Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, Jiangsu, China.
School of Basic Medical Sciences, Kunming Medical University, Kunming 650500, Yunnan, China.
J Agric Food Chem. 2021 May 26;69(20):5638-5651. doi: 10.1021/acs.jafc.1c01353. Epub 2021 May 17.
Extensive studies focused on the therapeutic efficacy of epigallocatechin-3-gallate (EGCG) against bacterial infection. However, little is known about its prophylactic efficacy against bacterial infection. Herein, we found that EGCG showed an effective prophylactic efficacy against bacterial infection with a broad spectrum, including Gram-negative, Gram-positive, and drug-resistant bacteria. Pretreatment with EGCG through intraperitoneal injection, intravenous injection, or intragastric administration significantly reduced the bacterial load, inflammatory response, and mortality in mouse abdominal infection models induced by bacterial inoculation or cecal ligation and puncture. Pretreatment with EGCG by intraperitoneal injection significantly increased the numbers of neutrophils and monocytes/macrophages in the abdominal cavity and peripheral blood of mice, and depletion of neutrophils and monocytes/macrophages by specific antibodies or chemical drugs obviously increased the bacterial load in mice. Of note, EGCG did not directly induce neutrophil and macrophage migration, and it just induced phagocyte migration in the presence of macrophages in a co-cultured system, implying that EGCG-induced phagocyte migration relies on its immunoregulatory effects on macrophages. EGCG markedly induced the production of cytokines and chemokines in macrophages and mouse peritoneal lavage, including tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β), IL-6, CXC chemokine ligands 1 and 2 (CXCL1 and 2), and monocyte chemotactic protein-1 (MCP-1). EGCG significantly induced the phosphorylation of p38 and JNK mitogen-activated protein kinases (MAPKs) in macrophages, and inhibition of p38 and JNK MAPKs markedly reduced EGCG-induced chemokine and cytokine production. Anti-67-kDa laminin receptor (67LR) antibody treatment significantly reduced EGCG-induced chemokine production and p38 and JNK phosphorylation in macrophages. Together, EGCG showed an obvious prophylactic efficacy against bacterial infection by inducing a pro-inflammatory response in macrophages through the 67LR/p38/JNK signaling pathway, supporting the further development of EGCG as a potent prophylaxis for bacterial infection and providing new clues to understand the healthcare function of green tea.
大量研究集中于表没食子儿茶素没食子酸酯（EGCG）在细菌感染治疗方面的疗效。然而，其对细菌感染的预防作用知之甚少。在此，我们发现 EGCG 对革兰氏阴性菌、革兰氏阳性菌和耐药菌等多种细菌感染具有有效的预防作用。通过腹腔注射、静脉注射或灌胃给予 EGCG 预处理可显著降低细菌接种或盲肠结扎穿刺诱导的小鼠腹部感染模型中的细菌负荷、炎症反应和死亡率。腹腔注射 EGCG 预处理可显著增加小鼠腹腔和外周血中性粒细胞和单核细胞/巨噬细胞的数量，并且用特异性抗体或化学药物耗竭中性粒细胞和单核细胞/巨噬细胞可明显增加小鼠的细菌负荷。值得注意的是，EGCG 不会直接诱导中性粒细胞和巨噬细胞迁移，并且仅在存在巨噬细胞的共培养系统中诱导吞噬细胞迁移，表明 EGCG 诱导的吞噬细胞迁移依赖于其对巨噬细胞的免疫调节作用。EGCG 可显著诱导巨噬细胞和小鼠腹腔灌洗液中细胞因子和趋化因子的产生，包括肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、CXC 趋化因子配体 1 和 2（CXCL1 和 2）以及单核细胞趋化蛋白-1（MCP-1）。EGCG 可显著诱导巨噬细胞中 p38 和 JNK 丝裂原活化蛋白激酶（MAPK）的磷酸化，并且抑制 p38 和 JNK MAPK 可明显减少 EGCG 诱导的趋化因子和细胞因子的产生。抗 67kDa 层粘连蛋白受体（67LR）抗体治疗可显著减少 EGCG 诱导的巨噬细胞中趋化因子的产生和 p38 和 JNK 的磷酸化。总之，EGCG 通过 67LR/p38/JNK 信号通路诱导巨噬细胞产生促炎反应，从而对细菌感染表现出明显的预防作用，这支持将 EGCG 进一步开发为预防细菌感染的有效药物，并为理解绿茶的保健功能提供了新线索。
