Atopic dermatitis susceptible gene NLRP10 suppresses inflammatory reaction and NLRP10 SNP mutation down-regulates NLRP10 expression

Inflammasome plays a central role in the onset and progression of various diseases. In a recent report, it was suggested that OR10A-NLRP10 SNP region (rs878860) is one of the susceptible SNPs in Japanese patients with atopic dermatitis (AD). In this study we investigated the effect of this SNP on the expression of NLRP10 in human keratinocytes (KCs). NLRP10 expression was strongly up-regulated in air-exposed keratinocytes. When NLRP10 was overexpressed in cultured KCs, they showed strong resistance against various cell death stimuli including NLRP3 inflammasome activation, indicating that NLRP10 works as a suppressor of inflammation. Next, we analyzed in silico the region of transcriptional activation including the SNP rs878860. Interestingly this SNP mutation (5′-GGATGA-3′) resulted in the increased similarity with the GATA consensus sequence (5′-AGATAG-3′). We also noticed that in the NLRP10 promoter region, three GATA binding elements were present within the 500 bp upstream of the transcription start site. Therefore, we examined effects of GATA3 and its cofactor FOG1 on the transcriptional regulation of NLRP10 promoter (1500 bp) with or without the SNP. We found that NLRP10 promoter activity was suppressed by the concomitant expression of GATA3 and FOG1 in both growing and differentiated keratinocytes. When the core promoter region of NLRP10 was fused with OR10A-NLRP10 SNP region, it showed further suppression by GATA3 and FOG1. These results suggest that AD susceptible SNP near the NLRP10 gene contributes to down-regulate NLRP10 expression, which will lead to further suppression of the anti-inflammatory activity. Collectively, NLRP10 inflammasome and OR10A-NLRP10 SNP (rs878860) would be involved in pathophysiology of Japanese patients with AD.