Microglia are activated after neuronal injury and in neurodegenerative diseases, and trigger neuroinflammation in the central nervous system (CNS). Microglia-derived neuroinflammation has both ...beneficial and detrimental effects on neurons. Because the timing and magnitude of microglial activation is thought to be a critical determinant of neuronal fate, understanding the molecular mechanisms underlying microglial activation is required to enable establishment of microglia-targeted therapies for neural diseases. Plasma membrane receptors play primary roles as activators of microglia and in this review, we focus on a receptor complex involving triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12), both of which are causative genes for Nasu-Hakola disease, a dementia with bone cysts. Recent transcriptome approaches demonstrated TREM2/DAP12 signaling as the principal regulator that transforms microglia from a homeostatic to a neural disease-associated state. Furthermore, animal model studies revealed critical roles for TREM2/DAP12 in the regulation of microglial activity, including survival, phagocytosis, and cytokine production, not only in Alzheimer's disease but also in other neural diseases, such as Parkinson's disease, demyelinating disease, ischemia, and peripheral nerve injury. Intriguingly, while TREM2/DAP12-mediated microglial activation is detrimental for some diseases, including peripheral nerve injury, it is beneficial for other diseases. As the role of activated microglia differs among disease models, TREM2/DAP12 signaling may result in different outcomes in different diseases. In this review we discuss recent perspectives on the role of TREM2/DAP12 in microglia and their contribution to neural diseases.
Elimination of dead or live cells take place in both a healthy and diseased central nervous system (CNS). Dying or dead cells are quickly cleared by phagocytosis for the maintenance of a healthy CNS ...or for recovery after injury. Live cells or parts thereof, such as the synapses and myelin, are appropriately eliminated by phagocytosis to maintain or refine neural networks during development and adulthood. Microglia, the specific population of resident macrophages in the CNS, are classically considered as primary phagocytes; however, astrocytes have also been highlighted as phagocytes in the last decade. Phagocytic targets and receptors are reported to be mostly common between astrocytes and microglia, which raises the question of how astrocytic phagocytosis differs from microglial phagocytosis, and how these two phagocytic systems cooperate. In this review, we address the consequences of astrocytic phagocytosis, particularly focusing on these elusive points.
Main Points
Phagocytic targets are mostly common between astrocytes and microglia.
Various factors determine whether either of the glial cell types phagocytose the targets.
Interaction of astrocytes and microglia may provide microglia with a phagocytic advantage.
•Mitochondrial behavior in an axon reflects axonal condition.•Increased supply of healthy mitochondria facilitates axon regeneration.•In vivo imaging of mitochondrial dynamics in lesioned axon ...provides a new insight.
Over the last decade, mitochondrial dynamics beyond function during axon regeneration/degeneration have received attention. Axons have an effective delivery system of mitochondria shuttling between soma and axonal terminals, due to their polarized structure. The proper axonal transport of mitochondria, coordinated with mitochondrial fission/fusion and clearance, is vital for supplying high power energy in injured axons. Many researchers have studied mitochondrial dynamics using in vitro cultured cells with significant progress reported. However, the in vitro culture system is missing a physiological environment including glial cells, immune cells, and endothelial cells, whose communications are indispensable to nerve regeneration/degeneration. In line with this, the understanding of mitochondrial behavior in injured axon in vivo is necessary for promoting the physiological understanding of damaged axons and the development of a therapeutic strategy. In this review, we focus on recent insights into in vivo mitochondrial dynamics during axonal regeneration/degeneration, and introduce the advances of mouse strains to visualize mitochondria in a neuron-specific or an injury-specific manner, which are extremely useful for nerve regeneration/degeneration studies.
Neuropathic pain afflicts millions of people, and the development of an effective treatment for this intractable pain is an urgent issue. Recent evidence has implicated microglia in neuropathic pain. ...The present study showed that the DNAX-activating protein of 12 kDa (DAP12) and its associated "triggering receptor expressed on myeloid cells 2" (TREM2) were predominantly expressed by microglia in the dorsal horn after spinal nerve injury, revealing a role for TREM2/DAP12 signaling in neuropathic pain. Nerve injury-induced proinflammatory cytokine expression in microglia and pain behaviors were significantly suppressed in Dap12-deficient mice. Furthermore, intrathecal administration of TREM2 agonistic antibody induced proinflammatory cytokine expression, as well as neuropathic pain, in mice without nerve injury. The agonistic antibody induced proinflammatory responses and neuropathic pain was not observed in Dap12-deficient mice. Together, these results suggest that TREM2/DAP12-mediated signals in microglia exacerbate nerve injury-induced neuropathic pain by inducing proinflammatory cytokine secretion from microglia. Suppression of DAP12-mediated signals could be a therapeutic target for neuropathic pain.
Recent studies have revealed that activated microglia in the spinal dorsal horn exacerbate neuropathic pain, which has suggested that suppression of microglial activity should be considered as a therapeutic target. However, only a few molecules have been identified as regulators of microglial activity. In this study, we focused on a receptor complex of TREM2 and DAP12, both of which are expressed by microglia and have been implicated in the pathogenesis of Alzheimer's disease, and demonstrated that TREM2/DAP12 signaling promoted proinflammatory responses in microglia and exacerbates neuropathic pain. The present results revealed the functional significance of TREM2/DAP12 signaling in microglial activation after neuronal injury, and could help in the development of treatments for neuropathic pain and neurodegenerative diseases.
Microglia survey brain parenchyma, responding to injury and infections. Microglia also respond to systemic disease, but the role of blood-brain barrier (BBB) integrity in this process remains ...unclear. Using simultaneous in vivo imaging, we demonstrated that systemic inflammation induces CCR5-dependent migration of brain resident microglia to the cerebral vasculature. Vessel-associated microglia initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 and make physical contact with endothelial cells. During sustained inflammation, microglia phagocytose astrocytic end-feet and impair BBB function. Our results show microglia play a dual role in maintaining BBB integrity with implications for elucidating how systemic immune-activation impacts neural functions.
The dura mater contains abundant macrophages whose functions remain largely elusive. Recent studies have demonstrated the origin, as well as the gene expression pattern, of dural macrophages (dMΦs). ...However, their histological features have not been explored yet. In this study, we performed immunohistochemistry and electron microscopy to elucidate their precise morphology, localization, and postnatal development in mice. We found that the morphology, as well as the localization, of dMΦs changed during postnatal development. In neonatal mice, dMΦ exhibited an amoeboid morphology. During postnatal development, their cell bodies elongated longitudinally and became aligned along dural blood vessels. In adulthood, nearly half of the dMΦs aligned along blood vessel networks. However, most of these cells were not directly attached to vessels; pericytes and fibroblasts interposed between dMΦs and vessels. This morphological information may provide further indications for the functional significance of dMΦs.
A homozygous mutation in the gene for sigma 1 receptor (Sig1R) is a cause of inherited juvenile amyotrophic lateral sclerosis (ALS16). Sig1R localizes to the mitochondria‐associated membrane (MAM), ...which is an interface of mitochondria and endoplasmic reticulum. However, the role of the MAM in ALS is not fully elucidated. Here, we identified a homozygous p.L95fs mutation of Sig1R as a novel cause of ALS16. ALS‐linked Sig1R variants were unstable and incapable of binding to inositol 1,4,5‐triphosphate receptor type 3 (IP3R3). The onset of mutant Cu/Zn superoxide dismutase (SOD1)‐mediated ALS disease in mice was accelerated when Sig1R was deficient. Moreover, either deficiency of Sig1R or accumulation of mutant SOD1 induced MAM disruption, resulting in mislocalization of IP3R3 from the MAM, calpain activation, and mitochondrial dysfunction. Our findings indicate that a loss of Sig1R function is causative for ALS16, and collapse of the MAM is a common pathomechanism in both Sig1R‐ and SOD1‐linked ALS. Furthermore, our discovery of the selective enrichment of IP3R3 in motor neurons suggests that integrity of the MAM is crucial for the selective vulnerability in ALS.
Synopsis
Mitochondria‐associated membranes (MAM) are contact sites between endoplasmic reticulum and mitochondria, and play a key role in cellular homeostasis. Here, disruption of the MAM is shown to be tightly involved in the pathology of amyotrophic lateral sclerosis (ALS).
A novel ALS‐linked SIGMAR1 mutation, L95fs, is identified.
ALS‐linked sigma 1 receptor (Sig1R) mutants are unstable and non‐functional, indicating loss‐of‐function mechanism in SIGMAR1‐linked ALS.
Mutant SOD1 proteins are accumulated in the MAM, and a loss of Sig1R exacerbated the disease in mutant SOD1 transgenic mice.
Collapse of the MAM is a common pathological hallmark both in SOD1‐ and SIGMAR1‐linked ALS mouse models.
The selective enrichment of inositol triphosphate receptor type 3 (IP3R3) in the MAM of motor neurons suggests that integrity of the MAM is crucial for the selective vulnerability in ALS.
Mitochondria‐associated membranes (MAM) are contact sites between endoplasmic reticulum and mitochondria and play a key role in cellular homeostasis. Here, disruption of the MAM is shown to be tightly involved in the pathology of amyotrophic lateral sclerosis (ALS).
Microglia are the principal phagocytes that clear cell debris in the central nervous system (CNS). This raises the question, which cells remove cell debris when microglial phagocytic activity is ...impaired. We addressed this question using Siglechdtr mice, which enable highly specific ablation of microglia. Non‐microglial mononuclear phagocytes, such as CNS‐associated macrophages and circulating inflammatory monocytes, did not clear microglial debris. Instead, astrocytes were activated, exhibited a pro‐inflammatory gene expression profile, and extended their processes to engulf microglial debris. This astrocytic phagocytosis was also observed in Irf8‐deficient mice, in which microglia were present but dysfunctional. RNA‐seq demonstrated that even in a healthy CNS, astrocytes express TAM phagocytic receptors, which were the main astrocytic phagocytic receptors for cell debris in the above experiments, indicating that astrocytes stand by in case of microglial impairment. This compensatory mechanism may be important for the maintenance or prolongation of a healthy CNS.
Synopsis
Microglial ablation or microglial dysfunction actuates phagocytic activity of astrocytes. Astrocytes possess phagocytic machinery and have the potential to compensate for microglia with dysfunctional phagocytic activity.
Even in a healthy central nervous system, astrocytes possess phagocytic machinery, such as phagocytic receptors, Axl and Mertk.
After microglia‐specific ablation, activated astrocytes, rather than non‐microglial mononuclear phagocytes, engulf microglial debris.
Astrocytes phagocytose spontaneous apoptotic cells in Irf8‐deficient mice, in which microglia are present but dysfunctional.
Clearance of brain cell debris in the absence of functional microglia is not taken over by canonical phagocytic cell types, but surprisingly by astrocytes expressing TAM phagocytic receptors.
Microglia colonize the central nervous system (CNS) parenchyma during embryogenesis and contribute to various developmental processes leading to the formation of refined neural circuits. In this ...review, we focus on the bidirectional function of microglia during normal CNS development and discuss recent perspectives on the functions of microglia in neural circuit formation. Microglia participate in neurogenesis, migration, axonal growth, and synapse formation and remodeling, all of which are fundamental for the establishment of neural networks, by secreting a variety of molecules toward neurons and phagocytosing both live and dying neurons or their debris. Intriguingly, microglia play dual roles in each of the neurodevelopmental processes that they affect. For instance, microglia modulate synapse numbers by both promoting the formation of new synapses and eliminating unnecessary synapses. The study of the developmental roles of microglia is essential not only for understanding normal CNS development but also for preventing developmental brain disorders caused by microglial dysfunction.
•A technique for microglia-specific ablation in the embryonic CNS was established.•Siglec-H is specifically expressed by microglia in the embryonic CNS.•Diphtheria toxin was injected into the ...amniotic fluid of Siglechdtr embryos.•Microglia were depleted for several days throughout the CNS.•Other CNS macrophage species were not ablated, indicating microglial specificity.
Microglia, which migrate into the central nervous system (CNS) during the early embryonic stages, are considered to play various roles in CNS development. However, their embryonic roles are largely unknown, partly due to the lack of an effective microglial ablation system in the embryo. Here, we show a microglial ablation model by injecting diphtheria toxin (DT) into the amniotic fluid of Siglechdtr mice, in which the gene encoding DT receptor is knocked into the microglia-specific gene locus Siglech. We revealed that embryonic microglia were depleted for several days throughout the CNS, including some regions where microglia transiently accumulated, at any embryonic time point from embryonic day 10.5, when microglia colonize the CNS. This ablation system was specific for microglia because CNS-associated macrophages, which are a distinct population from microglia that reside in the CNS interfaces such as meninges, were unaffected. Therefore, this microglial ablation system is highly effective for studying the embryonic functions of microglia.
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