Division Infectious Diseases and Immunology, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands.
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands.
Front Immunol. 2022 Jul 26;13:777530. doi: 10.3389/fimmu.2022.777530. eCollection 2022.
Trained innate immunity can be induced in human macrophages by microbial ligands, but it is unknown if exposure to endogenous alarmins such as cathelicidins can have similar effects. Previously, we demonstrated sustained protection against infection by the chicken cathelicidin-2 analog DCATH-2. Thus, we assessed the capacity of cathelicidins to induce trained immunity. PMA-differentiated THP-1 (dTHP1) cells were trained with cathelicidin analogs for 24 hours and restimulated after a 3-day rest period. DCATH-2 training of dTHP-1 cells amplified their proinflammatory cytokine response when restimulated with TLR2/4 agonists. Trained cells displayed a biased cellular metabolism towards mTOR-dependent aerobic glycolysis and long-chain fatty acid accumulation and augmented microbicidal activity. DCATH-2-induced trained immunity was inhibited by histone acetylase inhibitors, suggesting epigenetic regulation, and depended on caveolae/lipid raft-mediated uptake, MAPK p38 and purinergic signaling. To our knowledge, this is the first report of trained immunity by host defense peptides.
通过微生物配体，可以诱导人巨噬细胞产生训练有素的先天免疫，但尚不清楚内源性警报素（如抗菌肽）是否具有类似的作用。之前，我们证明了对鸡抗菌肽-2 类似物 DCATH-2 的持续抗感染保护作用。因此，我们评估了抗菌肽诱导训练免疫的能力。用抗菌肽类似物对 PMA 分化的 THP-1（dTHP1）细胞进行 24 小时训练，然后在 3 天的休息期后进行再刺激。用 DCATH-2 训练 dTHP-1 细胞，当用 TLR2/4 激动剂再刺激时，可放大其促炎细胞因子反应。经训练的细胞表现出偏向于 mTOR 依赖性有氧糖酵解和长链脂肪酸积累的细胞代谢，并增强了杀菌活性。组蛋白乙酰酶抑制剂抑制了 DCATH-2 诱导的训练免疫，表明存在表观遗传调控，并且依赖于 caveolae/脂筏介导的摄取、MAPK p38 和嘌呤能信号。据我们所知，这是宿主防御肽诱导训练免疫的首次报道。
