Mst1 contributes to nasal epithelium inflammation via augmenting oxidative stress and mitochondrial dysfunction in a manner dependent on Nrf2 inhibition.

Abstract

Nasal epithelium inflammation plays an important role in transmitting and amplifying damage signals for the lower airway. However, the molecular basis of nasal epithelium inflammation damage has not been fully addressed. Mst1 is reported to modulate inflammation via multiple effects. Thus, the aim of our study is to understand the pathological mechanism underlying Mst1-related nasal epithelium inflammation in vitro. Our result indicated that Mst1 expression was rapidly increased in response to tumor necrosis factor-α (TNF-α) treatment in vitro and this effect was a dose-dependent manner. Interestingly, knockdown of Mst1 via transfecting small interfering RNA markedly reversed cell viability in the presence of TNF-α. Further, we found that Mst1 deficiency reduced cellular oxidative stress and attenuated mitochondrial dysfunction, as evidenced by reversed mitochondrial complex-I activity, decreased mitochondrial permeability transition pore opening rate, and stabilized mitochondrial membrane potential. Besides, we found that Nrf2 expression was increased after deletion of Mst1 whereas silencing of Nrf2 abolished the protective effects of Mst1 deletion on nasal epithelium survival and mitochondrial homeostasis. Moreover, Nrf2 overexpression also protected nasal epithelium against TNF-α-induced inflammation damage. Altogether, our data confirm that the Mst1 activation and Nrf2 downregulation seem to be the potential mechanisms responsible for the inflammation-mediated injury in nasal epithelium via mediating mitochondrial damage and cell oxidative stress.