Role of the neurovascular molecule Wnt in regulating CNS inflammatory responses

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PROJECT SUMMARY/ABSTRACT The goal of our lab is to investigate immune regulation by innate cells for the treatment and resolution/repair of central nervous system (CNS) inflammatory diseases. During neuroinflammation the concerted actions of the CNS and the immune system affect the pathological responses mediated by infiltrating and resident immune cells. In particular, during multiple sclerosis (MS), myeloid cells are found in abundance within lesions. These myeloid antigen-presenting cells (APCs) have the ability to phagocytose myelin debris, release neurotoxic factors and promote the expansion and polarization of T cells in the CNS. However, they can also antagonize inflammation and promote repair. The exact mechanism(s) by which the CNS environment regulates myeloid APCs function during neuroinflammation remains ill defined. Analysis of the transcripts associated with MS-like lesions in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, revealed a significant enrichment of genes associated with the Wnt/b-catenin pathway as compared to non-lesioned areas. Binding of Wnt proteins to the cell surface receptor Frizzled (Fzd) inhibits glycogen synthase kinase 3b (GSK3b) and b-catenin phosphorylation, allowing b-catenin translocation to the nucleus and activates transcription of Wnt target genes. It has been demonstrated that Wnt signaling in dendritic cells (DCs) plays a central role in regulating the balance between inflammatory vs. regulatory responses in the gut. Blockade of GSK3b kinase was shown to increase IL-10 production by monocytes while suppressing the release of pro-inflammatory cytokines. In addition, our preliminary results demonstrate that following activation of the Wnt/b-catenin pathway, PD-L1 and PD-L2 expression were increased on human and mouse myeloid cells, while IL-1b, IL-6, IL-12 and IL-23 were reduced. Significantly, in EAE, Wnt agonist treatment decreased the clinical severity of chronic and relapsing-remitting EAE. Wnt proteins are naturally expressed in the CNS by brain endothelial cells (BBB-ECs) and astrocytes, and are upregulated during neuroinflammation. These cells make the neurovascular unit (NVU), a structure serving as an interface between the periphery and the CNS and hence directly exposed to the effects of peripheral and CNS driven inflammation. We hypothesize that inflammatory signals at the neurovascular level induce Wnt production by ECs and astroglial cells, which will regulate myeloid APCs function and promote anti- inflammatory responses that support repair and limit neuropathology. Using in vitro and in vivo approaches, our goal is to understand how Wnt ligands affect the immune response in the CNS and to determine the possibility to manipulate it in order to regulate myeloid cell function to reduce CNS-inflammatory responses and stimulate the repair mechanism.