Immunomodulatory Functions of Insulin Growth Factor Like Proteins in Skin Inflammation

Background and Innovation: Significant gaps in knowledge exist regarding the molecular and cellular pathways that cause allergic skin inflammation, a key driver of the inflammatory skin diseases, allergic contact dermatitis (ACD) and atopic dermatitis (AD). Better understanding disease mechanisms of ACD and AD could lead to improved treatments and outcomes for Veterans. The preliminary studies for this project identified insulin growth factor like (IGFL) proteins and their putative receptor, insulin growth factor like receptor 1 (IGFLR1), whose biological functions remain to be defined, as potential mediators of allergic skin inflammation. These data suggest IGFLs are cytokines produced by keratinocytes that act through IGFLR1 to promote allergic skin inflammation and that IGFLs and IGFLR1 could be therapeutic targets. In addition to these key conceptual innovations, important technical innovations include use of new IGFL and IGFLR1 deficient mouse strains that will permit investigations into how IGFL and IGFLR1 contribute to mouse models of allergic skin inflammation. Significance and Impact to Veterans Healthcare: An estimated 75% of the U.S. population is sensitized to at least one of thousands of potential allergens that cause ACD, and approximately 10% of the U.S. population has AD. The tendencies for allergen sensitization and AD in adults to persist and the similar prevalence of ACD and AD in active-duty military and the general U.S. population, support the conclusion that ACD and AD are common in Veterans. In these diseases, skin itch and secondary infections contribute to a high degree of morbidity that markedly reduces quality of life. As current therapies are limited, often ineffective, and can cause significant immunosuppression and other types of morbidity, there is a critical need to better understand pathogenesis in order to identify more effective, more targeted, and safer therapies. The proposed studies hold the potential to directly inform development of new therapies for ACD and AD, paving the way to realize and implement personalized/precision medicine approaches for Veterans. Path to Translation/Implementation: This project will provide an understanding of how the IGFL/IGFLR1 axis (select pathway) contributes to inflammatory skin diseases, informing the next stages of translation that would include confirming the role of IGFL/IGFLR1 in disease and efforts to develop therapeutics targeting this pathway.