Neutrophils shape the therapeutic efficacy of sirtuin 1 activity modulators in murine influenza virus infection

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 Ly6G⁺IL-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 Ly6G⁺TNF-α⁺ cells and the Sirt1 levels in Ly6G^hi 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.