Palmitate Activates CCL4 Expression in Human Monocytic Cells via TLR4/MyD88 Dependent Activation of NF-κB/MAPK/ PI3K Signaling Systems

Kochumon, Shihab; Wilson, Ajit; Chandy, Betty; Shenouda, Steve; Tuomilehto, Jaakko; Sindhu, Sardar; Ahmad, Rasheed

doi:10.1159/000488824

Cited by 59 publications

(47 citation statements)

References 30 publications

(38 reference statements)

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“…occur via activation of the NF-κB signaling cascade (18)(19)(20), however, mechanisms by which the complex cytokine and chemokine network in the colonic microenvironment influences inflammatory MPh infiltration are not well defined and represent a fundamental gap in the understanding of homeostatic immune function and IBD development.…”

Section: Introductionmentioning

confidence: 99%

Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation

Song

et al. 2019

Journal of Clinical Investigation

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2E) and F4/80 + macrophages (Figure 2F) after DSS treatment for 5 days compared with expression in the colons of healthy mice. These results suggest that increased FBXW7 expression in monocytes and macrophages was correlated with local colonic inflammation in both humans and mice. Fbxw7 deficiency attenuates experimental colitis. To investigate the role of Fbxw7 in macrophages in colitis, LysM-Cre + Fbxw7 fl/fl (LysM + Fbxw7 fl/fl) mice and their control littermates (Fbxw7 fl/fl) were subjected to acute colitis induction using 3% DSS. Colitisinduced macroscopic changes (body weight loss, diarrhea, and rectal bleeding) were significantly alleviated in the LysM + Fbxw7 fl/fl mice compared with Fbxw7 fl/fl littermates (Figure 3A). LysM + Fbxw7 fl/fl mice sacrificed on day 9 displayed significantly longer colons (Figure 3B), milder epithelial damage, and deceased areas of mucosal ulceration (Figure 3C and Supplemental Figure 2A) compared with Fbxw7 fl/fl littermates. Moreover, expression levels of the tight junction genes Cldn1, Cldn2, Ocln, and Tjp1 (Supplemental Figure 2B) and of TJP1 protein (Supplemental Figure 2C) were significantly higher in the epithelia of LysM + Fbxw7 fl/fl mice compared with Fbxw7 fl/fl littermates after DSS treatment, which indicated that the epithelial barrier integrity was less disrupted in mice with myeloid-specific Fbxw7 deficiency. At the same time, LysM + Fbxw7 fl/fl mice showed significantly improved survival rates compared with Fbxw7 fl/fl littermates after 4% DSS treatment (Figure 3D), indicating that Fbxw7 deficiency protects mice from DSS-induced colitis. During the recovery period of intestinal inflammation, the rate of body weight gain was more rapid in LysM + Fbxw7 fl/fl mice than in Fbxw7 fl/fl littermates (Figure 3E). Moreover, LysM + Fbxw7 fl/fl mice had longer colon lengths than did their Fbxw7 fl/fl littermates (Figure 3F) on day 15. Similarly, TNBS-induced colon shortening, the disease activity index (DAI), body weight loss, and epithelial damage were also alleviated in LysM + Fbxw7 fl/fl mice compared with Fbxw7 fl/fl littermates (Supplemental Figure 3, AD). These findings indicate that myeloid Fbxw7 deficiency attenuates experimental colitis. Fbxw7 deficiency decreases proinflammatory MPh accumulation. Microbiota-induced inflammation is critical for the regulation of intestinal homeostasis. To determine whether the decreased DSS colitis susceptibility in LysM + Fbxw7 fl/fl mice was mediated by shifts in gut microbiota, we analyzed the fecal microbiota composition in LysM + Fbxw7 fl/fl mice and Fbxw7 fl/fl littermates. The relative abundance of bacteria at the phylum level and the species composition cluster according to operational taxonomic units (OTUs) among LysM + Fbxw7 fl/fl mice and Fbxw7 fl/fl littermates are shown in Supplemental Figure 4A and Figure 4A, respectively. Moreover, microbial community diversity (Figure 4B) and microbial community composition (Supplemental Figure 4B) were not significantly different between LysM + Fbxw7 fl/fl mice and Fbxw7 fl/fl li...

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Section: Introductionmentioning

confidence: 99%

Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation

Song

et al. 2019

Journal of Clinical Investigation

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“…This structural requirement illustrates the exquisite specificity of the binding site in the TLR4/MD2 complex to LPS raising reservations about the potential suitability of this complex for binding alternative ligands [95]. A functional and some structural evidence exists demonstrating TLR4-dependent cell activation triggered by lipid-like molecules (e.g., lipoteichoic acid [108], minimally oxidized LDL [109], and free saturated fatty acid palmitate [110]) whose binding might be supported by a hydrophobic site on CD14. Among other proposed TLR4-activating ligands, some structural evidence exists for a chemotherapeutic drug paclitaxel (PXL) [95,101] and endogenous ligands HMGB1 [111] and S100A8 [112].…”

Section: Lps Is the Most Rigorously Confirmed Tlr4 Agonistmentioning

confidence: 97%

TLR4-Induced Inflammation Is a Key Promoter of Tumor Growth, Vascularization, and Metastasis

Ran¹,

Bhattarai²,

Patel³

et al. 2020

Translational Studies on Inflammation

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Toll-like receptor-4 (TLR4) is a powerful pathway best known for inducing inflammation in response to bacteria-produced lipopolysaccharide. TLR4 is also activated by endogenous ligands produced by host-damaged cells and a chemo-drug paclitaxel. Under normal conditions, TLR4 is expressed mainly in macrophages and, at a lower level, in epithelial, endothelial, and stromal cells. Activated TLR4 significantly increases inflammatory cytokines and enhances cell proliferation, migration, invasion, and survival. While these functions in normal cells are essential for host defense and tissue repair, TLR4 overexpression in malignant cells promotes tumor growth and metastasis. This is because pro-oncogenic effects of activated TLR4 in tumor cells are amplified by similar event in TLR4-positive tumor-associated cells including endothelial cells and their mobilized progenitors. The collective activation of multiple cell types within the tumor promotes chemoresistance and metastasis. Here, we summarize the current knowledge of the TLR4 pathway and its functional outcomes in normal and tumor cells. We also discuss its underappreciated role in supporting tumor progression through vascular activation and recruitment of endothelial progenitors. The review considers several open questions regarding the impact of TLR4-mediated pro-and antitumor effects, structural requirements for recognition of the TLR4 complex, and a potential contribution of chemotherapy to tumor spread.

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“…Dysregulation of lipid metabolism has been linked to tumorigenesis. It has been shown that palmitate induces CCL4 expression through TLR4-mediated pathways in monocytes [15]. Interestingly, CCL4 expression plays an important role in the migration of tumor-infiltrating lymphocytes with immunological regulatory phenotypes in melanoma [74].…”

Section: Involvement Of Palmitate In Immune-related Cell Interactionsmentioning

confidence: 99%

“…Palmitate also enhances oxidative stress-induced TLR2 and TLR4 expression in peripheral blood mononuclear cells. Moreover, in human monocytic cells, palmitate triggers matrix metalloproteinase-9 and chemokine CCL4 production via TLR4/MyD88-dependent signaling to induce subsequent metabolic inflammation [14,15], suggesting a role of innate receptors in sensing metabolic fluctuations [16]. However, whether TLRs serve as CD36 co-receptors for palmitate bioactivity remains unclear.…”

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confidence: 99%

Shaping of Innate Immune Response by Fatty Acid Metabolite Palmitate

Tzeng

Chyuan

Chen

2019

Cells

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Innate immune cells monitor invading pathogens and pose the first-line inflammatory response to coordinate with adaptive immunity for infection removal. Innate immunity also plays pivotal roles in injury-induced tissue remodeling and the maintenance of tissue homeostasis in physiological and pathological conditions. Lipid metabolites are emerging as the key players in the regulation of innate immune responses, and recent work has highlighted the importance of the lipid metabolite palmitate as an essential component in this regulation. Palmitate modulates innate immunity not only by regulating the activation of pattern recognition receptors in local innate immune cells, but also via coordinating immunological activity in inflammatory tissues. Moreover, protein palmitoylation controls various cellular physiological processes. Herein, we review the updated evidence that palmitate catabolism contributes to innate immune cell-mediated inflammatory processes that result in immunometabolic disorders.Fatty acid β-oxidation is a major process that provides energy by degrading fatty acids. The enzymes responsible for fatty acid β-oxidation are mainly located in the mitochondria and peroxisomes. Each β-oxidation cycle can generate one acetyl-CoA molecule, which serves as the source for tricarboxylic acid cycle progression and yields more ATP per carbon than that from sugars by oxidative phosphorylation [7]. In contrast to the removal of two carbons from long-chain fatty acids in each β-oxidation round, fatty acid synthesis is catalyzed by joining two carbon units to the growing acyl chain via the cytosolic fatty acid synthase complex [8]. Palmitate is a 16-carbon saturated fatty acid produced via the fatty acid synthesis pathway in a fatty acid synthase-dependent manner, and acts as the major lipid mediator in inflammatory response regulation. Palmitic Acid-Regulated Innate Immune ResponsesCell uptake of palmitate is mainly mediated by the membrane fatty acid transporter CD36, also known as scavenger receptor B2 [9], although palmitate can also enter cells by other mechanisms, including direct membrane interactions, albumin-mediated transfer, and lipoprotein lipase-mediated uptake [10]. Accumulating evidence suggests a critical role by palmitic acid in modulating the activation of pattern recognition receptors in innate immune cells (Figure 1). Indeed, accumulating evidence reveals that although not through direct engagement of Toll-like receptors (TLRs), palmitate can modulate TLR downstream signaling in response to their ligand stimulation [11,12]. Palmitate is believed to be a TLR4 agonist that promotes macrophage activation and lipid metabolism-associated inflammation. Recently, however, it has been demonstrated that palmitate-induced inflammatory effects are not triggered by the direct binding of palmitate to TLR4, but through a combination of palmitate-mediated and TLR4-dependent priming, which alters cellular lipid metabolic pathways, gene expression, and membrane lipid composition, the prerequisite changes that are ...

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Palmitate Activates CCL4 Expression in Human Monocytic Cells via TLR4/MyD88 Dependent Activation of NF-κB/MAPK/ PI3K Signaling Systems

Cited by 59 publications

References 30 publications

Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation

Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation

TLR4-Induced Inflammation Is a Key Promoter of Tumor Growth, Vascularization, and Metastasis

Shaping of Innate Immune Response by Fatty Acid Metabolite Palmitate

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