Abstract 13761: Single Nucleotide Polymorphism of Mlx Gene Causes Txnip Accumulation and Inflammasome Formation, Thereby Promoting the Development of Takayasu Arteritis
Introduction: We have previously conducted genome-wide association study of Takayasu arteritis(TA) and revealed that single nucleotide polymorphism (SNP) of MLX,a gene encoding MLX transcription factor, was markedly associated with clinical phenotypes of TA. Recently, we also have shown that SNP of the MLX (rs665268), a missense mutation of MLX that alters the 139th glutamine to arginine (Q139R) on MLX facilitates the heterodimer formation of MLX with MondoA, which in turn promoting transcription of the thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of thioredoxin. However, it remains unknown how upregulation of TXNIP caused by SNP of MLX is associated with the pathogenesis of TA.
Hypothesis: Accumulation of TXNIP caused by mutation of MLX-Q139R plays an important role in the development of TA.
Methods and Results: The protein level of NLRP3, a major component of inflammasome, as well as that of TXNIP was significantly accumulated (TXNIP: 4.5 fold, NLRP3: 3.8 fold) in human aortic smooth muscle cells(hASMCs) transfected with MLX-Q139R plasmid than compared to those in transfected with wild-type MLX plasmid. Immunostaining demonstrated that both NLRP3 and TXNIP accumulated more prominently in the SMCs of aortas of TA than in normal aortas, suggesting that increased level of TXNIP by MLX-Q139R mutation is associated with accumulation of NLRP3 in hASMCs. To address the consequence of MLX-Q139R mutation on inflammatory cells, we isolated human peripheral blood mononuclear cells (hPBMCs) from TA patients and normal subjects. Treatment of IL-12 significantly enhanced the protein level of both TXNIP and caspase-1, another main component of inflammasome, in T lymphocytes differentiated from hPBMCs of TA patients compared to those from normal subjects. We conducted in vitro proliferation assays of hASMCs co-cultured with hPBMCs. hASMCs significantly proliferated when hPBMCs from normal subjects were co-cultured, and this proliferation was more prominent when hASMCs were co-cultured with hPBMCs from TA patients.
Conclusion: The increase of TXNIP caused by MLX-Q139R mutation promotes inflammasome formation in both hASMCs and hPBMCs, thereby facilitating proliferation of hASMCs, a pathological manifestation seen in the aortas of TA.
Author Disclosures: N. Tamura: None. Y. Maejima: None. M. Isobe: None.
- © 2015 by American Heart Association, Inc.