Activation of Proinflammatory Caspases by Cathepsin B in Focal Cerebral Ischemia

Abstract

Summary: Cathepsins and caspases are two families of proteases that play pivotal roles in ischemic cell death. This study investigated the existence of a cross-talk between cathepsin B and proinflammatory caspases in stroke-induced cell death, as recently suggested by in vitro data. Cortical ischemic damage was induced in mice by distal and permanent occlusion of the middle cerebral artery. Cytoplasmic activation of cathepsin B was observed from the early stages of infarction, and displayed an activation pattern parallel to the activation pattern of caspase-1 and -11. Immunohistochemistry revealed the colocalization of cathepsin B with each caspase in cells of the infarct core. The apical position of cathepsin B in both caspase-activation cascades was confirmed by pretreatment of the animals with the cathepsin B inhibitor CA-074, which also potently protected cortical structures from ischemic damage, indicating involvement of the proteases in the lesion process. The results show that cathepsin B release is an early event following occlusion of cerebral arteries, which eventually triggers the activation of proinflammatory caspases in the absence of reperfusion. This new pathway may play a critical role in brain infarction by promoting inflammatory responses, and/or by amplifying the apoptotic process.

Effects of cathepsins B and L inhibition on postischemic protein alterations in the brain

“…Such a critical pathway is the rapid activation of cysteine proteases including the cathepsins, calpains, and caspases [4][5][6][7][8]. Cathepsins B and L contribute to cerebral injury after focal ischemia with reperfusion [9][10][11][12][13]. Previously, we demonstrated that CP-1, a non-toxic cysteine protease inhibitor which is relatively selective for cathepsins B and L, but not the calpains or caspases, is effective at reducing infarct volume and improving functional scores when administered intravenously to rats after 2 hours of MCAO and reperfusion [12].…”

Death and survival of neuronal and astrocytic cells in ischemic brain injury: a role of autophagy

“…Under physiologic conditions, their activity is restricted to the lysosomal compartment, where they participate in protein turnover by degrading unneeded proteins into amino acids [65] . It has been demonstrated that cerebral ischemia induces the release of cathepsins into the cytoplasm, where they extensively perform their proteolytic function and can promote ischemia-induced apoptosis through alterations of mitochondrial homeostasis and the activation of proapoptotic members of the Bcl-2 family [7,8,66,67] . Cathepsin B possesses a caspaseprocessing activity, which mainly appears on caspase-11 and caspase-1.…”

“…Caspase-1 and caspase-11 play important roles in brain ischemia by promoting both apoptotic and inflammatory processes. In addition, cathepsin B proteolytic effects Cytochrome c is a key activator of the apoptosome, which regulates the mitochondrial caspase activation pathway mediated by caspase-9 [66] . Cathepsin L can activate caspase-3, and cathepsin D can activate caspase-8.…”

“…Cathepsin L can activate caspase-3, and cathepsin D can activate caspase-8. The inhibition of cathepsins leads to significant neuroprotection in a cathepsin-caspase dependent manner in the experimental model of stroke [66,[68][69][70][71] . Therefore, ischemia-induced ALP activation may be involved in neuronal and astrocytic apoptotic cell death via a cathepsin-caspase dependent manner in ischemic brain injury.…”

Mechanisms of lysosomal proteases participating in cerebral ischemia-induced neuronal death

“…Benchoua A et al reported that cytoplasmic activation of cathepsin B was an early event after a distal and permanent middle cerebral artery occlusion (pMCAO), and immunohistochemistry revealed the colocalization of cathepsin B with caspase-1 and caspase-11 in cells of the infarct core [7] . Tsubokawa T et al showed that an initial rise in calpain and cathepsin B activity was detected as early as 2 h after the reperfusion in the periinfarct penumbra cortex and the activation of MMP-9, calpain, and cathepsin B were extensively colocalized in both the neuronal cells and the neurovascular structures 24 h after the MCAO insult in rats [8] .…”