Abstract
Angiopoietin-2 (Ang2), a ligand of the endothelial Tie2 tyrosine kinase, is involved in vascular inflammation and leakage in critically ill patients. However, the role of Ang2 in demyelinating central nervous system (CNS) autoimmune diseases is unknown. Here, we report that Ang2 is critically involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis. Ang2 expression was induced in CNS autoimmunity, and transgenic mice overexpressing Ang2 specifically in endothelial cells (ECs) developed a significantly more severe EAE. In contrast, treatment with Ang2-blocking Abs ameliorated neuroinflammation and decreased spinal cord demyelination and leukocyte infiltration into the CNS. Similarly, Ang2-binding and Tie2-activating Ab attenuated the development of CNS autoimmune disease. Ang2 blockade inhibited expression of EC adhesion molecules, improved blood-brain barrier integrity, and decreased expression of genes involved in antigen presentation and proinflammatory responses of microglia and macrophages, which was accompanied by inhibition of α5β1 integrin activation in microglia. Taken together, our data suggest that Ang2 provides a target for increasing Tie2 activation in ECs and inhibiting proinflammatory polarization of CNS myeloid cells via α5β1 integrin in neuroinflammation. Thus, Ang2 targeting may serve as a therapeutic option for the treatment of CNS autoimmune disease.
Highlights
The blood-brain barrier (BBB) is indispensable for the maintenance of central nervous system (CNS) homeostasis, acting by restricting molecular and cellular trafficking across the blood vascular endothelium into the CNS [1]
Even in mice at a similar disease stage, Ang2 blockade led to a reduction of the number of infiltrated effector T cells (Supplemental Figure 1B), which suggests that Ang2 is involved in the regulation of immune cell recruitment into the CNS
These results show that Ang2 promotes leukocyte infiltration into the CNS in neuroinflammation without affecting the number of microglia under physiological conditions
Summary
The blood-brain barrier (BBB) is indispensable for the maintenance of CNS homeostasis, acting by restricting molecular and cellular trafficking across the blood vascular endothelium into the CNS [1]. Compromised BBB integrity and leukocyte infiltration into the CNS are crucial in the pathogenesis of inflammatory CNS diseases [2]. Identifying novel targets for therapeutic intervention that can improve BBB integrity and attenuate leukocyte recruitment into the CNS holds great promise for the development of effective strategies for treating CNS autoimmune diseases. Experimental autoimmune encephalomyelitis (EAE) is a well-characterized experimental model of multiple sclerosis (MS), which is the most common human demyelinating CNS autoimmune disease [3]. This makes EAE an ideal model for studying the cellular and molecular mechanisms underlying CNS autoimmune disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
