The domiNO effect turns macrophage activation deadly

Abstract

Macrophage activation is essential for effective immunity to infection but can also contribute to disease through incompletely understood mechanisms. In this issue of Immunity, Simpson et al. reveal that death of activated macrophages integrates extrinsic and intrinsic pathways of apoptosis that contribute to damaging host responses.

Figure 1

IFNγ priming stacks the dominos that program macrophage cell death by both extrinsic and intrinsic pathways of apoptosis Stimulation of macrophages with IFNγ prior to addition of TLR agonists engages caspase 8 to increase expression of iNOS and TNF but transcriptionally repress BCL-2 expression. In addition to lower BCL-2 expression, iNOS-dependent production of NO reduces expression of MCL-1 and A1. Reduced expression of multiple pro-survival proteins tips the cellular balance toward death through activation of BAX and BAK. These pore-forming proteins trigger loss of mitochondrial membrane permeability, release of cytochrome c, and downstream activation of the caspase-9 and caspase-3 cascade. In addition, NO production further sensitizes caspase-8 processing following ligation of death receptors including TNFR or FAS and promotes downstream signaling cascades. This form of cell death in an inflammatory environment may exacerbate inflammation through cellular release of cytokines (TNF, IL1-β, IL-6) and danger-associated molecular patterns (HMGB1, nitrite).