Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait.
Genetics & Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait.
Int J Mol Sci. 2021 Jul 19;22(14):7683. doi: 10.3390/ijms22147683.
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 TNFα-mediated MCP-1/CCL2 production in monocytes/macrophages and, if so, by which mechanism(s). Monocytic cells were exposed to acetate with/without TNFα for 24 h, and MCP-1 expression was measured. Monocytes treated with acetate in combination with TNFα resulted in significantly greater MCP-1 production compared to TNFα treatment alone, indicating a synergistic effect. On the contrary, treatment with acetate in combination with TNFα 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-κB signaling. The inhibition of ACSL1 attenuated the acetate/TNFα-mediated phosphorylation of p38 MAPK, ERK1/2, and NF-κB. Increased NF-κB/AP-1 activity, resulting from acetate/TNFα co-stimulation, was decreased by ACSL1 inhibition. In conclusion, this study demonstrates the proinflammatory effects of acetate on TNF-α-mediated MCP-1 production via the ACSL1/MAPK/NF-κB axis in monocytic cells, while a paradoxical effect was observed in THP-1-derived macrophages.
短链脂肪酸（SCFA）醋酸盐是肠道细菌代谢膳食纤维的副产品，具有多种免疫调节功能。醋酸盐的抗炎作用已有充分的文献记载；然而，其对单核细胞趋化蛋白-1（MCP-1）产生的影响尚不清楚。同样，SCFA 对单核细胞和巨噬细胞中 MCP-1 表达的比较影响也不清楚。我们研究了醋酸盐是否调节 TNFα 介导的单核细胞/巨噬细胞中 MCP-1/CCL2 的产生，如果是，通过哪种机制。将单核细胞暴露于有/没有 TNFα 的醋酸盐中 24 小时，测量 MCP-1 的表达。与单独用 TNFα 处理相比，用 TNFα 联合醋酸盐处理的单核细胞导致 MCP-1 产生显著增加，表明存在协同作用。相反，用 TNFα 联合醋酸盐处理巨噬细胞会抑制 MCP-1 的产生。MCP-1 的协同上调是通过激活长链脂肪酸酰基辅酶 A 合成酶 1（ACSL1）介导的。然而，抑制其他生物活性脂质酶[肉碱棕榈酰转移酶 I（CPT I）或丝氨酸棕榈酰转移酶（SPT）]并不影响这种协同作用。此外，通过抑制 p38 MAPK、ERK1/2 和 NF-κB 信号通路，MCP-1 的表达显著降低。ACSL1 的抑制减弱了醋酸盐/TNFα 介导的 p38 MAPK、ERK1/2 和 NF-κB 的磷酸化。由于醋酸盐/TNFα 的共刺激，NF-κB/AP-1 活性增加，通过 ACSL1 抑制而减少。总之，这项研究表明，在单核细胞中，醋酸盐通过 ACSL1/MAPK/NF-κB 轴对 TNF-α 介导的 MCP-1 产生具有促炎作用，而在 THP-1 衍生的巨噬细胞中则观察到一种矛盾的作用。
