NLRP12 c.1382dup Promotes the Development of Crohn Disease through the ERK/NLRP3/ IL-1b Pathway

Whole-genome sequencing was used to identify a dominant inherited NLRP12 c.1382dup mutation in refractory familial Crohn 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)-1b in CD patients with the NLRP12 c.1382dup mutation. However, the mechanisms by which the NLRP12 c.1382dup mutation mediates IL-1b remain unclear. We found significantly elevated p-ERK levels in NLRP12 c.1382dup macrophages, which correlated with increased expression of NLRP3 and IL-1b. Moreover, the inhibition of p-ERK by PD98059 significantly reduced the production of NLRP3 and IL-1b. In conclusion, our findings suggest that NLRP12 c.1382dup can promote the progression of CD by activating the ERK/NLRP3/IL-1b pathway, revealing a novel mechanism for the progression of CD induced by the NLRP12 novel mutation. These discoveries may provide novel insights and targets for treating CD.