DNA damage induced neuroinflammation in neurodegenerative disease

Abstract

AbstractBackgroundThe neurological symptom is highly related to the activation of innate immune system in the brain in neurodegenerative disease. The robust activation of microglia, which includes an overproduction of cytokines, creates a pro‐inflammatory environment that greatly contributes to the neuronal cell damage.MethodDNA damage was induced by either direct triggers of double strands break or blocking DNA damage repair. Conditioned media from microglia culture was collected and treated to the neuronal culture. Different neuronal parameters, including the morphological changes, synaptic counts and death markers, were measured afterwards.ResultIn microglia, DNA damage induces elevated level of cytoplasmic DNA, which primes the anti‐virus innate immune response via the cytosolic DNA sensor, STING. Knockdown of STING or inhibition of STING activity rescued the inflammatory response, specifically, the overproduction of cytokines. Cytosolic DNA species also works through the AIM2‐containing inflammasome to process pro‐IL‐1β to its active form, IL‐1β. DNA damage in microglia leads to the secretion of pro‐inflammatory cytokines to the conditioned with sever neuronal cell damage.ConclusionThe present work pointed out the fundamentality of accumulated DNA damage in triggering the activation of pro‐inflammatory pathway in the immune cells. Upon DNA damage, brain microglia, the major immune cells of the central nervous system become activated and assume a neurotoxic pro‐inflammatory phenotype. This also calls attention to the importance of the microglia‐neuron interaction in brain diseases. Meanwhile, the evidence for the presence of cytoplasmic DNA in other cell types under different disease conditions are also relevant to our understanding of a wider range of neurodegenerative diseases.