Wednesday, April 2, 2025
4/2/2025
Mucosal Macrophages and Tertiary Lymphoid Structures in IBD - The incidence and prevalence of inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), are increasing worldwide, and the treatment options for IBD are still limited for a large number of patients despite the development of targeted biologics. A mechanistic model of pathogenic communication among immune, stromal and epithelial cells controlled by elaborate cytokine networks that underlies pathogenesis of inflammatory bowel disease (IBD) has been proposed. The next critical step is to establish the spatiotemporal organization of this abnormal immune response. Tertiary lymphoid structures (TLS) are ectopic disorganized lymphoid aggregates found around intestinal inflammatory lesions in patients with CD and UC, possibly in response to persisting pathobionts that breach intestinal mucosa. TLS are recognized as a pathologic hallmark in IBD, however, their precise cellular composition and mechanistic contribution to intestinal immunity and pathogenesis of IBD are largely unknown. The overall goal of this proposal is to unravel the mechanisms that drive TLS formation and elucidate their function in mouse models of colitis relevant to IBD Mononuclear phagocytes (MNPs) that comprise dendritic cell (DC) and macrophage (M) subsets are an important constituent of TLS. In a model of Salmonella colitis, we identified a subset of mucosa-resident (CX3CR1hi) Ms that functions as an antigen-presenting cell driving TLS formation and a Salmonella-specific T cell-dependent IgA response in TLS. We found that TLS play a protective role in Salmonella colitis by restricting systemic pathogen dissemination, but under conditions of chronic inflammation observed in IBD, TLS are likely to acquire a proinflammatory role. Such conversion of TLS function may occur via promotion of TLS-associated pathogenic T cell differentiation and proinflammatory IgG instead of IgA responses as suggested by recent single cell transcriptional analyses of human IBD. Our overall hypothesis is that a key step in the pathogenesis of IBD is dysregulation of CX3CR1hi Ms, and that such dysregulated Ms promote IBD by driving the development of pathogenic TLS that produce T-cell dependent IgG instead of IgA. We will test our hypothesis in three specific aims. Aim 1 will determine the role of antigen-presentation and B cell activation by CX3CR1hi Ms in the development of pathogenic TLS; and Aim 2 will establish the role of TNF signaling in CX3CR1hi Ms in the regulation of TLS function. If successful, the study will provide novel insight into the pathogenesis of IBD and identify potential biomarkers and therapeutic targets (e.g., CX3CR1hi M-derived mediators) associated with TLS in IBD.
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