Department of Medical Laboratory, The Central Hospital of Wuhan, Huazhong University of Science and Technology, Wuhan, China.
Department of Obstetrics and Gynecology, The First Hospital of Shijiazhuang City, Shijiazhuang, China.
Immunol Cell Biol. 2021 Aug;99(7):724-736. doi: 10.1111/imcb.12455. Epub 2021 May 3.
Macrophages exhibit distinct phenotypes in response to environmental signals. The polarization of M1 macrophages plays an essential role in the inflammatory response. However, the specific molecular mechanisms regulating the inflammatory response during M1 macrophage polarization remain to be further understood. Here, we found that the histone acetyltransferase P300/CBP-associated factor (PCAF) was a potential negative regulator of the M1 macrophage inflammatory response. During M1 macrophage polarization, the inflammatory response gradually reduced, but PCAF expression increased. Furthermore, the overexpression of PCAF significantly inhibited the expression of the M1 macrophage-related pro-inflammatory genes TNF-α, IL-6 and CXCL10, while PCAF deficiency enhanced the expression of these genes. Furthermore, we found that PCAF overexpression suppressed the NF-κB signaling pathway and promoted the expression of the Krüppel-like factors (KLF) KLF2 and KLF4 through regulating their transcriptional levels. In addition, KLF2 and KLF4 deficiency reversed the PCAF-induced inhibition of the expression of pro-inflammatory genes in M1 macrophages. Collectively, the present results demonstrate a potential negative regulatory mechanism of the inflammatory response during M1 macrophage polarization and propose a novel mechanism of inflammation resolution for maintaining homeostasis.
巨噬细胞对外界信号表现出不同的表型。M1 巨噬细胞的极化在炎症反应中起着至关重要的作用。然而，调节 M1 巨噬细胞极化过程中炎症反应的具体分子机制仍有待进一步理解。在这里，我们发现组蛋白乙酰转移酶 P300/CBP 相关因子（PCAF）是 M1 巨噬细胞炎症反应的潜在负调控因子。在 M1 巨噬细胞极化过程中，炎症反应逐渐减弱，但 PCAF 表达增加。此外，PCAF 的过表达显著抑制了 M1 巨噬细胞相关促炎基因 TNF-α、IL-6 和 CXCL10 的表达，而 PCAF 缺失增强了这些基因的表达。此外，我们发现 PCAF 过表达通过调节其转录水平抑制 NF-κB 信号通路，并促进 Krüppel 样因子（KLF）KLF2 和 KLF4 的表达。此外，KLF2 和 KLF4 的缺失逆转了 PCAF 诱导的 M1 巨噬细胞中促炎基因表达的抑制。总之，这些结果表明 M1 巨噬细胞极化过程中炎症反应的一个潜在负调控机制，并提出了一种维持内稳态的炎症消退的新机制。
