PDF(Pubmed)
Abstract：
Chronic inflammatory diseases are associated with hematopoietic lineage bias, including neutrophilia and anemia. We have recently identified that the canonical inflammasome mediates the cleavage of the master erythroid transcription factor GATA1 in hematopoietic stem and progenitor cells (HSPCs). We report here that genetic inhibition of Nlrp1 resulted in reduced number of neutrophils and increased erythrocyte counts in zebrafish larvae. We also found that the NLRP1 inflammasome in human cells was inhibited by LRRFIP1 and FLII, independently of DPP9, and both inhibitors regulated hematopoiesis. Mechanistically, erythroid differentiation resulted in ribosomal stress-induced activation of the ZAKα/P38 kinase axis which, in turn, phosphorylated and promoted the assembly of NLRP1 in both zebrafish and human. Finally, inhibition of Zaka with the FDA/EMA-approved drug Nilotinib alleviated neutrophilia in a zebrafish model of neutrophilic inflammation and promoted erythroid differentiation and GATA1 accumulation in K562 cells. In conclusion, our results reveal that the NLRP1 inflammasome regulates hematopoiesis and pave the way to develop novel therapeutic strategies for the treatment of hematopoietic alterations associated with chronic inflammatory and rare diseases.
摘要：
慢性炎症性疾病与造血谱系偏见有关,包括嗜中性粒细胞增多症和贫血.我们最近发现，典型的炎性体介导造血干细胞和祖细胞（HSPC）中主类红细胞转录因子GATA1的裂解。我们在此报告，Nlrp1的遗传抑制导致斑马鱼幼虫的中性粒细胞数量减少和红细胞计数增加。我们还发现人细胞中的NLRP1炎性体被LRRFIP1和FLII抑制，与DPP9无关，两种抑制剂均可调节造血。机械上,红系分化导致核糖体应激诱导的ZAKα/P38激酶轴的激活，反过来,磷酸化并促进了斑马鱼和人类NLRP1的组装。最后,用FDA/EMA批准的药物尼洛替尼抑制Zaka可以减轻斑马鱼中性粒细胞炎症模型中的中性粒细胞增多症，并促进K562细胞中的红细胞分化和GATA1积累。总之,我们的研究结果表明,NLRP1炎性小体可调节造血功能,并为开发与慢性炎症和罕见疾病相关的造血功能改变的新型治疗策略铺平了道路.
