Regulation of Neutrophil Survival/Apoptosis by Mcl-1
Figure 1
Mcl-1 integrates survival and proapoptosis cues in human neutrophils. Mcl-1 functions as a survival signal for human neutrophils by blocking the proapoptotic action of Bak (and/or Bim) at the outer mitochondrial membrane. In aging neutrophils, decreases in Mcl-1 level may precede initiation of the cell death program. At later stages, Mcl-1 is rapidly degraded by the proteasome and/or cleaved by caspase-3. Ligation of Fas accelerates Mcl-1 proteasomal degradation. Falls in Mcl-1 lead to collapse of mitochondrial function, and apoptosis. Cytoplasmic accumulation of the nuclear protein MNDA further accelerates Mcl-1 degradation. Survival cues from GM-CSF, acute-phase proteins, and ligation of Mac-1 have been reported to enhance transcription of Mcl-1, promote dissociation of Mcl-1 from Bax (and/or Bad) in the cytoplasm and translocation of Mcl-1 to the mitochondria, and/or inhibit Mcl-1 degradation. GM-CSF predominantly influences proteasomal degradation of Mcl-1. Blockade of survival signalling circuits by MAPK inhibitors, lipoxin A4, or aspirin-triggered 15-epi-LXA4 redirects neutrophils to apoptosis by decreasing Mcl-1 level. Likewise, the CDK inhibitor roscovitine evokes drops in Mcl-1 through yet undefined mechanisms. Therapeutic induction of neutrophil apoptosis through modulation of Mcl-1 expression would contribute to clearance of emigrated neutrophils, thereby enhancing the resolution of inflammation.
