Benzyl isothiocyanate alleviates endotoxin-induced uveitis in association with LOX-1 downregulation to modulate JAK2-STAT3 signaling, endoplasmic reticulum stress and apoptosis.

Uveitis is a sight-threatening inflammatory ocular disorder. Benzyl isothiocyanate (BITC) exhibits potent anti-inflammatory pharmacological activity. This research was designed to explore the therapeutic mechanism of BITC in acute uveitis (AU). We established a mouse model of endotoxin-induced uveitis (EIU) to evaluate the therapeutic efficacy of BITC. Results demonstrated that BITC (20 mg/kg) significantly alleviated intraocular inflammation and tissue damage in EIU mice, while inhibiting microglial activation, JAK2/STAT3 signaling pathway activation, and proinflammatory cytokine secretion. BITC (4 and 8 μM) also decreased levels of nitric oxide, reactive oxygen species, IL-1β, TNF-α, and IL-6 induced by LPS in BV2 cells. Furthermore, BITC significantly suppressed the endoplasmic reticulum (ER) stress markers PERK and eIF-2α phosphorylation, and the expression of GRP78, ATF4, CHOP in vivo and in vitro. It also reduced apoptosis and caspase-3 activation, and increased the BCL2/BAX ratio. Notably, BITC downregulated lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression. Overexpression of LOX-1 in BV2 cells markedly reversed the protection actions of BITC on JAK-STAT pathway, inflammation, ER stress, and apoptosis. Collectively, this study reveals that BITC ameliorates the progression of AU. Its protective action is closely coupled with the downregulation of LOX-1, leading to the inhibition of JAK2/STAT3 signaling pathway and the attenuation of ER stress and apoptosis.