Autophagy in Macrophages: Impacting Inflammation and Bacterial Infection

Figure 3

The regulation of early and late phases of inflammasome activity through the autophagic process is shown. Distinct inflammasome complexes are assembled by a variety of different stimuli. For example, reactive oxygen species (ROS), adenosine triphosphate (ATP), potassium efflux, nigericin, and lysosomal rupture trigger the activation of the sensor molecule NLRP3, whereas mitochondrial DNA (mtDNA) and pathogen-associated DNA activate the sensor molecule AIM2. The activation of sensor molecules leads to their oligomerization and further assembly of inflammasome complexes by recruiting adaptor protein ASC and procaspase-1 leading to the cleavage of the proform. Activated caspase-1 then cleaves the proinflammatory cytokine precursors prointerleukin-1β (pro-IL-1β) and pro-IL-18 into biologically active forms of IL-1β and IL-18. (1) At the early phase of inflammasome activation, biologically active forms of IL-1β and IL-18 are transported into autophagic vesicles via GRASP proteins and secreted outside of the cell through autophagic vesicles. Hence, autophagic pathway regulates inflammasome activity by contributing the secretion of IL-1β and IL-18. (2) In the late phase, inflammasome complexes are selectively degraded by autophagic vesicles. The multimeric inflammasome structures are ubiquitinated; one target is the adaptor protein ASC. The autophagic adaptor protein p62 mediates the recruitment of ubiquitinated inflammasomes as autophagic cargo into autophagic vesicles. Inflammasome structures are later degraded by hydrolytic enzymes following lysosomal fusion. Hence, the autophagic pathway acts to limit inflammasome activity by engulfing and degrading them.