| Autor: |
Li, Zhilin, Antila, Salli, Nurmi, Harri, Chilov, Dmitri, Korhonen, Emilia A., Fang, Shentong, Karaman, Sinem, Engelhardt, Britta, Alitalo, Kari |
| Zdroj: |
Science Immunology; 2023, Vol. 8 Issue 82, p1-18, 18p |
| Abstrakt: |
The recent discovery of lymphatic vessels (LVs) in the dura mater, the outermost layer of meninges around the central nervous system (CNS), has opened a possibility for the development of alternative therapeutics for CNS disorders. The vascular endothelial growth factor C (VEGF-C)/VEGF receptor 3 (VEGFR3) signaling pathway is essential for the development and maintenance of dural LVs. However, its significance in mediating dural lymphatic function in CNS autoimmunity is unclear. We show that inhibition of the VEGF-C/VEGFR3 signaling pathway using a monoclonal VEGFR3-blocking antibody, a soluble VEGF-C/D trap, or deletion of the Vegfr3 gene in adult lymphatic endothelium causes notable regression and functional impairment of dural LVs but has no effect on the development of CNS autoimmunity in mice. During autoimmune neuroinflammation, the dura mater was only minimally affected, and neuroinflammation-induced helper T (TH) cell recruitment, activation, and polarization were significantly less pronounced in the dura mater than in the CNS. In support of this notion, during autoimmune neuroinflammation, blood vascular endothelial cells in the cranial and spinal dura expressed lower levels of cell adhesion molecules and chemokines, and antigen-presenting cells (i.e., macrophages and dendritic cells) had lower expression of chemokines, MHC class II–associated molecules, and costimulatory molecules than their counterparts in the brain and spinal cord, respectively. The significantly weaker TH cell responses in the dura mater may explain why dural LVs do not contribute directly to CNS autoimmunity. Dispensable dural lymphatics in CNS autoimmunity: Lymphatic vessels in the dura, the outermost layer of the meninges, provide a vascular path for immune cells connecting the meninges with the systemic circulation. Dural lymphatics have been proposed as a gateway that T cells targeting CNS autoantigens use to access the brain and spinal cord. Formation and maintenance of dural lymphatics can be abrogated by genetic or pharmacologic interference with vascular endothelial growth factor C (VEGF-C) or its receptor VEGFR3. Li et al. found that atrophy of dural lymphatics by VEGFR3 blockade in mice was insufficient to block autoimmune neuroinflammation initiated by immunization with myelin autoantigens or transfer of encephalitogenic T cells. These findings suggest that therapies aimed at disrupting dural lymphatics are unlikely to attenuate human autoimmune neuroinflammatory diseases such as multiple sclerosis. —IRW [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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