Grant: Operating Grant: SickKids-CIHR-IHDCYH New Investigator Grants

Atopic dermatitis (AD), also known as eczema, is a chronic, pruritic, inflammatory skin disease that occurs most frequently in children, affecting up to 20% of children worldwide. The incidence and prevalence of AD is on the rise. Studies have shown that AD patients often mount a T-helper-2 (Th2)-skewed immune response, leading to the emergence of IL-4 and IL-13 inhibitors as the first FDA-approved targeted therapies. However, more than 60% of phase III clinical trial patients failed to meet the primary endpoints in disease improvement, and relapse often occurs when IL-4 blocker treatment is stopped, suggesting that Th2 inhibition fails to erase skin-resident factors mediating disease relapse. Strikingly, the healed skin during AD therapy showed a mature dendritic cell population not found in healthy controls. This cell population harboured a characteristic inflammatory phenotype and persisted up to a year after remission. Our preliminary evidence shows that dermal dendritic cells express an orphan receptor (Mas-related G protein-coupled receptor [Mrgpr]) that recognizes virulent peptides produced by antibiotic-resistant Staphylococcus aureus (MRSA). Research has shown that an overabundance of Staphylococcal species drives inflammation in AD. The specifics of the role Mrgpr plays in inflammatory S. aureus-dependent signaling within the skini s unknown. We hypothesize that S. aureus-derived virulence peptides activate Mrgp receptor to orchestrate dendritic cell-mediated skin inflammation in AD. The proposed research aims to (1) determine the role of Mrgpr in the development of AD-like skin inflammation and (2) characterize the function of Mrgpr-expressing dendritic cells in AD-like phenotype. The project will use a multimodal approach involving both in vitro and in vivo molecular, cellular, and genetic strategies to reveal critical host-pathogen interactions underlying the pathophysiology of AD. Results from this work could lead to new avenues for AD treatment options and drug targets to reduce skin inflammation associated with increased S. aureus colonization.