper is an updated overview about the role of inflammatory processes in the genesis of both diabetic macular edema (DME) and ME secondary to retinal vein occlusion (RVO). We focus on the inflammatory mediators implicated, the effect of the different intravitreal therapies, the recruitment of leukocytes mediated by adhesion molecules, and the role of retinal Müller glial (RMG) cells.

scholarly journals Ischemic Cerebral Endothelial Cell–Derived Exosomes Promote Axonal Growth

Stroke ◽  
2020 ◽  
Vol 51 (12) ◽  
pp. 3701-3712
Author(s):  
Yi Zhang ◽  
Yi Qin ◽  
Michael Chopp ◽  
Chao Li ◽  
Amy Kemper ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Neuronal Cell ◽  
Axonal Growth ◽  
Mature Mirnas ◽  
Bioinformatic Analysis ◽  
Axonal Outgrowth ◽  
Ischemic Brain ◽  
Neuronal Homeostasis ◽  
Neuronal Cell Bodies

Background and Purpose: Cerebral endothelial cells (CECs) and axons of neurons interact to maintain vascular and neuronal homeostasis and axonal remodeling in normal and ischemic brain, respectively. However, the role of exosomes in the interaction of CECs and axons in brain under normal conditions and after stroke is unknown. Methods: Exosomes were isolated from CECs of nonischemic rats and is chemic rats (nCEC-exos and isCEC-exos), respectively. A multicompartmental cell culture system was used to separate axons from neuronal cell bodies. Results: Axonal application of nCEC-exos promotes axonal growth of cortical neurons, whereas isCEC-exos further enhance axonal growth than nCEC-exos. Ultrastructural analysis revealed that CEC-exos applied into distal axons were internalized by axons and reached to their parent somata. Bioinformatic analysis revealed that both nCEC-exos and isCEC-exos contain abundant mature miRNAs; however, isCEC-exos exhibit more robust elevation of select miRNAs than nCEC-exos. Mechanistically, axonal application of nCEC-exos and isCEC-exos significantly elevated miRNAs and reduced proteins in distal axons and their parent somata that are involved in inhibiting axonal outgrowth. Blockage of axonal transport suppressed isCEC-exo–altered miRNAs and proteins in somata but not in distal axons. Conclusions: nCEC-exos and isCEC-exos facilitate axonal growth by altering miRNAs and their target protein profiles in recipient neurons.

Evidence for a protective role of the CX3CL1/CX3CR1 axis in a model of amyotrophic lateral sclerosis

2019 ◽  
Vol 400 (5) ◽  
pp. 651-661 ◽  
Author(s):  
Chang Liu ◽  
Kun Hong ◽  
Huifang Chen ◽  
Yanping Niu ◽  
Weisong Duan ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Communication System ◽  
Microglial Activation ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Degradation Pathway ◽  
Neuroprotective Effects ◽  
End Stage ◽  
Lateral Sclerosis

Abstract Aberrant microglial activation and neuroinflammation is a pathological hallmark of amyotrophic lateral sclerosis (ALS). Fractalkine (CX3CL1) is mostly expressed on neuronal cells. The fractalkine receptor (CX3CR1) is predominantly expressed on microglia. Many progressive neuroinflammatory disorders show disruption of the CX3CL1/CX3CR1 communication system. But the exact role of the CX3CL1/CX3CR1 in ALS pathology remains unknown. F1 nontransgenic/CX3CR1+/− females were bred with SOD1G93A/CX3CR1+/− males to produce F2 SOD1G93A/CX3CR1−/−, SOD1G93A/CX3CR1+/+. We analyzed end-stage (ES) SOD1G93A/CX3CR1−/− mice and progression-matched SOD1G93A/CX3CR1+/+ mice. Our study showed that the male SOD1G93A/CX3CR1−/− mice died sooner than male SOD1G93A/CX3CR1+/+ mice. In SOD1G93A/CX3CR1−/− mice demonstrated more neuronal cell loss, more microglial activation and exacerbated SOD1 aggregation at the end-stage of ALS. The NF-κB pathway was activated; the autophagy-lysosome degradation pathway and the autophagosome maturation were impaired. Our results indicated that the absence of CX3CR1/CX3CL1 signaling in the central nervous system (CNS) may worsen neurodegeneration. The CX3CL1/CX3CR1 communication system has anti-inflammatory and neuroprotective effects and plays an important role in maintaining autophagy activity. This effort may lead to new therapeutic strategies for neuroprotection and provide a therapeutic target for ALS patients.

scholarly journals Novel insights into the neuroendocrine control of inflammation: the role of GR and PARP1

2014 ◽  
Vol 3 (1) ◽  
pp. R1-R12 ◽  
Author(s):  
Fernando Aprile-Garcia ◽  
María Antunica-Noguerol ◽  
Maia Ludmila Budziñski ◽  
Ana C Liberman ◽  
Eduardo Arzt
Keyword(s):  
Inflammatory Mediators ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Activator Protein 1 ◽  
Post Translational Modification ◽  
Cytokines And Chemokines ◽  
Inflammatory Processes ◽  
Neuroendocrine Axis

Inflammatory responses are elicited after injury, involving release of inflammatory mediators that ultimately lead, at the molecular level, to the activation of specific transcription factors (TFs; mainly activator protein 1 and nuclear factor-κB). These TFs propagate inflammation by inducing the expression of cytokines and chemokines. The neuroendocrine system has a determinant role in the maintenance of homeostasis, to avoid exacerbated inflammatory responses. Glucocorticoids (GCs) are the key neuroendocrine regulators of the inflammatory response. In this study, we describe the molecular mechanisms involved in the interplay between inflammatory cytokines, the neuroendocrine axis and GCs necessary for the control of inflammation. Targeting and modulation of the glucocorticoid receptor (GR) and its activity is a common therapeutic strategy to reduce pathological signaling. Poly (ADP-ribose) polymerase 1 (PARP1) is an enzyme that catalyzes the addition of PAR on target proteins, a post-translational modification termed PARylation. PARP1 has a central role in transcriptional regulation of inflammatory mediators, both in neuroendocrine tumors and in CNS cells. It is also involved in modulation of several nuclear receptors. Therefore, PARP1 and GR share common inflammatory pathways with antagonic roles in the control of inflammatory processes, which are crucial for the effective maintenance of homeostasis.

Potential Role of Cytokines in Children with Acute Appendicitis and Acute Mesenteric Lymphadenitis

2011 ◽  
Vol 11 (1) ◽  
pp. 130-133
Author(s):  
Astra Zviedre ◽  
Arnis Engelis ◽  
Mohit Kakar ◽  
Aigars Pētersons
Keyword(s):  
Early Detection ◽  
Acute Appendicitis ◽  
Inflammatory Mediators ◽  
Potential Role ◽  
Clinical Symptoms ◽  
Future Research ◽  
Mesenteric Lymphadenitis ◽  
Proper Diagnosis ◽  
Near Future

Potential Role of Cytokines in Children with Acute Appendicitis and Acute Mesenteric Lymphadenitis Although, AAP and AML have different etiological factors, clinical symptoms are very much similar but treatment tactics in both the disease differ a lot. In case of AML, treatment is more conservative and does not require hospitalization while in case of AAP immediate hospitalization and maybe further surgery can be mandatory. With the identification of group of cytokines serum inflammatory mediators IL-8, IL-10, IL-12[p70], IL-17, TNF-a and MCP-1, it is believed early and proper diagnosis of AAP in the near future. Research of cytokines-serum inflammatory mediators has opened new opportunities for an early detection and differentiation of these two diseases in children.

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