Working model of microglial polarization. (A) A variety of cytokines are able to polarize microglia to unique phenotypes. These phenotypes constitute a spectrum as opposed to two binary states. Depending on the stimulus, microglia can be polarized towards one end of the spectrum and be more M1- or M2-like. (B) Upon prolonged or chronic inflammation, an overabundance of inflammatory cytokines skews microglial polarization towards the M1 phenotype. M1 microglia, in turn, produce additional inflammatory cytokines, generating a cycle that further induces inflammation and maintains the M1 state. This skewed population of M1 microglia exhibits impaired phagocytosis and is cytotoxic in, for example, Alzheimer’s disease and multiple sclerosis. (C) To treat neuroinflammatory diseases, certain therapeutic agents, such as glatiramer acetate, bexarotene, and PPARγ agonists, have been used. These treatments have been shown to inhibit inflammation as well as induce M2 activation, resulting in reduced disease severity. A more complete list of such therapeutic agents can be found in Table 2. AD, Alzheimer’s disease, EAE, experimental autoimmune encephalomyelitis; GA, glatiramer acetate; MS, multiple sclerosis.