Angiopoietin-like protein 2 mediates endotoxin-induced acute inflammation in the eye

Angiopoietin-like protein (Angptl) 2 is a key mediator linking obesity to chronic adipose-tissue inflammation and systemic insulin resistance, and increasing evidence has shown that Angptl2 is associated with various chronic inflammatory diseases such as cancer and dermatomyositis; however, it remains unclear that Angptl2 functions in acute inflammation. In this study, we investigate whether Angptl2 has a role in acute inflammation in the eye with endotoxin-induced uveitis (EIU). Angptl2 was widely expressed in the normal mouse retina, while Angptl2(-/-) mice did not exhibit any changes in retinal cell marker expression and morphological analyses. Treatment with lipopolysaccharide (LPS) stimulated retinal Angptl2 mRNA expression in vivo and in vitro. We generated EIU in wild-type (C57BL/6) and Angptl2(-/-) mice by injecting LPS intraperitoneally. Compared with wild-type animals, Angptl2(-/-) mice significantly reduced various EIU-associated cellular and molecular parameters including leukocyte adhesion to the retinal vessels and infiltration into the vitreous cavity and retinal mRNA expression levels of monocyte chemotactic protein-1, intercellular adhesion molecule-1, interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha, together with nuclear translocation of nuclear factor (NF)-kappa B p65 subunit. In vitro, antibody-based inhibition of alpha 5 beta 1 integrin, a receptor for Angptl2, significantly repressed LPS-induced expression of IL-6 and TNF-alpha, both of which are the major inflammatory cytokines derived from macrophages. The present findings indicate that Angptl2 mediates endotoxin-induced retinal inflammation through the activation of NF-kappa B signaling pathway and suggest a potential validity of Angptl2 as a new molecular target for the treatment of acute inflammation. Laboratory Investigation (2012) 92, 1553-1563; doi:10.1038/labinvest.2012.111; published online 6 August 2012