The interplay between host:microbial interactions is critical at mucosal surfaces. Dysregulation in these interactions can lead to intestinal inflammatory diseases, such as inflammatory bowel disease (IBD). The recognition and response to microbes is initially mediated by pattern recognition receptors (PRR). PRR responses lead to secretion of cytokines and cellular activation, as well as microbial clearance. The balance between these outcomes influences susceptibility between inflammatory diseases and infectious diseases. Our long-term goal is to understand the mechanisms mediating IBD pathogenesis, thereby ultimately improving the management and therapy of human IBD. Polymorphisms in IRF5 are associated with a wide-range of immune-mediated diseases, included IBD. We recently found that IRF5 is a critical determinant of the inter-individual variation in PRR-initiated signaling and cytokines from myeloid-derived cells across the population;carriers of the IRF5 disease risk polymorphisms secrete high levels of cytokines in response to a range of PRR stimuli. Despite the importance of IRF5 in regulating inter-individual variation in human myeloid-derived PRR-induced cytokines, the mechanism through which it contributes to PRR-initiated signaling pathways in human cells is not well defined (SA 1). We hypothesize that IRF5 regulates PRR- initiated signaling and outcomes in human myeloid cells through a combination of mechanisms associated with its localization in both the cytoplasm and nucleus, ultimately contributing to its broad and critical role in regulating PRRs. The role of IRF in mediating differentiation of related cellular subsets (e.g. M1 vs. M2) will be explored (SA 2a). Moreover, how IRF5 affects clearance of both resident and pathogenic intestinal microbes is not known (SA 2b). Importantly, the mechanism through which IRF5 contributes to IBD pathogenesis in vivo has not been examined (SA 3). We will integrate studies in primary human cells with in vivo mouse studies to dissect IRF5 contributions to IBD pathogenesis. We hypothesize that IRF5 will contribute to functions in multiple immune cell subsets essential in intestinal immune homeostasis in vivo, and that although it may contribute to inflammatory outcomes in colitis, it is essential for regulating intestinal pathogens.

Public Health Relevance

Polymorphisms in IRF5 are associated with a wide-range of immune-mediated diseases, included IBD. We have found that carriers of the IRF5 disease risk polymorphisms secrete high levels of cytokines in response to a range of PRR stimuli. We will dissect the mechanisms through which IRF5 regulates PRR-initiated signaling and outcomes in human myeloid cells, and contributes to IBD pathogenesis and clearance of intestinal commensal and pathogenic bacteria in mice in vivo.

Agency
National Institute of Health (NIH)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI110458-01
Application #
8915927
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Rothermel, Annette L
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510