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

Abstract

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 to 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)-α, together with nuclear translocation of nuclear factor (NF)-κB p65 subunit. In vitro, antibody-based inhibition of α5β1 integrin, a receptor for Angptl2, significantly repressed LPS-induced expression of IL-6 and TNF-α, 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-κB signaling pathway and suggest a potential validity of Angptl2 as a new molecular target for the treatment of acute inflammation

MMP-3 Deficiency Alleviates Endotoxin-Induced Acute Inflammation in the Posterior Eye Segment

“…Consistent with previous mouse EIU studies, the number of leukocytes that firmly adhered to the retinal vasculature in WT or vehicle-treated eyes was significantly increased during EIU [4,5]. Importantly, our study established, using genetic and pharmacological approaches, that MMP-3 is involved in leukocyte adhesion during acute inflammation in the eye.…”

“…These studies are of fundamental significance to increase our understanding of ocular inflammation, as inflammatory processes and BRB dysfunctions are strongly implicated in the pathogenesis of highly prevalent ocular diseases such as diabetic retinopathy, age-related macular degeneration (AMD), Behçet’s disease, retinitis pigmentosa and posterior uveitis [4,49,50]. Therefore, a potential common therapeutic strategy in combatting these disorders will presumably link with the regulation of inflammatory processes [50].…”

“…Besides its power to investigate acute vascular inflammation at the uveal tract [3], EIU is also a compelling tool to evaluate inflammatory responses at the posterior part of the eye. It is characterized by an increment in adhesion of leukocytes to the retinal vasculature and infiltration of leukocytes into the retina/vitreous cavity [4,5]. Increased oxidative stress, inflammatory cytokines (e.g., interleukin (IL)-6 and tumor necrosis factor (TNF)-α) and chemokines (e.g., monocyte chemoattractant protein (MCP)-1 and C-X-C motif ligand (CXCL) 1/2), and adhesion molecules (e.g., soluble vascular cell adhesion molecule (sVCAM) and intracellular adhesion molecules (ICAMs)) are key inflammatory mediators that contribute to the pathology of rodent EIU [5,6,7,8,9,10].…”

Macrophage-Derived Angiopoietin-Like Protein 2 Exacerbates Brain Damage by Accelerating Acute Inflammation after Ischemia-Reperfusion

“…A previous report indicated that ANGPTL2 derived from retinal cells or macrophages leads to leukocyte adhesion, infiltration, and expression of pro-inflammatory cytokines such as TNF-α in the acute phase of endotoxin-induced uveitis. [8] Here, we provide additional evidence that ANGPTL2 functions in acute cerebral ischemia and worsens neurological deficits, increases infarct volume, and promotes expression of neurotoxic inflammatory cytokines, including TNF-α and IL-1β (Fig 6). …”

“…[5] However, once the vascular network known as the blood brain barrier (BBB) is disrupted by ischemia, circulating or perivascular macrophages infiltrate the parenchyma of brain tissue. [3] Activated infiltrated macrophages cause neuronal injury by amplifying inflammation via secretion of pro-inflammatory cytokines such as interleukin (IL)-1β[6, 7] or tumor necrosis factor (TNF)-α[8]. Sustained inflammation in ischemic brain caused by pro-inflammatory cytokines further injures neurons.…”