Figure 12.

Microglial phagocytosis of apoptotic cells was impaired in mouse and macaque models of stroke induced by tMCAo. This impairment was related to the lack of oxygen and nutrients, which lead to reduced process motility, possibly related to the decreased engulfment; and reduced lysosomal numbers and increased pH, possibly related to the decreased degradation in primary and hippocampal organotypic cultures. In vivo tMCAo and in vitro energetic depletion also induced a protective autophagy response, possibly related to the lysosomal depletion. The maintenance of basal autophagy was critical for microglial survival and phagocytosis, as shown in mice that lacked expression of autophagy genes such as atg4b KO or Tmem119-becn1 iKO mice, or in primary and organotypic cultures treated with the ULK1-ULK2 inhibitor MRT68921. While the autophagy inducer rapamycin did not improve the phagocytosis blockade in vitro, it was effective in preventing the phagocytosis impairment induced by tMCAo, supporting the possibility of pharmacological modulation of microglial phagocytosis in vivo.