Expression and functional analysis of nucleic acid sensors in the CNS : implications for infection, sterile brain injury and neurodegeneration

Abstract

The recognition of nucleic acids is essential in combating viral and bacterial pathogens. The sensors and pathways involved in RNA/DNA detection have only recently been discovered and have expanded over the last number of years. TLR9 was the first DNA sensor to be identified followed by the cytosolic DNA receptors which include members of the PYHIN family and the enzyme cyclic GMP-AMP synthase (cGAS). The PYHIN family are so called as they contain an N-terminal PYRIN domain and a C-terminal HIN domain. These proteins bind DNA directly via their HIN domains culminating in the production of anti-viral and pro-inflammatory cytokines. Moreover, some members of the PYHIN family (e.g. AIM2 and IFI16/p204) can form inflammasome complexes, resulting in interleukin-1β (IL-1β) processing by caspase-1. Microglia and astrocytes can respond to cytosolic poly (I:C) via RIG-like receptors, however, the contribution of DNA sensors has not been fully explored in neuroimmune cells. Furthermore, the contribution of individual cell types, in particular astrocytes, has been confounded by difficulties in obtaining pure populations of cells devoid of contaminating microglia. The study outlined herein, involves extensive expression profiling of DNA sensors in highly purified primary astrocytes and microglia and demonstrates that both cell types express the majority of these genes.