The immunology of neurodegeneration (original) (raw)
Neurodegeneration ultimately targets neurons and can range from damage to synapses or neurites to cell death. It seems therefore obvious to ask whether cell autonomous immune responses in neurons may have a role in neurodegeneration. However, only in the past few years have scientists started to explore how neurons sense danger using intracellular or surface immune sensors (Figure 2). Once a danger signal is detected, neurons can activate intracellular defense mechanisms and can alert neighboring cells via cell-cell interactions or the release of signaling proteins, neurotransmitters, and other messengers.
Innate immune receptors as sensors of intraneuronal distress. Neurons express innate immune receptors that serve as sensors of danger signals. TLRs may recognize endogenous molecules and protein aggregates such as Aβ assemblies, ssRNA, or dsRNA aside from molecules associated with pathogens. While TLR4 and its co-receptor CD14 are present at the cell surface, TLR3, -7, -8, and -9 are located in the ER and endosomal compartments. Activation of TLRs can lead to initiation of autophagy via TRIF/RIP1 and possibly induce the clearance of defective organelles or protein aggregates. Activation of NOD1 or NOD2 may result in NF-κB–mediated transcription of pro-inflammatory genes or initiation of autophagy via Atg16L. The adaptor protein p62 can detect viral proteins in neurons and initiate clearance of viral particles via autophagy involving Atg5 and Atg7. It may also assist in the clearance of abnormal protein aggregates. Atg, autophagy-related protein; NOD, nucleotide binding oligomerization domain-like; p62, nucleoporin 62; TRIF, TIR domain–containing adapter-inducing IFN-β; RIP1, receptor interacting protein-1.
Innate immune sensors of cell-autonomous distress. The best studied innate immune sensors are TLRs, which signal through various adaptor molecules to activate NF-κB and/or Stat signaling pathways to induce the production of mostly pro-inflammatory cytokines and chemokines (reviewed in ref. 5). Mammalian TLRs not only recognize pathogen-derived molecules such as lipoproteins, peptidoglycans, single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), and unmethylated CpG motifs, but also endogenous molecules produced by stressed and injured cells, including hsp, mRNA, and fibrinogen. Neurons and neural progenitor cells express several TLRs, including TLR2, -3, -4, -7/8, and -9, and their functions range from regulating neurogenesis to triggering neurite retraction or cell death (reviewed in ref. 6). Because TLRs can be functionally expressed in the ER and in endolysosomes (7, 8), molecules associated with injury or aging could in principle trigger a pathogenic cascade from within neurons. In support of this idea, mitochondrial DNA (mtDNA), which is released from damaged mitochondria, is recognized by TLR9 in the endosome and can lead to an inflammatory and injurious response (9). While very little is known at this point about the role of innate immune sensors in neurons, studies in macrophages show that stimulation of TLR3, -4, and -7 can be beneficial by inducing autophagy (10, 11). Autophagy, which is a degradation pathway for long-lived proteins and organelles (12), has largely beneficial functions in postmitotic neurons, and it is possible that damaged mitochondria or intracellular protein aggregates in aged neurons may trigger TLR-dependent autophagy for clean up. Defects in autophagy, as they occur in neurodegenerative diseases (13–16), might thus interfere with such an innate immune process.
Another group of innate immune sensors, nucleotide binding oligomerization domain–like (NOD-like) receptors, form cytosolic protein complexes called inflammasomes, which can activate caspase-1, IL-1, and NF-κB–dependent inflammatory responses (17, 18). Recent studies show that NOD-like receptors (NLR) can also trigger autophagy (19–21), which supports an intriguing link among recognition of abnormal molecular patterns, initiation of inflammatory pathways, and activation of autophagy. This mechanism may well be evolutionarily conserved and could allow cells to purge themselves of abnormal protein aggregates, aged mitochondria, or other cellular junk apart from intracellular pathogens. That such a scenario may, at least in part, take place in neurons in a cell-autonomous way is supported by elegant studies demonstrating recognition of Sindbis virus capsid protein by the adaptor protein p62, leading to activation of autophagy and protection against virus-induced cell death (22). Additionally, studies in medicinal leech, which is able to regenerate the structure and function of its CNS after mechanical lesions (23), show that both intracellular leech NLR and TLR1 are temporally and spatially associated with regeneration of neurons (24). It will therefore be most interesting to test whether intracellular innate immune sensors are capable of recognizing abnormal patterns or assemblies of the disease-related proteins β-amyloid (Aβ), α-synuclein, huntingtin, or TAR DNA-binding protein 43 (TDP43). It will also be important to determine in which cellular compartment such protein aggregates may be accessible to TLRs, NLRs, and related receptors.
Alerting the neighbors. Once neurons have detected cell intrinsic abnormalities, they will alert their neighbors, which include microglia, astrocytes, and possibly other, less abundant cells in the CNS. Injured neurons can release ATP, ions, neurotransmitters, growth factors, cytokines, and other injury response factors, or they can retract inhibitory molecules that keep microglia in a quiet, surveillant state (25). Neurons may release nucleic acids or hsp, which are ligands for TLRs and other receptors, into the extracellular space. For example, hsp60 released from injured neurons can activate microglia via TLR4, causing enhanced nitric oxide production and in turn, neuronal cell death (26). An important mediator alerting other cells to neuronal injury is the DNA-binding protein high mobility group box 1 (HMGB1), which can be released actively from injured cells or passively from dying cells. HMGB1 promoted neurodegeneration in a mouse model of ischemic stroke by activating microglia through receptor for advanced glycation end products (RAGE) (27). Likewise, in a cellular model of Parkinson disease (PD) using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), HMGB1 binds to CD11b/Mac1 on microglia to induce a neurotoxic response (28).
Neuronal sensing of tissue injury through immune receptors. Neurons are remarkably well equipped with immune receptors and sensor molecules to detect injury in their local environment. In addition to TLRs, they express cytokine and growth factor receptors, major histocompatibility class I, and complement receptors. While dozens of studies have manipulated immune pathways in mouse models of neurodegeneration (Tables 1 and 2), most used global or CNS-wide genetic manipulations, and it is unclear to what extent the effects are mediated through neurons, glial cells, or both. A notable exception was the directed expression of RAGE, one of several known receptors for Aβ, in neurons. These studies found that RAGE activates NF-κB and MAPK signaling and results in increased synaptic transmission deficits and cognitive impairment (29). Also, expression of a dominant-negative TGF-β type II receptor in neurons impaired signaling in these cells and resulted in a two-fold increase in amyloid accumulation and increased neurodegeneration in mutant APP transgenic mice, a mouse model of familial Alzheimer disease (AD) (30). Because brains from patients with AD have significantly reduced levels of this TGF-β receptor compared with those without disease (30), it is possible that deficiency in neuronal TGF-β signaling may contribute to AD.
Genetic modifications in mouse models of neurodegenerative diseases: molecules with beneficial effects
Recently an exciting approach to studying the effect of prostaglandins in the brain was described in a stroke model (31). The COX-2 product prostaglandin E2 can bind to four different prostanoid receptors making it difficult to understand how COX-2 inhibitors, which seem to strongly reduce risk of AD (32) and PD (33), work in the brain. Liang and coworkers showed that genetic deletion of prostanoid receptor 4 in neurons worsened stroke injury and decreased cerebral perfusion, pointing to a beneficial effect of this receptor in neurons (31). Clearly, this is a direction in which the field of neurodegeneration has to move in order to gain a more complete understanding of the complex action of immune factors in neuronal distress and degeneration.