PDF(Pubmed)
Abstract：
Legionella pneumophila (L. pneumophila) is a prevalent pathogenic bacterium responsible for significant global health concerns. Nonetheless, the precise pathogenic mechanisms of L. pneumophila have still remained elusive. Autophagy, a direct cellular response to L. pneumophila infection and other pathogens, involves the recognition and degradation of these invaders in lysosomes. Histone deacetylase 6 (HDAC6), a distinctive member of the histone deacetylase family, plays a multifaceted role in autophagy regulation. This study aimed to investigate the role of HDAC6 in macrophage autophagy via the autophagolysosomal pathway, leading to alleviate L. pneumophila-induced pneumonia. The results revealed a substantial upregulation of HDAC6 expression level in murine lung tissues infected by L. pneumophila. Notably, mice lacking HDAC6 exhibited a protective response against L. pneumophila-induced pulmonary tissue inflammation, which was characterized by the reduced bacterial load and diminished release of pro-inflammatory cytokines. Transcriptomic analysis has shed light on the regulatory role of HDAC6 in L. pneumophila infection in mice, particularly through the autophagy pathway of macrophages. Validation using L. pneumophila-induced macrophages from mice with HDAC6 gene knockout demonstrated a decrease in cellular bacterial load, activation of the autophagolysosomal pathway, and enhancement of cellular autophagic flux. In summary, the findings indicated that HDAC6 knockout could lead to the upregulation of p-ULK1 expression level, promoting the autophagy-lysosomal pathway, increasing autophagic flux, and ultimately strengthening the bactericidal capacity of macrophages. This contributes to the alleviation of L. pneumophila-induced pneumonia.
摘要：
嗜肺军团菌（L.嗜肺）是一种常见的致病菌，引起了重大的全球健康问题。尽管如此，嗜肺乳杆菌的确切致病机制仍然难以捉摸。自噬,对嗜肺乳杆菌感染和其他病原体的直接细胞反应，涉及溶酶体中这些入侵者的识别和降解。组蛋白脱乙酰酶6(HDAC6),组蛋白脱乙酰酶家族的独特成员，在自噬调节中起着多方面的作用。本研究旨在探讨HDAC6通过自噬溶酶体通路在巨噬细胞自噬中的作用,导致缓解肺炎支原体引起的肺炎。结果表明，在嗜肺乳杆菌感染的鼠肺组织中，HDAC6表达水平显着上调。值得注意的是,缺乏HDAC6的小鼠表现出对肺炎支原体诱导的肺组织炎症的保护性反应，其特征是细菌负荷减少和促炎细胞因子的释放减少。转录组学分析揭示了HDAC6在小鼠肺炎支原体感染中的调节作用，特别是通过巨噬细胞的自噬途径。使用来自具有HDAC6基因敲除的小鼠的嗜肺乳杆菌诱导的巨噬细胞的验证表明细胞细菌负荷的减少,自噬溶酶体途径的激活，和细胞自噬通量的增强。总之,研究结果表明，HDAC6敲除可导致p-ULK1表达水平上调，促进自噬-溶酶体途径，增加自噬通量，并最终增强巨噬细胞的杀菌能力。这有助于减轻嗜肺乳杆菌引起的肺炎。
