scholarly journals Mediterranean Diet Reduces Monocyte Inflammatory Gene Expression and Influences Social Behavior in Nonhuman Primates

2020 ◽  
Author(s):  
Corbin S.C. Johnson ◽  
Carol A. Shively ◽  
Kristofer T. Michalson ◽  
Amanda J. Lea ◽  
Ryne J. DeBo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mediterranean Diet ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Western Diet ◽  
Primate Model ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Increased Risk ◽  
Diet Manipulation

AbstractWestern diet consumption is associated with inflammation, cardiometabolic disease, and mortality in humans, while Mediterranean diet consumption confers protective effects. One likely pathway for this association is through environmentally induced changes in monocyte function, yet the underlying mechanisms remain elusive. We conducted the first randomized, long-term diet manipulation in a non-human primate model to determine whether Western- or Mediterranean-like diets alter monocyte polarization and health. Monocyte gene expression profiles differed markedly between the two diet groups, with significant differences in over 40% of expressed genes. The Western diet induced a more proinflammatory monocyte phenotype overall and upregulated specific monocyte polarization genes. Diet also disrupted the coexpression of numerous gene pairs, including small RNAs and transcription factors associated with metabolism and adiposity in humans. Diet altered affiliative and anxiety-associated behaviors and mediation analysis showed that the diet-altered behaviors contributed significantly (∼50% of the effect of diet on gene expression) to 25% of the differentially expressed genes, suggesting that diet effects on central mechanisms also modulate monocyte gene expression. Together, these results identify both behavioral and molecular mechanisms underlying the health benefits of a Mediterranean diet regimen.Significance StatementSome of our largest public health burdens are driven by dietary changes associated with industrialization, but we still know very little about the molecular mechanisms underlying this link. Characteristic “Western diets” have been associated with increased risk for diseases related to chronic inflammation, while Mediterranean diets have anti-inflammatory benefits. Here, we identify causal effects of diet on inflammatory gene expression where consumption of the Mediterranean diet reduced inflammatory gene expression in monocytes. Additionally, our diet manipulation induced behavioral changes associated with anxiety and social integration, where Mediterranean-fed animals exhibited more positive affiliative behaviors and reduced anxiety. These behaviors were associated with 25% of the diet-affected genes, suggesting an important behavioral route through which diet can impact immune function.

scholarly journals Silencing the lncRNA Maclpil in pro-inflammatory macrophages attenuates acute experimental ischemic stroke via LCP1 in mice

2019 ◽  
Vol 40 (4) ◽  
pp. 747-759 ◽  
Author(s):  
Yan Wang ◽  
Ying Luo ◽  
Yang Yao ◽  
Yuhua Ji ◽  
Liangshu Feng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ischemic Stroke ◽  
Expression Profiles ◽  
Brain Infarction ◽  
Cell Types ◽  
Specific Cell ◽  
Ischemic Brain ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Ischemic Brain Infarction

Long noncoding RNAs (lncRNA) expression profiles change in the ischemic brain after stroke, but their roles in specific cell types after stroke have not been studied. We tested the hypothesis that lncRNA modulates brain injury by altering macrophage functions. Using RNA deep sequencing, we identified 73 lncRNAs that were differentially expressed in monocyte-derived macrophages (MoDMs) and microglia-derived macrophages (MiDMs) isolated in the ischemic brain three days after stroke. Among these, the lncRNA, GM15628, is highly expressed in pro-inflammatory MoDMs but not in MiDMs, and are functionally related to its neighbor gene, lymphocyte cytosolic protein 1 (LCP1), which plays a role in maintaining cell shape and cell migration. We termed this lncRNA as Macrophage contained LCP1 related pro-inflammatory lncRNA, Maclpil. Using cultured macrophages polarized by LPS, M(LPS), we found that downregulation of Maclpil in M(LPS) decreased pro-inflammatory gene expression while promoting anti-inflammatory gene expression. Maclpil inhibition also reduced the migration and phagocytosis ability of MoDMs by inhibiting LCP1. Furthermore, adoptive transfer of Maclpil silenced M(LPS), reduced ischemic brain infarction, improved behavioral performance and attenuated penetration of MoDMs in the ischemic hemisphere. We conclude that by blocking macrophage, Maclpil protects against acute ischemic stroke by inhibiting neuroinflammation.

scholarly journals Frizzled-4 regulates β-catenin in endothelial cells exposed to disturbed flow via an atypical Wnt pathway leading to proinflammatory activation and increased permeability

2021 ◽  
Author(s):  
Matthew Rickman ◽  
Mean Ghim ◽  
Kuin Tian Pang ◽  
Ana Cristina von Huelsen Rocha ◽  
Elena M Drudi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Endothelial Dysfunction ◽  
Wnt Pathway ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Endothelial Permeability ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene

Objective: Endothelial cells are regulated by hemodynamic wall shear stress and multidirectional shear stress is known to promote endothelial dysfunction, although the molecular mechanisms are poorly defined. Wnt pathways play an important role in non-vascular mechanoresponsive cells. Here we investigated their role in endothelial mechanosignalling and endothelial dysfunction. Approach & Results: Human aortic endothelial cells were exposed to shear stress using an orbital shaker. The expression of Frizzled-4 receptors was significantly increased in endothelial cells exposed to low magnitude multidirectional flow (LMMF) relative to high magnitude uniaxial flow (HMUF). Increased expression was also detected in regions of the murine aortic arch exposed to LMMF. The increased Frizzled-4 expression in cultured cells was abrogated following knockdown of R-spondin-3 (RSPO-3) using RNA interference. LMMF also increased the stabilisation and nuclear localisation of β-catenin, an effect that was dependent on Frizzled-4 and RSPO-3. Inhibition of β-catenin using a small molecule inhibitor (iCRT5), or knockdown of Frizzled-4 or R-spondin-3 resulted in a significant reduction of pro-inflammatory gene expression in endothelial cells exposed to LMMF. Stabilisation of the β-catenin destruction complex using IWR-1 under LMMF also reduced pro-inflammatory gene expression, as did inhibition of Wnt5a signalling. Interestingly, inhibition of the canonical Wnt pathway had no effect. Inhibition of β-catenin signalling also reduced endothelial permeability; this was associated with altered junctional and focal adhesion organisation and cytoskeletal remodelling. Conclusions: These data suggest the presence of an atypical Wnt-β-catenin pathway in endothelial cells that promotes inflammatory activation and barrier disruption in response to LMMF.

scholarly journals AhR Regulates Peptidoglycan-Induced Inflammatory Gene Expression in Human Keratinocytes

2021 ◽  
pp. 1-11
Author(s):  
Lanqi Wang ◽  
Binbin Cheng ◽  
Qiang Ju ◽  
Bryan K. Sun
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Skin Diseases ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Skin Diseases ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Tlr2 Activation

Bacterial peptidoglycan (PGN) stimulates toll-like receptor 2 (TLR2) on the surface of keratinocytes (KCs), triggering signaling pathways that promote an innate immune response. However, excessive TLR2 activation can lead to inappropriate inflammation, which contributes to skin conditions such as rosacea. To better treat these conditions, there is a need to understand the molecular mechanisms that regulate the cellular response to TLR2 activation in the skin. Aryl hydrocarbon receptor (AhR) is a transcription factor that modulates the immune response in KCs and is a promising therapeutic target for inflammatory skin diseases. Here, we investigated the role of the AhR in regulating the transcriptional response of human KCs to PGN. We performed whole-transcriptome sequencing in wild-type and AhR-depleted KCs after PGN stimulation. AhR depletion altered the expression of 72 genes in response to PGN, leading to increased expression of 48 genes and repression of 24 genes, including interleukin (IL)-1β. Chromatin immunoprecipitation showed that PGN stimulation resulted in AhR binding the promoters of IL-1β and IL-6 to activate them. More broadly, AhR promoted inflammatory gene expression by increasing JNK/mitogen-activated protein kinase signaling and FosB expression. Finally, we observed that AhR depletion increased TLR2 expression itself, raising the hypothesis that AhR may serve to restrain TLR2-mediated inflammation in KCs through negative feedback. Viewed together, our findings demonstrate a significant and complex role for AhR in modulating the expression of inflammatory genes in KCs in response to PGN.

scholarly journals Contrasting effects of Western vs. Mediterranean diets on monocyte inflammatory gene expression and social behavior in a primate model

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Corbin SC Johnson ◽  
Carol Shively ◽  
Kristofer T Michalson ◽  
Amanda J Lea ◽  
Ryne J DeBo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Diseases ◽  
Mediterranean Diet ◽  
Cynomolgus Macaque ◽  
Western Diet ◽  
Primate Model ◽  
Public Health Burden ◽  
Evolutionary Mismatch ◽  
Central Nervous System Activity ◽  
The Mediterranean

Dietary changes associated with industrialization substantially increase the prevalence of chronic diseases, such as obesity, type II diabetes, and cardiovascular disease, major contributors to the public health burden. The high prevalence of these chronic diseases is often attributed to an 'evolutionary mismatch' between human physiology and modern nutritional environments. Western diets enriched with foods that were scarce throughout human evolutionary history (e.g., simple sugars and saturated fats) promote inflammation and disease relative to diets more akin to ancestral human hunter-gatherer diets, such as a Mediterranean diet. Peripheral blood monocytes, precursors to macrophages and important mediators of innate immunity and inflammation, are sensitive to the environment and may represent a critical intermediate in the pathway linking diet to disease. We evaluated the effects of 15 months of whole diet manipulations mimicking human Western or Mediterranean diet patterns on monocyte polarization using a well-established model of human health, the cynomolgus macaque (Macaca fascicularis). Monocyte transcriptional profiles differed markedly between the two diets, with 40% of transcripts showing differential expression (FDR < 0.05). Monocytes from Western diet consumers were polarized toward a more proinflammatory phenotype. Compared to the Mediterranean diet, the Western diet shifted the co-expression of 445 gene pairs, including small RNAs and transcription factors associated with metabolism and adiposity in humans, and dramatically altered behavior. For example, Western-fed individuals were more anxious and less socially integrated compared to the Mediterranean-fed subjects. These behavioral changes were also associated with some of the effects of diet on gene expression, suggesting an interaction between diet, central nervous system activity, and monocyte gene expression. The results of this study provide new insights into evolutionary mismatch at the molecular level and uncover new pathways through which Western diets alter monocyte polarization toward a proinflammatory phenotype.

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