Regulation of caspase-3 processing by cIAP2 controls the switch between pro-inflammatory activation and cell death in microglia

Abstract

The activation of microglia, resident immune cells of the central nervous system, and inflammation-mediated neurotoxicity are typical features of neurodegenerative diseases, for example, Alzheimer's and Parkinson's diseases. An unexpected role of caspase-3, commonly known to have executioner role for apoptosis, was uncovered in the microglia activation process. A central question emerging from this finding is what prevents caspase-3 during the microglia activation from killing those cells? Caspase-3 activation occurs as a two-step process, where the zymogen is first cleaved by upstream caspases, such as caspase-8, to form intermediate, yet still active, p19/p12 complex; thereafter, autocatalytic processing generates the fully mature p17/p12 form of the enzyme. Here, we show that the induction of cellular inhibitor of apoptosis protein 2 (cIAP2) expression upon microglia activation prevents the conversion of caspase-3 p19 subunit to p17 subunit and is responsible for restraining caspase-3 in terms of activity and subcellular localization. We demonstrate that counteracting the repressive effect of cIAP2 on caspase-3 activation, using small interfering RNA targeting cIAP2 or a SMAC mimetic such as the BV6 compound, reduced the pro-inflammatory activation of microglia cells and promoted their death. We propose that the different caspase-3 functions in microglia, and potentially other cell types, reside in the active caspase-3 complexes formed. These results also could indicate cIAP2 as a possible therapeutic target to modulate microglia pro-inflammatory activation and associated neurotoxicity observed in neurodegenerative disorders.

Spatio-temporal activation of caspase-8 in myeloid cells upon ischemic stroke

“…It is believed that non-apoptotic functions of caspases rely on a moderate activity and a restricted subcellular localization. We have demonstrated that a differential processing of caspase-3 zymogen may ultimately lead to apoptosis (caspase-3 subunit p17; nuclear localization) or microglia activation (caspase-3 subunit p19; cytosolic localization) [25]. Our confocal analysis demonstrated a non-nuclear localization of active caspase-3 within myeloid cells early after stroke, a view that fits well with the non-apoptotic role of caspases in regulating myeloid cell activation.…”

Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson’s Disease

“…Ionized calcium-binding adaptor molecule 1 (IBA1) and glial fibrillary acidic protein (GFAP) are markers of microglia and astrocyte activation, respectively (Ghosh et al, 2012b). The key proinflammatory enzyme iNOS is typically elevated in disease conditions (Kavanagh et al, 2014) and thereby serves as a marker for glial pro-inflammatory activation. To determine if Mito-Apo protects against MPP + -induced microglia activation and astrogliosis, we treated mouse primary microglia and astrocytes with 10 μM MPP + in the presence or absence of 10 μM Mito-Apo for 24 h. In immunocytochemistry experiments, the expression of IBA-1 and GFAP were significantly increased in MPP + -treated primary microglia (Fig.…”

Retracted: Anti‐inflammatory properties of tianeptine on lipopolysaccharide‐induced changes in microglial cells involve toll‐like receptor‐related pathways

“…Importantly, both complexes exert distinct roles: cytoplasmic caspase-3 p19/p12 complex is in charge of regulating the proinflammatory activation of microglia. On the other hand, the nuclear caspase-3 p17/p12 complex seems to promote apoptotic processes in microglia (Kavanagh et al 2014). The caspase-3 p19/p12 subunit potentiates microglial activation by the cleavage of PKCd.…”

“…Recently it has been shown that microglia activation can also be governed by mechanisms involving caspase signaling. It has been proved that orderly activation of caspase-3 (p19 caspase-3 subunit) by LPS regulates microglial activation through a protein kinase C delta (PKCd)-dependent pathway and this signaling appears to be a possible therapeutic target to modulate microglia proinflammatory status (Burguillos et al 2011;Kavanagh et al 2014).…”

“…Recently it has been shown that microglia activation can also be governed by mechanisms involving caspase signaling. It has been proved that orderly activation of caspase-3 (p19 caspase-3 subunit) by LPS regulates microglial activation through a protein kinase C delta (PKCd)-dependent pathway and this signaling appears to be a possible therapeutic target to modulate microglia proinflammatory status (Burguillos et al 2011;Kavanagh et al 2014).Several reports have suggested that inflammatory processes and disturbed neuron-microglia interactions may play an important role in the pathogenesis of depression. Brain inflammatory processes are causally related to the enhanced neurodegeneration changes and reduced neurogenesis observed in the course of depression.…”