Dynamic interplay between IL-36 and IL-1 in inflammation and infections

总结

SUMMARY Atopic dermatitis (AD) is an inflammatory skin condition that paradoxically increases the risk of skin infections. The most common bacterial infection of clinical significance is Staphylococcus aureus, while the herpes viruses herpes simplex virus (HSV) and varicella zoster virus (VZV) greatly affect quality of life and can lead to severe infections requiring hospitalization. While it is known that AD dysregulates the barrier function of the skin, how this impacts immunity against microbial pathogens is poorly understood. Improved insight into how immune mechanisms in the skin are initiated and resolved may underpin future development of preventive and therapeutic strategies. Interleukin-36 (IL-36) represents IL-36a, IL-36b and IL-36g, which are related to IL-1a and IL-1b. Elevated IL- 36 levels are associated with S. aureus colonization and severe AD. Using HSV1 as a model herpes virus, we published studies on the roles IL-1 and IL-36 play in initiating protective immune responses. Additional data from our lab identified critical activities that contribute to inflammation and the elimination of S. aureus. These findings improved our understanding of functions that are common for both IL-36 and IL-1. New unpublished data indicate mechanisms whereby the two cytokine groups also have distinct functions and how they may contribute to AD when dysregulated. To elucidate these mechanisms, we will here use mouse models of in vivo skin infections with HSV1 and S. aureus to identify the IL-1 and IL-36 sensing cell types essential for immune responses that promote inflammation and restrict the pathogens. These studies will involve a new floxed IL-36 receptor mouse strain we developed, in conjunction with an existing floxed IL-1 receptor strain. Complementary and mechanistic studies will also be conducted in human and mouse primary cells. A comprehensive in-depth understanding of these systems is needed to successfully suppress immune responses therapeutically, while at the same time maintaining functional protective immunity against pathogens such as HSV and S. aureus.