Atopic dermatitis (AD), a common chronic pruritic inflammatory skin disorder, features recurrent eczematous lesions. Interleukin (IL)-33, a cytokine of the IL-1 family, plays an important role in the pathogenesis of AD. However, the role of NLRP3 inflammasome in the pathogenesis of AD and IL-33 processing remains controversial. 

If NLRP3 can mediate IL-33 expression and secretion independently of the inflammasome in the epithelium of AD remains unclear. A recent study found that the mRNA expression of Il33 and Nlrp3 notably increases in the lesional skin of AD patients compared to healthy controls. It also found a significant positive correlation between the expression of Nlrp3 and Il33 in the epithelium of the MC903-mediated AD mice model. Further, it found changes for Il36α, Il36γ, Il1β or Il18 mRNA expression, as well as IL-1β or IL-18 production. 

Overexpression of NLRP3 in human immortalized epithelial cells increases IL-33 expression, while siRNA targeting NLRP3 abolishes IL-33 expression. Additionally, inhibition of NLRP3 inflammasome activation or caspase-1 activity with MCC950 or VX-765 does not affect the expression and secretion of IL-33 in AD mice. Unlike myeloid cells, NLRP3 is located predominantly in the nucleus of epithelial cells, can directly bind to Il33 specific-promoters, and transactivate it via interacting with transcription factor IRF4. 

Furthermore, they observed that NLRP3 deficient mice exhibited a significant alleviation in epidermis inflammation and a decrease in mRNA expression and secretion of IL-33 in MC903-mediated AD mice without interfering with TSLP and IL-1β production. 

These results show a novel ability of NLRP3 to act as a crucial transcription factor of IL-33 in epithelium independently of inflammasome to mediate the pathological process of AD.

Source: Zheng J, Yao L, Zhou Y, et al. A novel function of NLRP3 independent of inflammasome as a key transcription factor of IL-33 in epithelial cells of atopic dermatitis. Cell Death Dis. 2021;12(10):871.