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.

Figure 1

Overview of the TLR-dependent and JAK/STAT-dependent signaling pathways in microglia. TLRs 1, 2, 5, 6, 7, 8 and 9 trigger the classical myeloid differentiation primary response gene (88) (MyD88)-dependent signaling pathway. TLR3 triggers an alternative MyD88-independent, TIR-domain-containing, adapter-inducing IFN-β (TRIF)-dependent pathway through the TRIF. TLR4 triggers both the MyD88-dependent pathway through TIR domain-containing adaptor protein (TIRAP)–MyD88 interaction and the MyD88-independent pathway through TRIF-related adapter molecule (TRAM)–TRIF interaction. The MyD88-dependent pathway results in the activation of NF-κB, mitogen-activated protein kinase (MAPK) or IRF7 downstream signaling pathways (the latest upon TLR9 activation) through the IL receptor-associated kinase (IRAK) complex (which includes four subunits: two kinases, IRAK-1 and 4, and two non-catalytic units, IRAK-2 and M) and the TNF receptor-associated factor-6 (TRAF6). The MyD88-independent pathway results in the activation of IRF3 through the use of two kinases (IκB kinase-ɛ (IKKɛ) and TANK-binding kinase-1 (TBK1)). The TRAF family member-associated NF-κB activator (TANK) interacts with NF-κB essential modulator (NEMO), TBK1 and IKKβ, and may therefore bridge the MyD88-dependent and MyD88-independent pathways. The ligation of the IFN-γ receptor (IFNGR) with IFN-γ leads to the activation of Jak1and Jak2. STAT1 is phosphorylated by Jak kinases and translocates to the nucleus. Socs counteract STAT1 activation

Figure 2

Mechanisms of cell death in AD and PD involving inflammation. A degenerating neuron shows key neuropathological features of PD (left side of the neuron) and AD (right side of the neuron). Unfolded α-synuclein and proteasomal dysfunction induce the formation of oligomers of α-synuclein, the main component of Lewy bodies, which are the most distinctive histopathological feature of PD. In AD, sequential action of β-secretase and γ-secretase gives rise to the formation of toxic Aβ (mainly Aβ₁₋₄₀ and Aβ₁₋₄₂) from the amyloid-β precursor protein (APP). These peptides are proinflammatory and their extraneuronal accumulation form amyloid plaques, a typical histopathological feature of AD. The presence of oxidative stress in PD and other factors in AD commit neurons to die. Degenerating DA neurons in PD release different proinflammatory factors, including α-synuclein and neuromelanin. All these factors are recognized by different pattern-recognition receptors, including TLRs 2 and 4, CD14, CD36 and RAGE. Binding to these receptors induces the activation of transcription factors such as NF-κB and AP-1 (not shown) leading to microglia activation. Nurr-1 is a repressor of NF-κB, whereas active caspase-3 is an activator. Activation of microglia release different proinflammatory cytokines and activate ROS-producing enzymes such as iNOS, NADPH oxidase and myeloperoxidase (not shown). NADPH oxidase is a major source of extracellular ROS in response to diverse stimuli. It is a membrane-bound enzyme that catalyzes the production of superoxide anion (O^·₂⁻) from oxygen and it is strongly induced in response to different proinflammatory stimuli. O^·₂⁻ easily reacts with NO (mainly derived for upregulation of iNOS by reactive microglia) to produce peroxynitrite, the most reactive free radical, thus inducing nitrosative stress. Peroxynitrite has the potential to both initiate and sustain an autotoxic loop considered as a neuronal damaging mechanism in neurodegenerative diseases. Over-activation of microglia is deleterious to neurons, thus enhancing neuronal cell death, which in turn release more proinflammatory factors thus establishing a self-perpetuating process of neuroinflammation and neurodegeneration

Figure 3

Apoptotic caspases control microglia activation. Activation of TLRs with lipoteichoic acid (LTA, TLR2 agonist), PamC3sk4 (synthetic lipopeptide TLR1/2 agonist) or LPS (TLR4 agonist) leads to the orderly activation of caspase-8 and caspase-3. Caspase-3 activates the NF-κB pathways through processing and activation of PKCδ. Nuclear accumulation of NF-κB leads to the transcriptional activation of inflammatory gene expression