Tissue-specific production of MicroRNA-155 inhibits melanocortin 5 receptor-dependent suppressor macrophages to promote experimental autoimmune uveitis.

Tissue-specific immune regulation is an important component of the immune response relevant to many areas of immunology. The focus of this study is on tissue-specific mechanisms that contribute to autoimmune uveitis. Precise gene regulation is necessary for the proper expression of an inflammatory or regulatory response. This precision gene regulation can be accomplished by microRNA at the level of the mRNA transcript. miR-155, in particular, has a complicated role in the immune response with positive and negative inflammatory effects. In this work, we identify a decrease in miR-155 in suppressor macrophages and further examine how tissue-specific production of miR-155 impacts experimental autoimmune uveitis. Importantly, we show that eliminating miR-155 expression by the target tissue before initiation reduces disease severity, but elimination of miR-155 after the onset of inflammation does not alter the course of disease. Additionally, expression of miR-155 by the target tissue before initiation is necessary for the induction of regulatory immunity that protects from further autoimmune disease, but not after the onset of inflammation. In summary, we find a MC5r-dependent decrease in miR-155 in postexperimental autoimmune uveitis APC, miR-155 production by the target tissue is necessary for the initiation of autoimmune uveitis, and may have a role in establishing protective regulatory immunity.