Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Exp Biol Med (Maywood). 2023 Jun;248(11):922-935. doi: 10.1177/15353702231165707. Epub 2023 May 21.
Sepsis is characterized by uncontrolled inflammatory response and altered polarization of macrophages at the early phase. Akt is known to drive macrophage inflammatory response. However, how macrophage inflammatory response is fine-tuned by Akt is poorly understood. Here, we found that Lys14 and Lys20 of Akt is deacetylated by the histone deacetylase SIRT1 during macrophage activation to suppress macrophages inflammatory response. Mechanistically, SIRT1 promotes Akt deacetylation to inhibit the activation of NF-κB and pro-inflammatory cytokines. Loss of SIRT1 facilitates Akt acetylation and thus promotes inflammatory cytokines in mouse macrophages, potentially worsen the progression of sepsis in mice. By contrast, the upregulation of SIRT1 in macrophages further contributes to the inhibition of pro-inflammatory cytokines via Akt activation in sepsis. Taken together, our findings establish Akt deacetylation as an essential negative regulatory mechanism that curtails M1 polarization.
脓毒症的特征是在早期阶段出现不受控制的炎症反应和巨噬细胞极化的改变。Akt 已知可驱动巨噬细胞炎症反应。然而，Akt 如何精细调节巨噬细胞炎症反应尚不清楚。在这里，我们发现 Akt 的 Lys14 和 Lys20 在巨噬细胞激活过程中被组蛋白去乙酰化酶 SIRT1 去乙酰化，以抑制巨噬细胞炎症反应。在机制上，SIRT1 促进 Akt 去乙酰化，从而抑制 NF-κB 和促炎细胞因子的激活。SIRT1 的缺失促进 Akt 乙酰化，从而促进小鼠巨噬细胞中的炎症细胞因子，可能使小鼠脓毒症的进展恶化。相比之下，在脓毒症中，巨噬细胞中 SIRT1 的上调通过 Akt 激活进一步有助于抑制促炎细胞因子。总之，我们的研究结果确立了 Akt 去乙酰化作为一种重要的负调控机制，可限制 M1 极化。
