Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Chemotherapy, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China.
Int J Biol Sci. 2018 Jan 13;14(2):147-155. doi: 10.7150/ijbs.23231. eCollection 2018.
Neutrophils are the most important component of the innate immune system. Mechanistic understanding of the mechanism underlying neutrophil differentiation remains elusive. Using genome-wide RNA-seq, we identified genes whose expression is dramatically up-regulated during neutrophil differentiation. Among them is nucleotide-binding leucine-rich repeat and pyrindomain-containing receptor 12 (NLRP12), which plays a role in immune inflammatory responses. Genetic ablation of NLRP12 suppresses NF-κB inducing kinase (NIK) stabilization, RelB nuclear translocation and neutrophil differentiation in vitro. At a mechanistic level, NLRP12 inhibits the activity of mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinases (ERK1/2), relieves ERK1/2 suppression of NIK protein levels. Thus, NLRP12 enhances noncanonical NF-κB signaling through inhibition of ERK1/2 signaling, thereby promoting neutrophil differentiation.
中性粒细胞是先天免疫系统的最重要组成部分。对中性粒细胞分化所涉及的机制的理解仍然难以捉摸。使用全基因组 RNA-seq，我们鉴定了在中性粒细胞分化过程中表达显著上调的基因。其中包括核苷酸结合富含亮氨酸重复和吡咯并嘧啶结构域受体 12（NLRP12），它在免疫炎症反应中发挥作用。NLRP12 的基因缺失抑制 NF-κB 诱导激酶（NIK）的稳定，RelB 核易位和体外中性粒细胞分化。在机制水平上，NLRP12 抑制丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（ERK1/2）的活性，解除 ERK1/2 对 NIK 蛋白水平的抑制。因此，NLRP12 通过抑制 ERK1/2 信号转导增强非经典 NF-κB 信号转导，从而促进中性粒细胞分化。
