Huang Yang, Xu Lincheng, Yang Qingqing, Xiao Xueyi, Ye Zhenyu, Li Rongqing, Guan Yanyan, Wu Xudong
Department of Gastroenterology, The Yancheng Clinical College of Xuzhou Medical University, 224006 Yancheng, Jiangsu, China.
Department of Pathology, Yancheng NO.1 People's Hospital., China.
Gene. 2024 Dec 30;931:148855. doi: 10.1016/j.gene.2024.148855. Epub 2024 Aug 22.
Whole-genome sequencing was used to identify a dominant inherited NLRP12 c.1382dup mutation in refractory familial Crohn's disease (CD) patients. Additionally, we observed a T insertion at position 1382 in the third exon of NLRP12, leading to a frameshift mutation. Isolation of peripheral blood from mutation carriers and subsequent experiments demonstrated increased interleukin (IL)-1β in CD patients with the NLRP12 c.1382dup mutation. However, the mechanisms by which the NLRP12 c.1382dup mutation mediates IL-1β remain unclear. Our research findings reveal a close correlation between elevated p-ERK levels and increased expression of NLRP3 and IL-1β in the presence of the NLRP12 c.1382dup mutation. Further experiments demonstrate that inhibiting p-ERK with PD98059 effectively reduces the production of NLRP3 and IL-1β. This discovery provides new insights into the pathogenesis of CD, highlighting the significant role of the ERK/NLRP3/IL-1β pathway in the progression of CD. Not only does this offer novel therapeutic targets for treating CD, but it also lays the groundwork for the development of treatment strategies targeting this pathway.
全基因组测序用于鉴定难治性家族性克罗恩病（CD）患者中一种显性遗传的NLRP12基因c.1382dup突变。此外，我们观察到NLRP12基因第三外显子第1382位有一个T插入，导致移码突变。从突变携带者中分离外周血并进行后续实验表明，携带NLRP12基因c.1382dup突变的CD患者中白细胞介素（IL）-1β水平升高。然而，NLRP12基因c.1382dup突变介导IL-1β的机制仍不清楚。我们的研究结果揭示，在存在NLRP12基因c.1382dup突变的情况下，p-ERK水平升高与NLRP3和IL-1β表达增加之间存在密切关联。进一步实验表明，用PD98059抑制p-ERK可有效降低NLRP3和IL-1β的产生。这一发现为CD的发病机制提供了新见解，突出了ERK/NLRP3/IL-1β通路在CD进展中的重要作用。这不仅为治疗CD提供了新的治疗靶点，也为开发针对该通路的治疗策略奠定了基础。
