Work

Identification of Tie2 as a sensor for reactive oxygen species and its therapeutic implication

Year: 2025

Type: article

Abstract: Psoriasis is a chronic inflammatory disease characterized by hyperproliferation of keratinocytes and abnormal blood vessels. As hyperproliferation is driven by pro-inflammatory cytokines produced by activated immune cells, therapeutic strategies often target these cytokines to manage the disease. However, the role of abnormally developed blood vessels has often been overlooked in treatment approaches. In this study, we focused on blood vessels in psoriatic lesions and investigated the potential interplay between immune and endothelial cells by adopting imiquimod treated mice as in vivo model, together with various cell biological, biochemical, and structural analyses. We found that activated immune cells can generate reactive oxygen species, subsequently inducing oxidative stress in endothelial cells. Oxidative stress impairs endothelial cell layer integrity, thereby facilitating transendothelial migration of immune cells. Mechanistically, oxidative conditions inhibit Tie2 activation, potentially by modifying its cysteine residues, leading to deactivation of its vessel-stabilizing functions. Additionally, we demonstrated that reactivating Tie2 under such conditions could restore endothelial barrier function and alleviate the disease. These results suggest that Tie2 serves as a receptor that is directly responsive to oxidative environments, thereby modulating its kinase activity. Furthermore, we suggest that Tie2 reactivation is a promising alternative therapeutic approach for psoriasis. • Tie2 phosphorylation can be reduced in vessels within an inflammatory environment. • Hydrogen peroxide can directly act on cysteine residues in the Tie2 kinase domain, leading to its inactivation. • Activation of Tie2 can overcome the detrimental effects of oxidative stress both in vitro and in vivo.

Source: Redox Biology

DOI: 10.1016/j.redox.2025.103555