Recombinant Sgp130 attenuates alkali-burn cornea through inhibition of IL-6 trans-signaling: From production to therapeutic application.

Interleukin-6 (IL-6) is a highly promising therapeutic target across numerous pathological conditions. This cytokine mediates two distinct downstream signaling cascades: classic signaling, which primarily regulates regenerative and anti-inflammatory processes; and trans-signaling, which drives pathological and pro-inflammatory processes. Non-selective IL-6 inhibition affects both pathways, carrying significant risk of severe clinical adverse effects. Soluble glycoprotein 130 (Sgp130) enables pathway-specific blockade of IL-6 trans-signaling only, making it a compelling candidate for treating disorders driven by this signaling axis. However, its therapeutic potential in ocular diseases remains poorly defined. We investigated the ability of recombinant tag-free Sgp130 (rSgp130) to alleviate corneal inflammation and angiogenesis induced by alkali burn, a common cause of visual impairment. In human umbilical vein endothelial cells (HUVECs), rSgp130 reduced IL-6 trans-signaling-activated phosphorylation of STAT3, ERK and AKT. Functional assays of rSgp130 demonstrated suppression of IL-6 trans-signaling-induced angiogenic activities, including cell migration and tubular formation. In a mouse model of corneal alkali burn, topical administration of 1.5 mg/mL rSgp130 diminished inflammatory cell infiltration and neovascularization, exhibiting comparable efficacy to fluorometholone, a standard ocular corticosteroid. Notably, rSgp130 outperformed fluorometholone in reducing vascular remodeling area, highlighting its superior anti-angiogenic activity. Consistent with these findings, rSgp130 attenuated alkali burn-induced phosphorylation of STAT3, ERK and AKT in corneal tissue. Pharmacokinetic analysis revealed rapid corneal penetration, with increased intracellular levels at 5 min and sustained tissue presence beyond 2 h. Safety evaluation confirmed favorable toxicity profiles in major organs. Collectively, these findings validate rSgp130 as a promising topical therapeutic for corneal pathologies linked to IL-6 trans-signaling.