As mentioned in the previous section, the inflammatory response needs to be downregulated for proper healing to take place. In contrast with acute inflammation, chronic neuroinflammation is a long-lived, persistent response that starts with an initial inflammatory stimulus, but becomes self-propagating. Inflammatory factors produced by microglia and astrocytes can damage local tissue and, together with released DAMPs, can further increase inflammation and glial activation, leading to a vicious inflammatory cycle. This long-term inflammation can have disastrous consequences in the CNS, ranging from loss of synapses to impaired cognition and overt neurodegeneration [104-107]. This shift away from reparative responses may be due to a failed M2 response. Not only could the lack of M2 microglia fail to control inflammation; fewer M2 cells also mean lower levels of neuroprotective factors like IGF1 or brain-derived neurotrophic factor, which microglia produce. Thus the lack of an appropriate M2 response might be an important mechanism underlying neurodegeneration. Indeed, many investigators are starting to recognize the importance of M1/M2 dynamics in diseases characterized by chronic neuroinflammation.
