Blockade of VEGFR3 signaling leads to functional impairment of dural lymphatic vessels without affecting autoimmune neuroinflammation

Abstract

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 (T H ) 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 T H cell responses in the dura mater may explain why dural LVs do not contribute directly to CNS autoimmunity.

The murine meninges acquire lymphoid tissue properties and harbour autoreactive B cells during chronicTrypanosoma bruceiinfection

“…All of these populations participate in changes in the ECM during infection, including collagen and proteoglycan deposition and regulation of the ECM, highlighting the extensive ECM remodelling taking place in the meninges during chronic infection. The ontogeny of the meningeal FDC-like cells that we detected under chronic infection with T. brucei, and whether they play an active role in the neuroinflammatory process in this infection setting 86 , requires further investigation. Nevertheless, to our knowledge, this is the first report characterising the response of meningeal fibroblasts to chronic infections with a protozoan parasite, which has important implications for understanding how dynamic and adaptable the meningeal stroma is under chronic inflammatory processes.…”

“…The ontogeny of the meningeal FDC-like cells that we detected under chronic infection with T. brucei, and whether they play an active role in the neuroinflammatory process in this infection setting 73 requires further examination. Nevertheless, to our knowledge, this is the first report characterising the dynamics of meningeal fibroblasts to chronic infections with a protozoan parasite, which have important implications for understanding how dynamic and adaptable the meningeal stroma is under chronic inflammatory processes.…”

Glymphatic and lymphatic communication with systemic responses during physiological and pathological conditions in the central nervous system

“…Altogether, these data might suggest that brain-to-CLN signaling is responsible for triggering systemic inflammatory responses after acute stroke 13 . However, another study using a mouse model of the active experimental autoimmune encephalomyelitis (EAE) shows that VEGFR3 blockade in mice induced dural lymphatic vessel impairment and was insufficient to block autoimmune neuroinflammation 102 , implicating that lymphatic inflammation can have complex double-edged sword actions of either one can worsen acute tissue damage, or under some conditions the other mechanism can also help resolve damage and promote repair 103 , 104 .…”

The cerebral lymphatic drainage system and its implications in epilepsy

“…does not significantly contribute to progressing autoimmune neuroinflammation (Li et al, 2023). Therefore, in-depth basic research is needed to determine the molecular mechanisms of epilepsy and to measure the strengths and weaknesses of Vegfc as a therapeutic agent.…”

“…However, such treatment may also lead to MLV degeneration, altering CSF and ISF homeostasis and affecting neurological function and immunity (Blanchette & Daneman, 2017). Although a recent study has shown that inhibiting Vegfc/Vegfr3 does not significantly contribute to progressing autoimmune neuroinflammation (Li et al., 2023). Therefore, in‐depth basic research is needed to determine the molecular mechanisms of epilepsy and to measure the strengths and weaknesses of Vegfc as a therapeutic agent.…”