Differential Roles for α(M)β(2) Integrin Clustering or Activation in the Control of Apoptosis via Regulation of Akt and ERK Survival Mechanisms

The role of integrins in leukocyte apoptosis is unclear, some studies suggest enhancement, others inhibition. We have found that β(2)-integrin engagement on neutrophils can either inhibit or enhance apoptosis depending on the activation state of the integrin and the presence of proapoptotic stimuli. Both clustering and activation of α(M)β(2) delays spontaneous, or unstimulated, apoptosis, maintains mitochondrial membrane potential, and prevents cytochrome c release. In contrast, in the presence of proapoptotic stimuli, such as Fas ligation, TNFα, or UV irradiation, ligation of active α(M)β(2) resulted in enhanced mitochondrial changes and apoptosis. Clustering of inactive integrins did not show this proapoptotic effect and continued to inhibit apoptosis. This discrepancy was attributed to differential signaling in response to integrin clustering versus activation. Clustered, inactive α(M)β(2) was capable of stimulating the kinases ERK and Akt. Activated α(M)β(2) stimulated Akt, but not ERK. When proapoptotic stimuli were combined with either α(M)β(2) clustering or activation, Akt activity was blocked, allowing integrin activation to enhance apoptosis. Clustered, inactive α(M)β(2) continued to inhibit stimulated apoptosis due to maintained ERK activity. Therefore, β(2)-integrin engagement can both delay and enhance apoptosis in the same cell, suggesting that integrins can play a dual role in the apoptotic progression of leukocytes.