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

• Published in: Gene Vol. 931; p. 148855
• Main Authors: Huang, Yang, Xu, Lincheng, Yang, Qingqing, Xiao, Xueyi, Ye, Zhenyu, Li, Rongqing, Guan, Yanyan, Wu, Xudong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 30.12.2024
• Subjects: Adult; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Crohn Disease - genetics; Crohn Disease - metabolism; Crohn Disease - pathology; Crohn’s disease; ERK; Female; Humans; IL-1β; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Male; MAP Kinase Signaling System; Middle Aged; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP12 c.1382dup; NLRP3; Signal Transduction; CDAI; NLRP3; IBD; NLRP12 c.1382dup; IL-1β; list: CD; PBMC; UC; Crohn’s disease; ERK
• ISSN: 0378-1119; 1879-0038; 1879-0038
• DOI: 10.1016/j.gene.2024.148855

•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.