Toll/Interleukin-1 Receptor Domain-Containing Adapter Inducing Interferon-β Mediates Microglial Phagocytosis of Degenerating Axons

Hosmane, Suneil; Tegenge, Million Adane; Rajbhandari, Labchan; Uapinyoying, Prech; Kumar, Nishant Ganesh; Thakor, Nitish V.; Venkatesan, Arun

doi:10.1523/jneurosci.0203-12.2012

Cited by 95 publications

(98 citation statements)

References 71 publications

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“…The failure to clear free myelin debris could inhibit the differentiation of oligodendrocyte precursors and could be toxic to neurons (20,21). Furthermore, myelin debris may contain inhibitory molecules that antagonize axonal regeneration (45), and the removal of axonal debris by microglia increases axonal regeneration (46,47). Additionally, microglial phagocytosis of myelin debris can promote resolution of the CNS inflammatory response (16,48), and myelin-phagocytosing microglia express genes involved in the activation, migration, proliferation, and differentiation of oligodendrocyte precursor cells (49).…”

Section: Discussionmentioning

confidence: 99%

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

Sosa

Murphey

Robinson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Evidence has suggested both a pathogenic and a protective role for the proinflammatory cytokine IFN-γ in experimental autoimmune encephalomyelitis (EAE). However, the mechanisms underlying the protective role of IFN-γ in EAE have not been fully resolved, particularly in the context of CNS antigen-presenting cells (APCs). In this study we examined the role of IFN-γ in myelin antigen uptake by CNS APCs during EAE. We found that myelin antigen colocalization with APCs was decreased substantially and that EAE was significantly more severe and showed a chronic-progressive course in IFN-γ knockout (IFN-γ −/− ) or IFN-γ receptor knockout (IFN-γR −/− ) mice as compared with WT animals. IFN-γ was a critical regulator of phagocytic/activating receptors on CNS APCs. Importantly, "free" myelin debris and lipid peroxidation activity at CNS lesions was increased in mice lacking IFN-γ signaling. Treatment with N-acetyl-L-cysteine, a potent antioxidant, abolished lipid peroxidation activity and ameliorated EAE in IFN-γ-signalingdeficient mice. Taken together the data suggest a protective role for IFN-γ in EAE by regulating the removal of myelin debris by CNS APCs and thereby limiting the substrate available for the generation of neurotoxic lipid peroxidation products.

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Section: Discussionmentioning

confidence: 99%

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

Sosa

Murphey

Robinson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…Microglial clearance of this debris may be neither beneficial nor harmful in the relatively short time scale assessed in these experiments, but could play an important role in long-term chronic sequelae of injury, including axonal sprouting and regeneration not assessed here. 50 Indeed, microglia are important sources of brain-derived neurotrophic factor and other neurotrophins that stimulate axonal sprouting and may be central to recovery from injury. 51,52 Future work may help to address these questions and provide deeper insight into the biological function of microglia after injury.…”

Section: Discussionmentioning

confidence: 99%

Acute Reduction of Microglia Does Not Alter Axonal Injury in a Mouse Model of Repetitive Concussive Traumatic Brain Injury

Bennett

Brody

2014

Journal of Neurotrauma

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The pathological processes that lead to long-term consequences of multiple concussions are unclear. Primary mechanical damage to axons during concussion is likely to contribute to dysfunction. Secondary damage has been hypothesized to be induced or exacerbated by inflammation. The main inflammatory cells in the brain are microglia, a type of macrophage. This research sought to determine the contribution of microglia to axon degeneration after repetitive closed-skull traumatic brain injury (rcTBI) using CD11b-TK (thymidine kinase) mice, a valganciclovir-inducible model of macrophage depletion. Lowdose (1 mg/mL) valganciclovir was found to reduce the microglial population in the corpus callosum and external capsule by 35% after rcTBI in CD11b-TK mice. At both acute (7 days) and subacute (21 days) time points after rcTBI, reduction of the microglial population did not alter the extent of axon injury as visualized by silver staining. Further reduction of the microglial population by 56%, using an intermediate dose (10 mg/mL), also did not alter the extent of silver staining, amyloid precursor protein accumulation, neurofilament labeling, or axon injury evident by electron microscopy at 7 days postinjury. Longer treatment of CD11b-TK mice with intermediate dose and treatment for 14 days with high-dose (50 mg/mL) valganciclovir were both found to be toxic in this injury model. Altogether, these data are most consistent with the idea that microglia do not contribute to acute axon degeneration after multiple concussive injuries. The possibility of longer-term effects on axon structure or function cannot be ruled out. Nonetheless, alternative strategies directly targeting injury to axons may be a more beneficial approach to concussion treatment than targeting secondary processes of microglial-driven inflammation.

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“…Microfluidic platforms, consisting of a poly-dimethylsiloxane (PDMS) device bonded to a glass coverslip, were generated as previously described (Hosmane et al, 2012). Briefly, two layers of photoresist structures were generated on a flat silicon wafer – one for the 100 µm cell chambers (SU-8 3050) and one for the 3 µm microgrooves (SU-8 2002).…”

Section: Methodsmentioning

confidence: 99%

NGF-TrkA Signaling by Sensory Nerves Coordinates the Vascularization and Ossification of Developing Endochondral Bone

et al. 2016

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SUMMARY Developing tissues dictate the amount and type of innervation they require by secreting neurotrophins, which promote neuronal survival by activating distinct tyrosine kinase receptors. Here, we show that NGF-TrkA signaling directs innervation of the developing mouse femur to promote vascularization and osteoprogenitor lineage progression. At the start of primary ossification, TrkA positive axons were observed at perichondrial bone surfaces, coincident with NGF expression in cells adjacent to centers of incipient ossification. Inactivation of TrkA signaling during embryogenesis in TrkAF592A mice impaired innervation, delayed vascular invasion of the primary and secondary ossification centers, decreased numbers of Osx-expressing osteoprogenitors, and decreased femoral length and volume. These same phenotypic abnormalities were observed in mice following tamoxifen-induced disruption of NGF in Col2-expressing perichondrial osteochondral progenitors. We conclude that NGF serves as a skeletal neurotrophin to promote sensory innervation of developing long bones, a process critical for normal primary and secondary ossification.

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Toll/Interleukin-1 Receptor Domain-Containing Adapter Inducing Interferon-β Mediates Microglial Phagocytosis of Degenerating Axons

Cited by 95 publications

References 71 publications

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

Acute Reduction of Microglia Does Not Alter Axonal Injury in a Mouse Model of Repetitive Concussive Traumatic Brain Injury

NGF-TrkA Signaling by Sensory Nerves Coordinates the Vascularization and Ossification of Developing Endochondral Bone

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