Figure 1.

Suggested mechanism of primary phagocytosis in inflammatory neurodegeneration. Inflammatory microglial activation with lipopolysaccharide (LPS), lipoteichoic acid (LTA), or amyloid-β (Aβ) through Toll-like receptors-2/4 induces expression of inducible nitric oxide synthase (iNOS) and assembly of the phagocytic NADPH oxidase (PHOX). iNOS and PHOX produce nitric oxide (NO) and superoxide $\left({\text{O}}_2^{-}\right),$ respectively, which react to form low concentrations of peroxynitrite. These sublethal levels of peroxynitrite (while not causing neuronal death) are sufficient to cause neuronal exposure of phosphatidylserine (PS), which is recognized by the bridging protein MFG-E8 (milk fat globule EGF-like factor 8). MFG-E8 also binds to the microglial vitronectin receptor (the heterodimeric α_vβ_3/5 integrin), thereby causing engulfment of the PS-exposing neuron. If phagocytosis is blocked, however, neurons are able to re-internalize PS, thus evading phagocytosis and death.