Activation profile of dorsal root ganglia Iba-1 (+) macrophages varies with the type of lesion in rats

Ton, Bich-Hoai Thi; Chen, Qingmin; Găină, Gisela; Țucureanu, Cătălin; Georgescu, Adelina; Strungaru, Carmen; Flonta, Maria-Luiza; Sah, Dinah W.Y.; Ristoiu, Violeta

doi:10.1016/j.acthis.2013.04.007

Cited by 42 publications

(35 citation statements)

References 61 publications

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“…Additionally, inflammatory agents induce a form of peripheral conditioning (Lu and Richardson, 1991; Steinmetz et al, 2005) while macrophages pre-incubated with injured sciatic nerve have been shown to promote regenerative growth (Lazarov-Spiegler et al, 1996). Within the DRG, Iba1-immunoreactive macrophages are activated following sensory axon injury, surrounding large-diameter NF200 immunoreactive neurons (Ton et al, 2013). Recently, it has been proposed that activation or increase of DRG macrophages is required for conditioning-mediated pro-regenerative effects (Kwon et al, 2013; Niemi et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

A novel and robust conditioning lesion induced by ethidium bromide

Hollis

Ishiko

Tolentino

et al. 2015

Experimental Neurology

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Molecular and cellular mechanisms underlying the peripheral conditioning lesion remain unsolved. We show here that injection of a chemical demyelinating agent, ethidium bromide, into the sciatic nerve induces a similar set of regeneration-associated genes and promotes a 2.7-fold greater extent of sensory axon regeneration in the spinal cord than sciatic nerve crush. We found that more severe peripheral demyelination correlates with more severe functional and electrophysiological deficits, but more robust central regeneration. Ethidium bromide injection does not activate macrophages at the demyelinated sciatic nerve site, as observed after nerve crush, but briefly activates macrophages in the dorsal root ganglion. This study provides a new method for investigating the underlying mechanisms of the conditioning response and suggests that loss of the peripheral myelin may be a major signal to change the intrinsic growth state of adult sensory neurons and promote regeneration.

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Section: Resultsmentioning

confidence: 99%

A novel and robust conditioning lesion induced by ethidium bromide

Hollis

Ishiko

Tolentino

et al. 2015

Experimental Neurology

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“…1, C and D, and fig. S2, A and B) (21). In the spinal cord of the recipient YG8R mice, HSPC-derived cells were abundant in the ascending sensory axon tracts, within the dorsal and ventral roots, motor neuron pools, and dorsal spinal cord gray matter (Fig.…”

Section: Resultsmentioning

confidence: 99%

Transplantation of wild-type mouse hematopoietic stem and progenitor cells ameliorates deficits in a mouse model of Friedreich’s ataxia

et al. 2017

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Friedreich’s ataxia (FRDA) is an incurable autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin due to an intronic GAA-repeat expansion in the FXN gene. We report the therapeutic efficacy of transplanting wild-type mouse hematopoietic stem and progenitor cells (HSPCs) into the YG8R mouse model of FRDA. In the HSPC-transplanted YG8R mice, development of muscle weakness and locomotor deficits was abrogated as was degeneration of large sensory neurons in the dorsal root ganglia (DRGs) and mitochondrial capacity was improved in brain, skeletal muscle, and heart. Transplanted HSPCs engrafted and then differentiated into microglia in the brain and spinal cord and into macrophages in the DRGs, heart, and muscle of YG8R FRDA mice. We observed the transfer of wild-type frataxin and Cox8 mitochondrial proteins from HSPC-derived microglia/macrophages to FRDA mouse neurons and muscle myocytes in vivo. Our results show the HSPC-mediated phenotypic rescue of FRDA in YG8R mice and suggest that this approach should be investigated further as a strategy for treating FRDA.

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“…In this study, Pdk2/4 deficiency remarkably lessened the hyperglycemia-induced activation of SGCs, demonstrating that PDK2/4 play a crucial role in the pathological alterations of SGCs. Hyperglycemia also drives the inflammatory infiltration of macrophages in the DRG, which subsequently contributes to nerve demyelination and release of different proinflammatory mediators having an important role in the pathogenesis of painful neuropathy (14,84,85). Macrophage-derived proinflammatory cytokines, such as TNF-␣, IL-1␤, and IL-6, are documented to contribute to the pathogenesis of painful diabetic neuropathy (86,87).…”

Section: Discussionmentioning

confidence: 99%

Pyruvate Dehydrogenase Kinase-mediated Glycolytic Metabolic Shift in the Dorsal Root Ganglion Drives Painful Diabetic Neuropathy

Rahman

Jha

Kim

et al. 2016

Journal of Biological Chemistry

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The dorsal root ganglion (DRG) is a highly vulnerable site in diabetic neuropathy. Under diabetic conditions, the DRG is subjected to tissue ischemia or lower ambient oxygen tension that leads to aberrant metabolic functions. Metabolic dysfunctions have been documented to play a crucial role in the pathogenesis of diverse pain hypersensitivities. However, the contribution of diabetes-induced metabolic dysfunctions in the DRG to the pathogenesis of painful diabetic neuropathy remains ill-explored. In this study, we report that pyruvate dehydrogenase kinases (PDK2 and PDK4), key regulatory enzymes in glucose metabolism, mediate glycolytic metabolic shift in the DRG leading to painful diabetic neuropathy. Streptozotocin-induced diabetes substantially enhanced the expression and activity of the PDKs in the DRG, and the genetic ablation of Pdk2 and Pdk4 attenuated the hyperglycemia-induced pain hypersensitivity. Mechanistically, Pdk2/4 deficiency inhibited the diabetes-induced lactate surge, expression of pain-related ion channels, activation of satellite glial cells, and infiltration of macrophages in the DRG, in addition to reducing central sensitization and neuroinflammation hallmarks in the spinal cord, which probably accounts for the attenuated pain hypersensitivity. Pdk2/4-deficient mice were partly resistant to the diabetes-induced loss of peripheral nerve structure and function. Furthermore, in the experiments using DRG neuron cultures, lactic acid treatment enhanced the expression of the ion channels and compromised cell viability. Finally, the pharmacological inhibition of DRG PDKs or lactic acid production substantially attenuated diabetes-induced pain hypersensitivity. Taken together, PDK2/4 induction and the subsequent lactate surge induce the metabolic shift in the diabetic DRG, thereby contributing to the pathogenesis of painful diabetic neuropathy.Painful neuropathy is one of the most common complications of diabetes. Patients with diabetes frequently exhibit a variety of aberrant sensations, including pain hypersensitivity (1, 2). Interrelation and mutual perpetuation of distinct aberrations of specific metabolic pathways cause painful diabetic neuropathy. Furthermore, painful diabetic neuropathy probably results from a combination of metabolic and immune factors (3, 4). Metabolic aberrations are thought to be early events in painful diabetic neuropathy, leading to biochemical, structural, and functional changes in the dorsal root ganglion (DRG) 3 and its nerve trunk (5, 6). Likewise, hyperglycemia-induced immune activation creates an inflammatory microenvironment surrounding the influenced nerves (7).The DRG is pathologically important in diabetes presenting with painful neuropathic states, which patients with early polyneuropathy commonly experience (8). Ganglionic sensory neurons are devoid of any special protection by the blood-brain or blood-nerve barrier and have higher metabolic requirements than the nerve trunk, which makes the ganglion a vulnerable site in the pathogenesis of diabetic neurop...

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Activation profile of dorsal root ganglia Iba-1 (+) macrophages varies with the type of lesion in rats

Cited by 42 publications

References 61 publications

A novel and robust conditioning lesion induced by ethidium bromide

A novel and robust conditioning lesion induced by ethidium bromide

Transplantation of wild-type mouse hematopoietic stem and progenitor cells ameliorates deficits in a mouse model of Friedreich’s ataxia

Pyruvate Dehydrogenase Kinase-mediated Glycolytic Metabolic Shift in the Dorsal Root Ganglion Drives Painful Diabetic Neuropathy

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