UBC Theses and Dissertations
The role of ROR alpha and CD34 in mucosal inflammation and fibrosis Lo, Bernard Clement
Fibrosis is the result of dysregulated tissue regeneration and is characterized by excessive accumulation of matrix proteins that become detrimental to tissue function. Type 2 immunity has long been associated with fibrotic scarring because of its role in wound healing and parasite-initiated tissue remodeling. Our objective was to examine two components of this inflammatory pathway that could potentially be modulated to limit fibrosis, namely RORα, a nuclear receptor required for ILC2 development, and CD34, a sialomucin involved in trafficking of eosinophils and mast cells to peripheral tissues. Using a model of infection-induced chronic gut inflammation, we demonstrate that Rora-deficient mice are protected from fibrosis; infected intestinal tissues displayed diminished pathology and attenuated collagen deposition. Although Rora is known for its role in ILC2s, we found that Salmonella-induced fibrosis was independent of eosinophils, STAT6 signaling and Th2 cytokines arguing that ILC2s are dispensable in this disease model. Instead, we observed reduced levels of ILC3- and T cell-derived IL-17A and IL-22 in infected tissues. Furthermore, using Rorasg/sg/Rag1-/- bone marrow chimeric mice, we found that restoring ILC function was sufficient to re-establish IL-17A and IL-22 production and a profibrotic phenotype. Our findings suggest that RORα-dependent ILC3 functions are pivotal in mediating gut fibrosis and they offer an avenue for therapeutic intervention in Crohn’s-like diseases. CD34 has been shown to drive lung inflammation and colitis by coordinating immune cell recruitment. However CD34 is also expressed by multiple non-hematopoietic subsets including endothelial and mesenchymal cells. To assess CD34 function in pulmonary repair, we induced lung injury by bleomycin administration. We found that Cd34-/- mice displayed severe weight loss and early mortality compared to WT controls. CD34-deficient animals developed severe interstitial edema and endothelial delamination, indicating impaired endothelial function. Chimeric Cd34-/- mice reconstituted with WT hematopoietic cells exhibited early mortality compared to WT mice reconstituted with Cd34-/- cells thus confirming this to be a non-hematopoietic defect. Lastly, CD34-deficient mice were more sensitive to lung damage caused by influenza infection, displaying greater weight loss and more extensive pulmonary remodeling. These results suggest that CD34 plays a protective role in maintaining vascular integrity in response to lung damage.
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