scholarly journals HspB4/αA-Crystallin Modulates Neuroinflammation in the Retina via the Stress-Specific Inflammatory Pathways

2021 ◽  
Vol 10 (11) ◽  
pp. 2384
Author(s):  
Madhu Nath ◽  
Yang Shan ◽  
Angela M. Myers ◽  
Patrice Elie Fort
Keyword(s):  
Inflammatory Response ◽  
Glial Cells ◽  
Inflammatory Markers ◽  
Regulatory Function ◽  
Low Grade ◽  
Causative Role ◽  
Inflammatory Pathways ◽  
Stress Dependent ◽  
Metabolic Stresses

Purpose: We have previously demonstrated that HspB4/αA-crystallin, a molecular chaperone, plays an important intrinsic neuroprotective role during diabetes, by its phosphorylation on residue 148. We also reported that HspB4/αA-crystallin is highly expressed by glial cells. There is a growing interest in the potential causative role of low-grade inflammation in diabetic retinopathy pathophysiology and retinal Müller glial cells’ (MGCs’) participation in the inflammatory response. MGCs indeed play a central role in retinal homeostasis via secreting various cytokines and other mediators. Hence, this study was carried out to delineate and understand the regulatory function of HspB4/αA-crystallin in the inflammatory response associated with metabolic stresses. Methods: Primary MGCs were isolated from knockout HspB4/αA-crystallin mice. These primary cells were then transfected with plasmids encoding either wild-type (WT), phosphomimetic (T148D), or non-phosphorylatable mutants (T148A) of HspB4/αA-crystallin. The cells were exposed to multiple metabolic stresses including serum starvation (SS) or high glucose with TNF-alpha (HG + T) before being further evaluated for the expression of inflammatory markers by qPCR. The total protein expression along with subcellular localization of NF-kB and the NLRP3 component was assessed by Western blot. Results: Elevated levels of IL-6, IL-1β, MCP-1, and IL-18 in SS were significantly diminished in MGCs overexpressing WT and further in T148D as compared to EV. The HG + T-induced increase in these inflammatory markers was also dampened by WT and even more significantly by T148D overexpression, whereas T148A was ineffective in either stress. Further analysis revealed that overexpression of WT or the T148D, also led to a significant reduction of Nlrp3, Asc, and caspase-1 transcript expression in serum-deprived MGCs and nearly abolished the NF-kB induction in HG + T diabetes-like stress. This mechanistic effect was further evaluated at the protein level and confirmed the stress-dependent regulation of NLRP3 and NF-kB by αA-crystallin. Conclusions: The data gathered in this study demonstrate the central regulatory role of HspB4/αA-crystallin and its modulation by phosphorylation on T148 in retinal MGCs. For the first time, this study demonstrates that HspB4/αA-crystallin can dampen the stress-induced expression of pro-inflammatory cytokines through the modulation of multiple key inflammatory pathways, therefore, suggesting its potential as a therapeutic target for the modulation of chronic neuroinflammation.

scholarly journals αA-Crystallin modulates neuroinflammation in the retina via stress-specific inflammatory pathways

2021 ◽  
Author(s):  
Madhu Nath ◽  
Yang Shan ◽  
Angela M Myers ◽  
Patrice E Fort
Keyword(s):  
Inflammatory Response ◽  
Glial Cells ◽  
Inflammatory Markers ◽  
Regulatory Function ◽  
Serum Starvation ◽  
Low Grade ◽  
Causative Role ◽  
Inflammatory Pathways ◽  
Stress Dependent

Abstract Purpose We have previously demonstrated that αA-crystallin, a molecular chaperone, plays an important intrinsic neuroprotective role during diabetes, by its phosphorylation on residue 148. We also reported that αA-crystallin is highly expressed by glial cells. There is a growing interest in the potential causative role of low-grade inflammation in diabetic retinopathy pathophysiology and retinal Müller glial cells (MGCs) participation in the inflammatory response. MGCs indeed play a central role in retinal homeostasis via secreting various cytokines and other mediators. Hence, this study was carried out to delineate and understand the regulatory function of αA-crystallin in the inflammatory response associated with metabolic stresses. Methods Primary MGCs were isolated from Ko-αA-crystallin mice. These primary cells were then transfected with plasmids encoding either wild-type (WT), phosphomimetic (T148D), or non-phosphorylatable mutants (T148A) of αA-crystallin. The cells were exposed to multiple metabolic stress including serum starvation (SS) or high glucose with TNF-alpha (HG + T) before being further evaluated for the expression of inflammatory markers by qPCR. The total protein expression along with subcellular localization of NF-kB & NLRP3 component was assessed by western blot. Results Elevated levels of IL-6, IL-1β, MCP-1, and IL-18 in SS were significantly diminished in MGCs overexpressing WT and further in T148D as compared to EV. The HG + T-induced increase in these inflammatory markers was also dampened by WT and even more significantly by T148D overexpression, whereas T148A was ineffective in either stress. Further analysis revealed that overexpression of WT or the T148D, also lead to a significant reduction of Nlrp3, Asc, and caspase-1 transcript expression in serum-deprived MGCs and nearly abolished the NF-kB induction in HG + T diabetes-like stress. This mechanistic effect was further evaluated at the protein level and confirmed the stress-dependent regulation of NLRP3 and NF-kB by αA-crystallin. Conclusion The data gathered in this study demonstrate the central regulatory role of αA-crystallin and its modulation by phosphorylation on T148 in retinal MGCs. For the first time, this study demonstrates that αA-crystallin can dampen the stress-induced expression of pro-inflammatory cytokines through modulation of multiple key inflammatory pathways, therefore, suggesting its potential as a therapeutic target for modulation of chronic neuroinflammation.

scholarly journals Lifestyle Factors that can Induce an Independent and Persistent Low-Grade Systemic Inflammatory Response: A Wholistic Approach

2016 ◽  
Vol 3 (1) ◽  
pp. 34-48
Author(s):  
George Vrousgos
Keyword(s):  
Inflammatory Response ◽  
Metabolic Diseases ◽  
Lifestyle Factors ◽  
Systemic Inflammatory Response ◽  
Low Grade ◽  
Related Disorder ◽  
Inflammatory Pathways ◽  
Regulation Of Metabolism ◽  
Inflammatory State ◽  
Ultra Endurance

Subclinical inflammation was first shown in numerous chronic medical illnesses and in the early 1900s, activation of immune-inflammatory pathways was initially observed in a lifestyle-related disorder such as depression. A chronic mild inflammatory state is also a key feature of obesity as well as insulin resistance and other metabolic diseases. This particular form of immune process has given rise to the concept of “metaflammation” (metabolically triggered inflammation) because it can target vital organs and tissues that are critical for the regulation of metabolism, and ultimately disrupt systemic homoeostasis with detrimental health effects. However, accumulating evidence demonstrates a link between metaflammation and a number of lifestyle factors. Lifestyle variables such as ultra-endurance exercise, physical inactivity, extremes of sleep duration, cigarette smoking, burnout, anxiety, and depression can activate multiple immune-inflammatory pathways. Therefore, this review of the literature that bears hallmarks of a systematic review investigates and presents published research data of these lifestyle factors that can induce an independent and persistent low-grade systemic inflammatory response, within the human body, evaluated through the measurement of various biomarkers.

scholarly journals Involvement of Transcription Factor FoxO1 in the Pathogenesis of Polycystic Ovary Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Renfeng Xu ◽  
Zhengchao Wang
Keyword(s):  
Transcription Factor ◽  
Polycystic Ovary Syndrome ◽  
Inflammatory Response ◽  
Polycystic Ovary ◽  
Cell Types ◽  
Low Grade ◽  
Childbearing Age ◽  
Forkhead Transcription Factor ◽  
Ovary Syndrome

FoxO1 is a member of the forkhead transcription factor family subgroup O (FoxO), which is expressed in many cell types, and participates in various pathophysiological processes, including cell proliferation, apoptosis, autophagy, metabolism, inflammatory response, cytokine expression, immune differentiation, and oxidative stress resistance. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in the women of childbearing age, which is regulated via a variety of signaling pathways. Currently, the specific mechanism underlying the pathogenesis of PCOS is still unclear. As an important transcription factor, FoxO1 activity might be involved in the pathophysiology of PCOS. PCOS has been associated with insulin resistance and low-grade inflammatory response. Therefore, the studies regarding the role of FoxO1 in the incidence and associated complications of PCOS will help provide novel ideas for establishing the treatment strategy of PCOS.

scholarly journals Effect of DHT-Induced Hyperandrogenism on the Pro-Inflammatory Cytokines in a Rat Model of Polycystic Ovary Morphology

Medicina ◽  
2020 ◽  
Vol 56 (3) ◽  
pp. 100
Author(s):  
Abhaya Krishnan ◽  
Sridhar Muthusami ◽  
Loganayaki Periyasamy ◽  
Jone A. Stanley ◽  
Vasudevan Gopalakrishnan ◽  
...  
Keyword(s):  
Inflammatory Markers ◽  
Polycystic Ovary ◽  
Elevated Serum ◽  
Model System ◽  
Reproductive Age ◽  
Albino Rats ◽  
Low Grade ◽  
Tnf Α ◽  
Inflammatory State

Background and Objectives: Polycystic ovary syndrome (PCOS) is one of the most prevalent disorders among women of reproductive age. It is considered as a pro-inflammatory state with chronic low-grade inflammation, one of the key factors contributing to the pathogenesis of this disorder. Polycystic ovary is a well-established criterion for PCOS. The present investigation aimed at finding the role of hyperandrogenism, the most important feature of PCOS, in the development of this inflammatory state. To address this problem, we adopted a model system that developed polycystic ovary morphology (PCOM), which could be most effectively used in order to study the role of non-aromatizable androgen in inflammation in PCOS. Materials and Methods: Six rats were used to induce PCOM in 21-days-old female Wistar albino rats by using a pre-determined release of dihydrotestosterone (DHT), a potent non-aromatizable androgen, achieved by implanting a DHT osmotic pump, which is designed to release a daily dose of 83 μg. Results: After 90 days, the rats displayed irregular estrous cycles and multiple ovarian cysts similar to human PCOS. Elevated serum inflammatory markers such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and the presence of a necrotic lesion in the liver, osteoclast in the femur, multinucleated giant cells and lymphocytes in the ovary based on histopathological observation of DHT-treated rats clearly indicated the onset of inflammation in the hyperandrogenic state. Our results show no significant alterations in serum hormones such as luteinizing hormone (LH), follicle stimulating hormone (FSH), insulin, and cortisol between control and hyperandrogenised rats. DHT was significantly elevated as compared to control. mRNA studies showed an increased expression level of TNF-α and IL-1β, further, the mRNA expression of urocortin 1 (Ucn-1) was stupendously elevated in the liver of hyperandrogenised rats. Conclusions: Thus, results from this study provide: (1) a good PCOM model system in order to study the inflammatory changes in PCOS aspects, (2) alteration of inflammatory markers in PCOM rats that could be either due to its direct effect or by the regulation of various inflammatory genes and markers in the liver of hyperandrogenic state suggesting the regulatory role of DHT, and (3) alteration in stress-related protein in the liver of PCOM rats.

Causative role of mast cell and mast cell-regulatory function of disialyllacto-N-tetraose in necrotizing enterocolitis

2021 ◽  
Vol 96 ◽  
pp. 107597
Author(s):  
Wenting Zhang ◽  
Jingqiu He-Yang ◽  
Wenjun Zhuang ◽  
Jie Liu ◽  
Xiaoying Zhou
Keyword(s):  
Mast Cell ◽  
Necrotizing Enterocolitis ◽  
Regulatory Function ◽  
Causative Role

scholarly journals Mitochondrial Dysfunction and Chronic Inflammation in Polycystic Ovary Syndrome

2021 ◽  
Vol 22 (8) ◽  
pp. 3923
Author(s):  
Siarhei A. Dabravolski ◽  
Nikita G. Nikiforov ◽  
Ali H. Eid ◽  
Ludmila V. Nedosugova ◽  
Antonina V. Starodubova ◽  
...  
Keyword(s):  
Chronic Inflammation ◽  
Polycystic Ovary ◽  
Low Grade ◽  
Causative Role ◽  
Mitochondrial Dysfunctions ◽  
Mtdna Mutations ◽  
Targeted Treatments ◽  
Tnf Α ◽  
Novel Biomarkers

Polycystic ovarian syndrome (PCOS) is the most common endocrine–metabolic disorder affecting a vast population worldwide; it is linked with anovulation, mitochondrial dysfunctions and hormonal disbalance. Mutations in mtDNA have been identified in PCOS patients and likely play an important role in PCOS aetiology and pathogenesis; however, their causative role in PCOS development requires further investigation. As a low-grade chronic inflammation disease, PCOS patients have permanently elevated levels of inflammatory markers (TNF-α, CRP, IL-6, IL-8, IL-18). In this review, we summarise recent data regarding the role of mtDNA mutations and mitochondrial malfunctions in PCOS pathogenesis. Furthermore, we discuss recent papers dedicated to the identification of novel biomarkers for early PCOS diagnosis. Finally, traditional and new mitochondria-targeted treatments are discussed. This review intends to emphasise the key role of oxidative stress and chronic inflammation in PCOS pathogenesis; however, the exact molecular mechanism is mostly unknown and requires further investigation.

scholarly journals Anti-inflammatory protein TNFα-stimulated gene-6 (TSG-6) reduces inflammatory response after brain injury in mice

2020 ◽  
Author(s):  
Kazadi Nadine Mutoji ◽  
Mingxia Sun ◽  
Amanda Nash ◽  
Sudan Puri ◽  
Vincent Hascall ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Markers ◽  
Brain Injuries ◽  
Glial Scar ◽  
Background Current ◽  
Littermate Control ◽  
Injury Site ◽  
Inflammatory Protein ◽  
Anti Inflammatory

Abstract Background: Current research suggests that the glial scar surrounding penetrating brain injuries is instrumental in preserving the surrounding uninjured tissue by limiting the inflammatory response to the injury site. We recently showed that (TNF)-stimulated gene-6 (TSG-6), a well-established anti-inflammatory molecule, is present within the glial scar. We hereby investigate the role of TSG-6 within the glial scar.Methods: TSG-6 null and littermate control mice were subjected to penetrating brain injuries, after which the injury site and remaining injured hemisphere were analyzed. The presence of activated astrocytes, inflammatory markers and glial scar components were evaluated by real-time PCR and immunohistochemistry.Results: Our findings demonstrate that mice lacking TSG-6 present a more severe inflammatory response after injury, which is correlated with an enlarged area of astrogliosis beyond the injury site.Conclusion: Our data provides evidence that TSG-6 has an anti-inflammatory role within the glial scar.

scholarly journals Asthma and obesity: endotoxin another insult to add to injury?

2021 ◽  
Vol 135 (24) ◽  
pp. 2729-2748
Author(s):  
Nikita Lad ◽  
Alice M. Murphy ◽  
Cristina Parenti ◽  
Carl P. Nelson ◽  
Neil C. Williams ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Inflammatory Response ◽  
Gut Microbiota ◽  
Inflammatory Diseases ◽  
Systemic Circulation ◽  
Current Evidence ◽  
Low Grade ◽  
Direct Role ◽  
Low Grade Inflammation

Abstract Low-grade inflammation is often an underlying cause of several chronic diseases such as asthma, obesity, cardiovascular disease, and type 2 diabetes mellitus (T2DM). Defining the mediators of such chronic low-grade inflammation often appears dependent on which disease is being investigated. However, downstream systemic inflammatory cytokine responses in these diseases often overlap, noting there is no doubt more than one factor at play to heighten the inflammatory response. Furthermore, it is increasingly believed that diet and an altered gut microbiota may play an important role in the pathology of such diverse diseases. More specifically, the inflammatory mediator endotoxin, which is a complex lipopolysaccharide (LPS) derived from the outer membrane cell wall of Gram-negative bacteria and is abundant within the gut microbiota, and may play a direct role alongside inhaled allergens in eliciting an inflammatory response in asthma. Endotoxin has immunogenic effects and is sufficiently microscopic to traverse the gut mucosa and enter the systemic circulation to act as a mediator of chronic low-grade inflammation in disease. Whilst the role of endotoxin has been considered in conditions of obesity, cardiovascular disease and T2DM, endotoxin as an inflammatory trigger in asthma is less well understood. This review has sought to examine the current evidence for the role of endotoxin in asthma, and whether the gut microbiota could be a dietary target to improve disease management. This may expand our understanding of endotoxin as a mediator of further low-grade inflammatory diseases, and how endotoxin may represent yet another insult to add to injury.

scholarly journals Elevated 2HG does not cause features of tumorigenesis

2021 ◽  
Vol 23 (Supplement_4) ◽  
pp. iv1-iv1
Author(s):  
Julie Adam ◽  
Alina Finch ◽  
Catarina Sepulveda ◽  
Martin Ducker ◽  
Maria Blanca Torroba ◽  
...  
Keyword(s):  
Brain Tumours ◽  
Driver Mutations ◽  
Low Grade ◽  
Causative Role ◽  
Dna Amount ◽  
Knock Out ◽  
Cellular Analysis ◽  
Enzymatic Function ◽  
Mouse Tissues

Abstract Aims Gliomas are the most frequent brain tumours, representing 75% of all primary malignant brain tumours in adults. IDH1 (and IDH2) driver mutations occur in >80% of low grade gliomas and secondary GBMs, in <10% of primary GBMs and other cancers. How IDH1/2 mutations contribute to tumorigenesis is mostly unknown. IDH1/2 convert isocitrate to α-ketoglutarate, but when mutated possess a novel enzymatic function that reduces α-ketoglutarate to D2-hydroxyglutarate (2HG). Indeed 2HG accumulates in IDH1/2-mutant tumours, and this discovery suggested that 2HG may have a role in IDH1/2-mutant tumours onset and progression, possibly by causing dysregulations of various enzymes in the cells. Studies are undergoing to clarify the causative role of 2HG in IDH1/2-mutant tumours, but it is still not clear whether 2HG is the driver/oncometabolite. Our aim is to understand the role of 2HG in developing and adult mouse tissues and whether its accumulation might cause features of gliomagenesis. Method A constitutive D2hgdh Knock-out mouse (D2hgdh KO) was generated and the relative molecular and cellular analysis were performed. Results Brains dissected from D2hgdh KO mice appeared to be histologically normal. No differences were found in the proliferation and labelling retaining capacity of neural stem and progenitors cells (NSC/NPC) of the D2hgdh KO mice compared to controls. A comprehensive metabolites analysis showed that D2hgdh KO mouse accumulated 2HG in various organs and tissues, included total brains and in the NSC/NPC microdissected from the subventricular zone, the site of origin of many human gliomas. The DNA amount of 5mC and 5hmC extracted from brains of D2hgdh KO mice was similar to controls. A normal number of haematopoietic progenitors was also found. Conclusion Although D2hgdh KO mice accumulated 2HG in all tissues analysed, they did not develop any abnormalities and remained completely asymptomatic. This suggests that a mere increment of 2HG in developing and adult tissues may be not sufficient to cause tumorigenesis (and gliomagenesis), leading some doubts on the oncogenic roles of the 2HG in IDH1/2-mutant tumours.

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