Immunorecognition of nucleic acids in microglia and implication for multiple sclerosis (MS)
Nucleic acid recognition in microglia and MS
Microglia is a unique and important component of both the innate and adaptive immune response, providing the CNS with a means to rapidly and efficiently respond to a wide variety of pathogens. In addition to infection, microglia is involved in inflammatory responses in multiple sclerosis (MS) and Alzheimer´s disease (SD). Viral nucleic acid serves as virus-associated molecular pattern that is used by specialized immune cells to detect and adequately respond to viral infection. There is good evidence that immunorecognition of endogenous nucleic acids is involved in autoimmunity, and there is recent evidence that recognition of endogenous DNA is involved in the pathogenesis of multiple sclerosis. Receptors for immunorecognition of nucleic acids are known to be expressed in murine microglia, but information for primary human microglia is limited. In preliminary studies we found that systemic administration of certain nucleic acid ligands induce systemic levels of IFN-β and show beneficial activity in experimental autoimmune encephalomyelitis (EAE). We hypothesize that (1) immunorecognition of nucleic acids plays a pivotal role in the pathogenesis of MS, and that (2) therapeutic intervention in MS has to address the contribution of nucleic acid immunorecognition and the beneficial effect of systemic IFN-β. In this project our goals are: (1) to define the role of nucleic acid immunorecognition in microglia, (2) to characterize the antiviral responses of microglia, (3) to identify reagents interfering with nucleic acid-stimulated microglia, (4) to define the role of endogenous nucleic acid ligands in EAE, and (5) to identify ways of therapeutic intervention in EAE based on nucleic acid immunorecognition. The results will provide a detailed picture of immunorecognition of nucleic acids in human microglia, and thus form the basis for the use of nucleic acid ligands and of corresponding inhibitors to modulate microglia function. Improved insight in microglia biology may lead to novel treatments of human brain disorders such as multiple sclerosis.