Simeonova Lora, Leseva Milena, Stoyanov Kalin, Mai Antonello, Saso Luciano, Dimitrova Petya
Department of Virology, Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 26 Georgi Bonchev Str., 1113 Sofia, Bulgaria.
Department of Immunology, Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 26 Georgi Bonchev Str., 1113 Sofia, Bulgaria.
Biochim Biophys Acta Mol Basis Dis. 2025 Oct;1871(7):167915. doi: 10.1016/j.bbadis.2025.167915. Epub 2025 May 24.
Sirtuin 1 (Sirt1), a class III histone deacetylase, is a key regulator of gene expression in various immune cell types, including neutrophils, during infection and acute inflammation. Herein, we studied the effect of the Sirt1 activator (SRT2183) and inhibitor (EX527) on the neutrophil pools in the bronchoalveolar lavage fluid (BAL), lung, blood and bone marrow (BM) in mild and severe influenza A virus (IAV) infection. We defined the correlation between parameters characteristic for neutrophil migration, their functional state and the infection-induced lung injury. SRT2183 had a protective effect in mild IAV infection but it failed to improve the lung pathology in severe IAV infection. The infection-induced lung injury in the SRT2183-treated group correlated positively with the counts of lung Ly6G cells, the frequency of BAL Ly6G producing interleukin (IL)-1β and tumor-necrosis factor (TNF)-α and the C-X-C chemokine receptor (CXCR) 2 on blood neutrophils, and correlated negatively with the BM Ly6G cell counts and the expression of CXCR2 on lung neutrophils as well as there was no correlation between BAL Ly6GIL-1β cells and BAL and lung neutrophils with aged phenotype. The lung pathology in EX527-treated group with infection was strongly associated with the BAL Ly6GTNF-α cells and the Sirt1 levels in Ly6G neutrophils. Overall, the results showed that although the Sirt1 activator had a greater effect in normalizing the BM and blood neutrophils in severe IAV infection, its effectiveness was compromised locally by its failure to inhibit the expanded neutrophil pools to a degree that was less detrimental.
沉默调节蛋白1（Sirt1）是一种III类组蛋白去乙酰化酶，在感染和急性炎症期间，它是包括中性粒细胞在内的多种免疫细胞类型中基因表达的关键调节因子。在此，我们研究了Sirt1激活剂（SRT2183）和抑制剂（EX527）对轻度和重度甲型流感病毒（IAV）感染时支气管肺泡灌洗液（BAL）、肺、血液和骨髓（BM）中中性粒细胞池的影响。我们确定了中性粒细胞迁移特征参数、其功能状态与感染诱导的肺损伤之间的相关性。SRT2183在轻度IAV感染中具有保护作用，但在重度IAV感染中未能改善肺部病理状况。在SRT2183治疗组中，感染诱导的肺损伤与肺Ly6G细胞计数、BAL中产生白细胞介素（IL）-1β和肿瘤坏死因子（TNF）-α的Ly6G频率以及血液中性粒细胞上的C-X-C趋化因子受体（CXCR）2呈正相关，与BM Ly6G细胞计数以及肺中性粒细胞上CXCR2的表达呈负相关，并且BAL Ly6GIL-1β细胞与具有衰老表型的BAL和肺中性粒细胞之间无相关性。EX527治疗的感染组的肺部病理与BAL Ly6GTNF-α细胞以及Ly6G中性粒细胞中的Sirt1水平密切相关。总体而言，结果表明，尽管Sirt1激活剂在重度IAV感染中对使BM和血液中性粒细胞正常化具有更大作用，但其有效性在局部受到损害，因为它未能将扩增的中性粒细胞池抑制到危害较小的程度。
