Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, UK.
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany.
Cell Rep. 2024 Sep 24;43(9):114736. doi: 10.1016/j.celrep.2024.114736. Epub 2024 Sep 13.
Short-chain fatty acids (SCFAs) are immunomodulatory compounds produced by the microbiome through dietary fiber fermentation. Although generally considered beneficial for gut health, patients suffering from inflammatory bowel disease (IBD) display poor tolerance to fiber-rich diets, suggesting that SCFAs may have contrary effects under inflammatory conditions. To investigate this, we examined the effect of SCFAs on human macrophages in the presence of Toll-like receptor (TLR) agonists. In contrast to anti-inflammatory effects under steady-state conditions, we found that butyrate and propionate activated the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in the presence of TLR agonists. Mechanistically, these SCFAs prevented transcription of FLICE-like inhibitory protein (cFLIP) and interleukin-10 (IL-10) through histone deacetylase (HDAC) inhibition, triggering caspase-8-dependent NLRP3 inflammasome activation. SCFA-driven NLRP3 activation was potassium efflux independent and did not result in cell death but rather triggered hyperactivation and IL-1β release. Our findings demonstrate that butyrate and propionate are bacterially derived danger signals that regulate NLRP3 inflammasome activation through epigenetic modulation of the inflammatory response.
短链脂肪酸（SCFAs）是微生物群通过膳食纤维发酵产生的免疫调节化合物。虽然通常被认为对肠道健康有益，但患有炎症性肠病（IBD）的患者对富含纤维的饮食耐受性差，这表明在炎症条件下 SCFAs 可能具有相反的作用。为了研究这一点，我们研究了 SCFAs 在 Toll 样受体（TLR）激动剂存在下对人巨噬细胞的影响。与稳态条件下的抗炎作用相反，我们发现丁酸盐和丙酸盐在 TLR 激动剂存在下激活了 NOD、LRR 和 pyrin 结构域包含蛋白 3（NLRP3）炎性体。在机制上，这些 SCFAs 通过组蛋白去乙酰化酶（HDAC）抑制阻止 FLICE 样抑制蛋白（cFLIP）和白细胞介素 10（IL-10）的转录，触发 caspase-8 依赖性 NLRP3 炎性体激活。SCFA 驱动的 NLRP3 激活与钾外流无关，不会导致细胞死亡，而是引发过度激活和 IL-1β 释放。我们的研究结果表明，丁酸盐和丙酸盐是细菌衍生的危险信号，通过炎症反应的表观遗传调节来调节 NLRP3 炎性体的激活。
