NLRP12 c.1382dup promotes the development of Crohn’s disease through the ERK/NLRP3/ IL-1β pathway

•RP12 c.1382 dup mutation was found in familial Crohn ’s patients.•In vitro and in vivo studies showed that interleukin (IL) −1β increased in CD patients with NLRP12 c.1382dup mutation.•The NLRP12 c.1382 dup mutation plays an important role in the progression of CD through the ERK / NLRP3 / IL-1β pa...

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Bibliographic Details
Published in:Gene 2024-12, Vol.931, p.148855, Article 148855
Main Authors: Huang, Yang, Xu, Lincheng, Yang, Qingqing, Xiao, Xueyi, Ye, Zhenyu, Li, Rongqing, Guan, Yanyan, Wu, Xudong
Format: Article
Language:English
Subjects:
Crohn’s disease
ERK
IL-1β
NLRP12 c.1382dup
NLRP3
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Summary:•RP12 c.1382 dup mutation was found in familial Crohn ’s patients.•In vitro and in vivo studies showed that interleukin (IL) −1β increased in CD patients with NLRP12 c.1382dup mutation.•The NLRP12 c.1382 dup mutation plays an important role in the progression of CD through the ERK / NLRP3 / IL-1β pathway. 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.
ISSN:0378-1119
1879-0038
1879-0038
DOI:10.1016/j.gene.2024.148855