Innate Immune Memory: Implications for Microglial Function and Neuroprogression

Immunostimulatory insults such as stress and infection are risk factors for the development of several neuropsychiatric disorders characterized by neuroprogression. Inflammatory and neurotoxic molecules in the brain can cause disruptions in neurogenesis, neuronal excitability, synaptic transmission, synaptic plasticity, and neuronal survival - changes that characterize neuroprogression. We draw on recent findings in the immunology literature that peripheral innate immune cells are capable of retaining long-term memory of infectious insults and displaying long-lasting upregulated proinflammatory function in response to repeated infectious insults - a concept known as "innate immune memory." In turn, we hypothesize that microglia, the resident innate immune cells of the brain, are also capable of retaining long-term memory of infectious and noninfectious insults, including stress. Microglia are capable of producing a variety of proinflammatory neurotoxic cytokines and chemokines. Persistent upregulation of microglial proinflammatory function as a result of memory for immunostimulatory insults may therefore contribute to persistent and progressive inflammation in neuropsychiatric illnesses and be an important driver of neuroprogression.