Monarch/NLRP12: A Newly discovered Innate Immune Receptor in Uveitis

? DESCRIPTION (provided by applicant): There is a pressing need to define key underlying mechanisms in uveitis because it is one of the leading causes of blindness worldwide. Increasingly high incidences of ocular inflammatory diseases demand more effective and innovative treatments. Unfortunately, while currently available medications help reduce inflammation, they do not offer a cure for disease. For a better therapeutic approach, we need to understand the basic mechanisms in initiation and early events that lead to disease. Such signals involved in initiation of inflammation are expected to involve innate immune receptors activated by microbial triggers. This current paradigm is recognized as an NEI Mission goal: understand the interaction between innate and adaptive immunity in ocular inflammation and evaluate the role of innate immunity in uveitis. This proposal--that aims to advance the mission of NEI--will address how the innate immune receptor, NLRP12, is involved in immune responses that suppress ocular inflammation. Very little is understood how NOD-like receptors (NLRs) such as NLRP12 function in the eye, but this previously unconsidered family of innate immune receptors may be a critical aspect of endogenous protection of the eye. The objectives of this study will (1) Test the hypothesis that NLRP12 exerts an important negative regulatory role in controlling TLR-responses activated locally within the eye; and (2) Test the hypothesis that NLRP12 is essential to mitigation of uveitogenic T cell responses and development of autoimmune uveitis. The molecular and cellular approaches combined with chronic experimental uveitis modeled in mice should inform us as to how NLRP12-dependent innate responses are involved in orchestration of adaptive immune responses and controlling susceptibility to uveitis. This application is based upon the most current concepts and research in immunological basis of disease and could shift the paradigm within which ocular inflammatory conditions are considered because it focuses on how innate signals may be involved in shutting off inflammation, rather than promoting inflammation. Results of the proposed studies delving into endogenous ocular protective mechanisms could open up new avenues for development of therapies for uveitis and potentially for other vision-threatening diseases.