Mechanisms underlying Mannheimia haemolytica leukotoxin-induced oncosis and apoptosis of bovine alveolar macrophages

Mannheimia (Pasteurella) haemolytica leukotoxin (LktA) binds to the bovine β2 integrins (such as LFA-1 - CD11a/CD18) and leads to subsequent cellular effects in a dose dependent manner. The objectives of this study were to delineate the mechanisms that underlie LktA-induced oncosis and apoptosis and to examine the role of LktA/LFA-1 interaction in these events. The results demonstrate that LktA-induced oncosis proceeds through a LFA-1 and caspase-1 dependent pathway referred to as 'pyrotosis', as well as through a LFA-1- and caspase-1-independent pathway. LktA-induced apoptosis in alveolar macrophages involves activation of caspase-3 and engages the extrinsic and intrinsic pathways of apoptosis, with the extrinsic pathway being dependent on LFA-1 signaling and TNFα.