Dectin-1 Signaling in Central Nervous System Autoimmunity

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2024-05-26

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2022

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Abstract

Dectin-1 is a C-type lectin receptor with diverse functions in orchestrating the innate immune response. Previous studies have primarily focused on the function of Dectin-1 in the setting of fungal infection. However, emerging evidence supports an important role for Dectin-1 in the context of autoimmunity and sterile inflammation. In this thesis, I investigated the function of Dectin-1 in central nervous system (CNS) autoimmunity. Specifically, I studied the role of Dectin-1 signaling in experimental autoimmune encephalomyelitis (EAE), a mouse model of Multiple Sclerosis (MS). Genetically modified mouse lines and immunophenotyping approaches were used to study Dectin-1 function in EAE. In addition, ex vivo studies using small molecule inhibitors and next-generation sequencing were used to perform in-depth characterization of Dectin-1 signaling mechanisms. Here I report that Dectin-1 limited EAE, while its downstream signaling molecule, Card9, promoted the disease. Myeloid cells mediated the pro-resolution function of Dectin-1 in EAE with enhanced gene expression of the neuroprotective molecule, Oncostatin M (Osm), through a Card9-independent pathway, mediated by the transcription factor NFAT. Furthermore, I found that the Osm receptor (OsmR) functioned specifically in astrocytes to reduce EAE severity. Notably, Dectin-1 did not respond to heat-killed Mycobacteria, an adjuvant to induce EAE. Instead, endogenous Dectin-1 ligands, including galectin-9, in the central nervous system (CNS) were involved to limit EAE. This thesis research reveals a mechanism of beneficial myeloid cell-astrocyte crosstalk regulated by a Dectin-1 pathway and identifies potential therapeutic targets for autoimmune neuroinflammation.

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Deerhake, Marion Elizabeth (2022). Dectin-1 Signaling in Central Nervous System Autoimmunity. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/25122.

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