Short Chain Fatty Acid Acetate Increases TNFα-Induced MCP-1 Production in Monocytic Cells via ACSL1/MAPK/NF-κB Axis

Short-chain fatty acid (SCFA) acetate, a byproduct of dietary fiber metabolism by gut bacteria, has multiple immunomodulatory functions. The anti-inflammatory role of acetate is well documented; however, its effect on monocyte chemoattractant protein-1 (MCP-1) production is unknown. Similarly, the comparative effect of SCFA on MCP-1 expression in monocytes and macrophages remains unclear. We investigated whether acetate modulates TNF alpha-mediated MCP-1/CCL2 production in monocytes/macrophages and, if so, by which mechanism(s). Monocytic cells were exposed to acetate with/without TNF alpha for 24 h, and MCP-1 expression was measured. Monocytes treated with acetate in combination with TNF alpha resulted in significantly greater MCP-1 production compared to TNF alpha treatment alone, indicating a synergistic effect. On the contrary, treatment with acetate in combination with TNF alpha suppressed MCP-1 production in macrophages. The synergistic upregulation of MCP-1 was mediated through the activation of long-chain fatty acyl-CoA synthetase 1 (ACSL1). However, the inhibition of other bioactive lipid enzymes [carnitine palmitoyltransferase I (CPT I) or serine palmitoyltransferase (SPT)] did not affect this synergy. Moreover, MCP-1 expression was significantly reduced by the inhibition of p38 MAPK, ERK1/2, and NF-kappa B signaling. The inhibition of ACSL1 attenuated the acetate/TNF alpha-mediated phosphorylation of p38 MAPK, ERK1/2, and NF-kappa B. Increased NF-kappa B/AP-1 activity, resulting from acetate/TNF alpha co-stimulation, was decreased by ACSL1 inhibition. In conclusion, this study demonstrates the proinflammatory effects of acetate on TNF-alpha-mediated MCP-1 production via the ACSL1/MAPK/NF-kappa B axis in monocytic cells, while a paradoxical effect was observed in THP-1-derived macrophages.

Automated summary

This study reveals the proinflammatory effects of acetate on TNF-alpha-mediated MCP-1 production in monocytic cells through the ACSL1/MAPK/NF-kappa B axis, while a paradoxical effect was observed in THP-1-derived macrophages.