Nuclear factor E2 related factor (NRF2) inhibits mast cell- mediated allergic inflammation via SIRT4-mediated mitochondrial metabolism.

BACKGROUND

Mast cell (MC)-mediated inflammation is essential for allergic rhinitis, and nuclear factor E2 related factor (NRF2) is found to inhibit inflammation. This study investigated whether NRF2 could inhibit MC inflammation and its molecular mechanisms concerning SIRT4.

METHODS

Real-time quantitative PCR (RT-qPCR) and western blot were used to detect gene expression, and Elisa kit was used to detect the content of histamine and inflammatory cytokines in the medium of MCs, and Seahorse XF instrument was used to measure the mitochondrial metabolism of MCs. Knockdown SIRT4 and establish SIRT4 overexpression of HMC-1 cells to study the function of SIRT4.

RESULTS

As an activator of NRF2, 4-Octyl Itaconate increases not only NRF2 expression but also increases SIRT4 expression. Although 4-Octyl Itaconate could reduce the histamine release and degranulation of MCs, which was induced by compound 48/80, SIRT4 knockdown decreased the inhibition of 4-Octyl Itaconate. Similarly,4-Octyl Itaconate inhibited the secretion of inflammatory cytokines (TNF-α, IL-1β, IL6, and IL-8) by MCs, which was induced by LPS, but SIRT4 knockdown decreases the inhibition of 4-Octyl Itaconate. Also, the up-regulation of SIRT4 significantly inhibited mitochondrial metabolism in MCs and inhibited SIRT1 and P-p65 protein expression after inducing by 100 ng/mL LPS for 1 hour.

CONCLUSIONS

NRF2 inhibits MC degranulation and MC-mediated inflammation by promoting SIRT4, and SIRT4 overexpression inhibits the mitochondrial metabolism of MCs.