The executioners sing a new song: killer caspases activate microglia

Abstract

Activation of microglia and inflammation-mediated neurotoxicity are suggested to have key roles in the pathogenesis of several neurodegenerative disorders. We recently published an article in Nature revealing an unexpected role for executioner caspases in the microglia activation process. We showed that caspases 8 and 3/7, commonly known to have executioner roles for apoptosis, can promote microglia activation in the absence of death. We found these caspases to be activated in microglia of PD and AD subjects. Inhibition of this signaling pathway hindered microglia activation and importantly reduced neurotoxicity in cell and animal models of disease. Here we review evidence suggesting that microglia can have a key role in the pathology of neurodegenerative disorders. We discuss possible underlying mechanisms regulating their activation and neurotoxic effect. We focus on the provocative hypothesis that caspase inhibition can be neuroprotective by targeting the microglia rather than the neurons themselves.

Melatonin Suppresses Toll Like Receptor 4-Dependent Caspase-3 Signaling Activation Coupled with Reduced Production of Proinflammatory Mediators in Hypoxic Microglia

“…We have reported the involvement of Toll like receptor 4 (TLR4) in hypoxic microglia activation both in vitro and in hypoxic neonatal rats [8]. In this connection, a novel role of TLR4-dependent caspase-3 activation has recently been reported in activated microglia after stimulation with lipopolysaccharide (LPS) [9, 10]. It was reported that TLR4-dependent caspase3 activation could promote microglia activation in the absence of cell death.…”

Caspases Playing in the Field of Neuroinflammation: Old and New Players

“…However, increasing evidence indicates that many of these so-called apoptotic caspases also exert nonapoptotic functions (for a review, see Hyman and Yuan [40 ]and Venero et al [41]). Similarly, typical ‘nonapoptotic' members such as caspases-1, -4 and -5 are proposed to induce ‘pyroptosis', a form of death associated with massive activation of inflammatory cells (for a review, see Labbe and Saleh [42]).…”

“…Intranigral administration of DEVD-fluoromethyl ketone (fmk), a caspase-3 inhibitor, or rottlerin, a PKCδ inhibitor, mitigated LPS-induced expression of cytokines and proinflammatory molecules, therefore supporting the view that killer caspases play a significant role in the activation of microglia. Since unregulated response or overactivation of microglia can have disastrous neurotoxic consequences, especially to the dopaminergic system [41,100], we also tested the ability of intranigral administration of IETD-fmk, a caspase-8 inhibitor, to prevent microglia activation and preserve the integrity of the dopaminergic system in the MPTP-lesion mouse model of PD. We found that caspase-8 inhibition in vivo significantly reduced the density of activated microglia and promoted a modest but yet significant protection of the nigrostriatal dopaminergic system.…”

“…As an example, nuclear disruption is viewed as an irreversible step in the apoptotic process, which precedes the final physical destruction of a cell, likewise terminal differentiation of many cell types including erythrocytes, keratinocytes, and lens fiber epithelial cells is characterized by the complete removal of the nucleus [41,81]. In fact, apoptotic caspases are emerging as the most versatile players in these two processes as accumulating evidence of nonapoptotic roles for these proteases during cell differentiation has notably increased in recent years.…”

Redesigning the procaspase‐8 dimer interface for improved dimerization

“…The apoptotic caspases are composed of initiator caspases, such as caspase-8, -9, and -10, and effector caspases, such as caspase-3, -6, and -7. 7,8 Effector caspases are responsible for cleaving various protein substrates, resulting in characteristic morphological changes and dismantling of the cell. 9 Caspases are synthesized as inactive zymogens, and effector caspases are activated following proteolysis by initiator caspases to separate the large and small subunits.…”