The Synergy between Palmitate and TNF-α for CCL2 Production Is Dependent on the TRIF/IRF3 Pathway: Implications for Metabolic Inflammation

Abstract

The chemokine CCL2 (also known as MCP-1) is a key regulator of monocyte infiltration into adipose tissue, which plays a central role in the pathophysiology of obesity-associated inflammation and insulin resistance. It remains unclear how CCL2 production is upregulated in obese humans and rodents. Because elevated levels of the free fatty acid (FFA) palmitate and TNF-α have been reported in obesity, we studied whether these agents interact to trigger CCL2 production. Our data show that combined treatment of THP-1 and primary human monocytic cells with palmitate and TNF-α led to a marked increase in CCL2 production compared to either treatment alone. Mechanistically, we found that cooperative production of CCL2 by palmitate and TNF-α did not require MyD88, but was attenuated by blocking TLR4 or TRIF. IRF3-deficient cells did not show synergistic CCL2 production in response to palmitate/TNF-α. Moreover, IRF3 activation by poly I:C augmented TNF-α induced CCL2 secretion. Interestingly, elevated NF-κB/AP-1 activity resulting from palmitate/TNF-α co-stimulation was attenuated by TRIF/IRF3 inhibition. Diet-induced C57BL/6 obese mice with high FFAs levels showed strong correlation between TNF-α and CCL2 in plasma and adipose tissue and, as expected, also showed increased adipose tissue macrophage accumulation compared to lean mice. Similar results were observed in the adipose tissue samples from obese humans. Overall, our findings support a model in which elevated FFAs in obesity create a milieu for TNF-α to trigger CCL2 production via the TLR4/TRIF/IRF3 signaling cascade, representing a potential contribution of FFAs to metabolic inflammation.

Shaping of Innate Immune Response by Fatty Acid Metabolite Palmitate

“…Interestingly, CCL4 expression plays an important role in the migration of tumor-infiltrating lymphocytes with immunological regulatory phenotypes in melanoma [74]. Recently, palmitate and TNF-α were shown to synergistically promote CCL2 production in monocytes [75], and CCL2 was demonstrated to drive radioresistance, metastasis, and epithelial-mesenchymal transition in nasopharyngeal carcinoma [76]. Additionally, palmitate induces monocytes to produce macrophage inflammatory protein 1 [77], a chemokine responsible for monocyte trafficking into tumor regions [78].…”

MCP-1 LEVELS AND ATYPICAL LYMPHOCYTES IN EARLY FEVER OF DENGUE VIRUS INFECTION WITH NON-STRUCTURAL PROTEIN 1 (NS-1) ANTIGEN TEST IN dr DARSONO HOSPITAL, PACITAN

“…Late activation of caspase-1 in monocytes infected with DENV can contribute to pro-inflammatory results that may play a role in the immunopathogenesis of dengue. 18 MCP-1 causes openings of tight endothelial cell connections in vitro 19 and expression of VEGF-induced MCP-1 in vascular endothelial cells increases changes in endothelial permeability in vivo. 20 Recombinant (RH)MCP-1 and MCP-1 containing conditioned media from DENVinfected monocytes increased the permeability of vascular endothelial cells and also clarified that MCP-1 but not VEGF in DENV-infected monocyte culture media increased endothelial permeability.…”

“…20 Recombinant (RH)MCP-1 and MCP-1 containing conditioned media from DENVinfected monocytes increased the permeability of vascular endothelial cells and also clarified that MCP-1 but not VEGF in DENV-infected monocyte culture media increased endothelial permeability. 19 MCP-1/ CCL2 s Elain recruit and direct the movement of leukocytes also may affect T-cell and CCL2 enhances the secretion of IL-4 by Tcells. Other chemokines and their receptors will be associated with specific T-helper cell responses.…”

Neutral sphingomyelinase 2 regulates inflammatory responses in monocytes/macrophages induced by TNF-α

“…Obesity-driven changes of the adipose tissue monocytes/macrophages alter the secretion of the proinflammatory cytokines which contribute to the progression of inflammation and development of insulin resistance. Tumor necrosis factor-α (TNF-α) is a cytokine identified as a key regulator of inflammation and insulin resistance, and it is overexpressed in obese humans and rodents (5). In settings of obesity, TNF-α has been considered mainly pro-inflammatory as it activates immune cells particularly monocytes and macrophages into inflammatory state, M1 vs M2 (6).…”