scholarly journals A peripheral lipid sensor GPR120 remotely contributes to suppression of PGD2-microglia-provoked neuroinflammation and neurodegeneration in the mouse hippocampus

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Kensuke Iwasa ◽  
Shinji Yamamoto ◽  
Kota Yamashina ◽  
Nan Yagishita-kyo ◽  
Kei Maruyama ◽  
...  
Keyword(s):  
Microglial Activation ◽  
Hippocampal Volume ◽  
Neuronal Function ◽  
Proinflammatory Mediators ◽  
Gene And Protein Expression ◽  
Prostaglandin D Synthase ◽  
Free Fatty Acid Receptor ◽  
Glucagon Like Peptide 1 ◽  
Lipid Sensor ◽  
The Relationship

Abstract Background Neuroinflammation is a key pathological component of neurodegenerative disease and is characterized by microglial activation and the secretion of proinflammatory mediators. We previously reported that a surge in prostaglandin D2 (PGD2) production and PGD2-induced microglial activation could provoke neuroinflammation. We also reported that a lipid sensor GPR120 (free fatty acid receptor 4), which is expressed in intestine, could be activated by polyunsaturated fatty acids (PUFA), thereby mediating secretion of glucagon-like peptide-1 (GLP-1). Dysfunction of GPR120 results in obesity in both mice and humans. Methods To reveal the relationship between PGD2-microglia-provoked neuroinflammation and intestinal PUFA/GPR120 signaling, we investigated neuroinflammation and neuronal function with gene and protein expression, histological, and behavioral analysis in GPR120 knockout (KO) mice. Results In the current study, we discovered notable neuroinflammation (increased PGD2 production and microglial activation) and neurodegeneration (declines in neurogenesis, hippocampal volume, and cognitive function) in GPR120 KO mice. We also found that Hematopoietic–prostaglandin D synthase (H-PGDS) was expressed in microglia, microglia were activated by PGD2, H-PGDS expression was upregulated in GPR120 KO hippocampus, and inhibition of PGD2 production attenuated this neuroinflammation. GPR120 KO mice exhibited reduced intestinal, plasma, and intracerebral GLP-1 contents. Peripheral administration of a GLP-1 analogue, liraglutide, reduced PGD2-microglia-provoked neuroinflammation and further neurodegeneration in GPR120 KO mice. Conclusions Our results suggest that neurological phenotypes in GPR120 KO mice are probably caused by dysfunction of intestinal GPR120. These observations raise the possibility that intestinal GLP-1 secretion, stimulated by intestinal GPR120, may remotely contributed to suppress PGD2-microglia-provoked neuroinflammation in the hippocampus.

scholarly journals Dysfunction of a Peripheral Lipid Sensor Gpr120 Causes Pgd2-microglia-provoked Neuroinflammation

2020 ◽  
Author(s):  
Kensuke Iwasa ◽  
Shinji Yamamoto ◽  
Kota Yamashina ◽  
Chiaki Sakemoto ◽  
Nan Yagishita-kyo ◽  
...  
Keyword(s):  
Microglial Activation ◽  
Hippocampal Volume ◽  
Neuronal Function ◽  
Proinflammatory Mediators ◽  
Prostaglandin D Synthase ◽  
Free Fatty Acid Receptor ◽  
Glucagon Like Peptide 1 ◽  
Lipid Sensor ◽  
The Relationship ◽  
The Brain

Abstract Background Neuroinflammation is a key pathological component of neurodegenerative disease and is characterized by microglial activation and the secretion of proinflammatory mediators. We previously reported that a surge in prostaglandin D2 (PGD2) production and PGD2-induced microglial activation could provoke neuroinflammation. We also reported that a lipid sensor GPR120 (free fatty acid receptor 4), which is expressed in enteroendocrine cells in the intestine, could be activated by polyunsaturated fatty acids (PUFA), thereby mediating secretion of glucagon-like peptide-1 (GLP-1). Dysfunction of GPR120 results in obesity in both mice and humans. To reveal the relationship between PGD2-microglia-provoked neuroinflammation and intestinal PUFA/GPR120 signaling, we investigated neuroinflammation and neuronal function in GPR120 knockout (KO) mice. Results In the current study, we discovered notable PGD2-microglia-provoked neuroinflammation (increased PGD2 production and microglial activation) and neurodegeneration (declines in neurogenesis, hippocampal volume, and cognitive function) in GPR120 KO mice. We also found that Hematopoietic-prostaglandin D synthase (H-PGDS) was expressed in microglia, microglia were activated by PGD2, H-PGDS expression was upregulated in GPR120 KO hippocampus, and inhibition of PGD2 production attenuated this neuroinflammatory pathway, suggesting that PGD2-microglia-provoked neuroinflammation was constantly occurring in the hippocampus of GPR120 KO mice. GPR120 mRNA was detected in the intestinal tissues, but not in the brain tissue of WT mice. GPR120 KO mice exhibited reduced intestinal, plasma, and intracerebral GLP-1 levels. Peripheral administration of a GLP-1 analogue, liraglutide, reduced PGD2-microglia-provoked neuroinflammation and further neurodegeneration in GPR120 KO mice. Conclusions Our results suggest that PGD2-microglia-provoked neuroinflammation and neurodegeneration observed in GPR120 KO mice are probably caused by defects in intestinal GPR120 function, and not in the CNS. Our results also suggest that GLP-1 secretion, stimulated by intestinal GPR120, may remotely contribute to suppression of PGD2-microglia-provoked neuroinflammation and further neurodegeneration in the hippocampus.

scholarly journals The relationship between CD204 M2-polarized tumour-associated macrophages (TAMs), tumour-infiltrating lymphocytes (TILs), and microglial activation in glioblastoma microenvironment: a novel immune checkpoint receptor target

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Maher Kurdi ◽  
Badrah Alghamdi ◽  
Nadeem Shafique Butt ◽  
Saleh Baeesa
Keyword(s):  
Microglial Activation ◽  
Inverse Correlation ◽  
Idh1 Mutation ◽  
High Expression ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Tumour Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes ◽  
The Relationship ◽  
Low Expression

Abstract Background Tumour associated macrophages (TAMs) and tumour infiltrating lymphocytes (TILs) are considered dominant cells in glioblastoma microenvironment. Aim The purpose of this study was to assess the expression of CD204+ M2-polarized TAMs in glioblastomas and their relationship with CD4+TILs, Iba+microglia, and IDH1 mutation. We also exploreed the prognostic value of these markers on the recurrence-free interval (RFI). Methods The expressions of CD204+TAMs, CD4+TILs, and Iba1+microglia were quantitively assessed in 45 glioblastomas using immunohistochemistry. Kaplan–Meier analysis and Cox hazards were used to examine the relationship between these factors. Results CD204+TAMs were highly expressed in 32 tumours (71%) and the remaining 13 tumours (29%) had reduced expression. CD4+TILs were highly expressed in 10 cases (22%) and 35 cases (77.8%) had low expression. There was an inverse correlation between CD204+TAMs and CD4+TILs, in which 85% of tumours had a high expression of CD204+TAMs and a low expression of CD4+TILs. Nevertheless, there was no significant difference in IDH1 mutation status between the two groups (p = 0.779). There was a significant difference in Iba1+microglial activation between IDH1mutant and IDH1wildtype groups (p = 0.031). For cases with a high expression of CD204+TAMs and a low expression of CD4+TILs, there was a significant difference in RFI after treatment with chemoradiotherapy or radiotherapy (p = 0.030). Conclusion Glioblastoma with a dense CD204+TAMs and few CD4+TILs is associated with IDH1wildtype. These findings suggest that TAMs masks tumour cell and suppress T-cell tumoricidal functions via immunomodulatory mechanisms. Blockade of the CD204-TAM receptor may prevent this mechanism and allow the evolution of TILs.

scholarly journals PET evaluation of light-induced modulation of microglial activation and GLP-1R expression in depressive rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yu Liu ◽  
Lizhen Wang ◽  
Donghui Pan ◽  
Mingzhu Li ◽  
Yaoqi Li ◽  
...  
Keyword(s):  
Microglial Activation ◽  
Light Therapy ◽  
Emission Tomography ◽  
Noninvasive Evaluation ◽  
Mild Stress ◽  
Positron Emission ◽  
Therapeutic Choice ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The Brain

AbstractLight therapy has been accepted as a promising therapeutic choice for depression. Positron emission tomography (PET) combined with specific radiotracers has great benefits for revealing pathogenesis and developing therapeutics. This study aimed to investigate the influences of light therapy on microglial activation and glucagon-like peptide-1 receptor (GLP-1R) expression in the brain of depressive rats using [18F]DPA-714 and [18F]exendin-4 PET. The results showed that chronic unpredictable mild stress (CUMS)-induced depressive rats had poorer performance in behavioral tests compared to normal rats (p < 0.05) and the depressive-like behavior could be ameliorated by light therapy. Besides, depressive rats had significantly higher [18F]DPA-714 uptake and lower [18F]FDG uptake compare to normal rats in 11 and 9 regions of interest (ROIs) of the brain, respectively (p < 0.05). After 5 weeks of light therapy, higher [18F]FDG and [18F]exendin-4 uptake was observed in most ROIs of light therapy-treated depressive rats compared to untreated depressive rats (p < 0.05) and no significant differences existed in [18F]DPA-714 uptake between the two groups. This study demonstrated that light therapy can ameliorate depressive-like behavior, improve glucose metabolism, and halt the decline of brain GLP-1R expression of depressive rats, but have no effects on microglial activation caused by CUMS. Besides, this study validated that [18F]DPA-714 and [18F]exendin-4 PET have the potential for noninvasive evaluation of microglial activation and GLP-1R expression in the brain of depression.

scholarly journals The Relationship Between Hippocampal Volume and Activity Diversity

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 652-653
Author(s):  
Emily Urban-Wojcik ◽  
Soomi Lee ◽  
Susan Charles ◽  
David Almeida ◽  
Richard Davidson ◽  
...  
Keyword(s):  
Brain Volume ◽  
Daily Diary ◽  
Brain Structures ◽  
Total Activity ◽  
The United States ◽  
Hippocampal Volume ◽  
Daily Activities ◽  
Activity Time ◽  
Left And Right ◽  
The Relationship

Abstract The hippocampus, implicated in learning, memory, and spatial navigation, is one of the few brain structures that demonstrates neurogenesis across the lifespan. Hippocampal volume (HV), then, may be a marker of exposure to and engagement with novel events and environments, which may in turn be related to cognitive functioning. The present study examined the relationship between HV and activity diversity (AD), which characterizes the range and evenness of participation in daily activities. In 52 participants who completed the daily-diary and neuroscience projects of the Midlife in the United States Refresher study, greater levels of AD across an 8-day period were related to greater HV averaged across the left and right hemispheres when adjusting for overall brain volume, total activity time, time between projects, and relevant sociodemographic variables, b=1128mm3, t(43)=2.54, p=.015. These findings may point to a mechanism through which AD has been related to better cognitive and mental health outcomes.

Hippocampal volume and subjective memory impairment in depressed patients

2004 ◽  
Vol 19 (7) ◽  
pp. 438-440 ◽  
Author(s):  
Armin von Gunten ◽  
Maria A. Ron
Keyword(s):  
Memory Impairment ◽  
Hippocampal Volume ◽  
Subjective Memory ◽  
Subjective Memory Impairment ◽  
Depressed Patients ◽  
The Right ◽  
The Relationship

AbstractThe relationship between severity of subjective memory impairment and volume of the hippocampus/amygdala complex was investigated in non-demented depressed patients and it was found to correlate with decreasing volume in the right hippocampus.

Plasma GLP-1 response to oral and intraduodenal nutrients in health and type 2 diabetes – impact on gastric emptying

2021 ◽  
Author(s):  
Cong Xie ◽  
Weikun Huang ◽  
Linda E Watson ◽  
Stijn Soenen ◽  
Richard L Young ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Gastric Emptying ◽  
Breath Test ◽  
Oral Glucose ◽  
Gastric Emptying Rate ◽  
Postprandial Glycemia ◽  
Glucagon Like Peptide 1 ◽  
The Relationship ◽  
Potato Meal

Abstract Context Both gastric emptying and the secretion of glucagon-like peptide-1 (GLP-1) are major determinants of postprandial glycemia in health and type 2 diabetes (T2D). GLP-1 secretion after a meal is dependent on the entry of nutrients into the small intestine, which, in turn, slows gastric emptying. Objective To define the relationship between gastric emptying and the GLP-1 response to both oral and small intestinal nutrients in subjects with and without T2D. Design We evaluated: (i) the relationship between gastric emptying (breath test) and postprandial GLP-1 levels after a mashed potato meal in 73 T2D subjects; (ii) inter-individual variations in GLP-1 response to (a) intraduodenal glucose (4kcal/min) during euglycemia and hyperglycemia in 11 healthy, and 12 T2D, subjects, (b) intraduodenal fat (2kcal/min) in 15 T2D subjects, and (c) intraduodenal protein (3kcal/min) in 10 healthy subjects; and (iii) the relationship between gastric emptying (breath test) of 75g oral glucose and the GLP-1 response to intraduodenal glucose (4kcal/min) in 21 subjects (9 healthy, 12 T2D). Results The GLP-1 response to the mashed potato meal was unrelated to the gastric half-emptying time (T50). The GLP-1 responses to intraduodenal glucose, fat and protein varied substantially between individuals, but intra-individual variation to glucose was modest. The T50 of oral glucose was related directly to the GLP-1 response to intraduodenal glucose (r=0.65, P=0.002). Conclusions In a given individual, gastric emptying is not a determinant of the postprandial GLP-1 response. However, the intrinsic gastric emptying rate is determined in part by the responsiveness of GLP-1 to intestinal nutrients.

scholarly journals Regulation of Neutrophil Degranulation and Cytokine Secretion: A Novel Model Approach Based on Linear Fitting

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Isabelle Naegelen ◽  
Nicolas Beaume ◽  
Sébastien Plançon ◽  
Véronique Schenten ◽  
Eric J. Tschirhart ◽  
...  
Keyword(s):  
Time Series ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Cytokine Secretion ◽  
Human Neutrophils ◽  
Cytokine Release ◽  
Linear Fitting ◽  
Proinflammatory Mediators ◽  
The Relationship ◽  
Model Approach

Neutrophils participate in the maintenance of host integrity by releasing various cytotoxic proteins during degranulation. Due to recent advances, a major role has been attributed to neutrophil-derived cytokine secretion in the initiation, exacerbation, and resolution of inflammatory responses. Because the release of neutrophil-derived products orchestrates the action of other immune cells at the infection site and, thus, can contribute to the development of chronic inflammatory diseases, we aimed to investigate in more detail the spatiotemporal regulation of neutrophil-mediated release mechanisms of proinflammatory mediators. Purified human neutrophils were stimulated for different time points with lipopolysaccharide. Cells and supernatants were analyzed by flow cytometry techniques and used to establish secretion profiles of granules and cytokines. To analyze the link between cytokine release and degranulation time series, we propose an original strategy based on linear fitting, which may be used as a guideline, to (i) define the relationship of granule proteins and cytokines secreted to the inflammatory site and (ii) investigate the spatial regulation of neutrophil cytokine release. The model approach presented here aims to predict the correlation between neutrophil-derived cytokine secretion and degranulation and may easily be extrapolated to investigate the relationship between other types of time series of functional processes.

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