Cutaneous tissue damage induces long-lasting nociceptive sensitization and regulation of cellular stress- and nerve injury-associated genes in sensory neurons

Rau, Kristofer K.; Hill, Caitlin E.; Harrison, Benjamin J.; Venkat, Gayathri; Koenig, Heidi M.; Cook, Sarah B.; Rabchevsky, Alexander G.; Taylor, Bradley K.; Hai, Tsonwin; Petruska, Jeffrey C.

doi:10.1016/j.expneurol.2016.06.002

Cited by 15 publications

(9 citation statements)

References 92 publications

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“…The susceptible small-diameter neurons have created further challenges in distinguishing the contributions made by changing intracellular signaling molecules. Although ATF3 upregulation was injury-inducible33 and cell type specific,33,34 the responses of the neuronal soma in patients with DPN, which contributed to neuropathic pain through modulated intracellular signaling molecules, remain ambiguous. The co-upregulation of ATF3 and p-PKCε determined the degrees of neuropathic behavior, and the linear analyses strengthened the molecular significance of p-PKCε.…”

Section: Discussionmentioning

confidence: 99%

Activating transcription factor 3 modulates protein kinase C epsilon activation in diabetic peripheral neuropathy

Chang¹,

Kan²,

Hsieh³

2019

JPR

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BackgroundSkin denervation that develops in patients with diabetes mellitus as a neuropathic manifestation is known as diabetic peripheral neuropathy (DPN). Skin denervation is parallel to neuronal injuries that alter intracellular signaling. To date, the correlation between nerve injury and the activation of intracellular responses to neuropathic manifestations has not been elucidated; specifically, whether activating transcription factor 3 (ATF3) is responsible for neuronal injury and a critical molecule that modulates the activation of intracellular protein kinase C epsilon (p-PKCε) and pain development in DPN is a crucial question.MethodsTo address, ATF3 knockout (atf3−/− group, C57/B6 genetic background) and wild-type mice (atf3+/+ group) received a single dose of streptozotocin (200 mg/kg) to generate a mouse model of DPN.ResultsBoth atf3+/+ and atf3−/− mice exhibited hyperglycemia and the same pathology of skin denervation at posttreatment month 2, but only atf3+/+ mice developed thermal hyperalgesia (P<0.001) and mechanical allodynia (P=0.002). The atf3+/+ group, but not the atf3−/− group, had preferential ATF3 upregulation on p-PKCε(+) neurons with a ratio of 37.7%±6.1% in p-PKCε(+):ATF3(+) neurons (P<0.001). In addition, B-cell lymphoma-extra large (Bcl-XL), an antiapoptotic Bcl2 family protein, exhibited parallel patterns to p-PKCε (ie, Bcl-XL upregulation was reversed in atf3−/− mice). These two molecules were colocalized and increased by approximately two-fold in the atf3+/+ group compared with the atf3−/− group (30.0%±3.4% vs 13.7% ± 6.2%, P=0.003). Furthermore, linear analysis results showed that the densities of p-PKCε and Bcl-XL had a reverse linear relationship with the degrees of thermal hyperalgesia and mechanical allodynia.ConclusionCollectively, this report suggested that ATF3 is a critical upstream molecule that modulates p-PKCε and Bcl-XL expression, which consequently mediated the development of neuropathic manifestation in DPN.

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Section: Discussionmentioning

confidence: 99%

Activating transcription factor 3 modulates protein kinase C epsilon activation in diabetic peripheral neuropathy

Chang¹,

Kan²,

Hsieh³

2019

JPR

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“…Several studies demonstrated modification of PGP 9.5 axonal nerve terminals and neuro-immune-endocrine cells in the skin during chronic cutaneous neuroinflammation [ 19 ]. Those abnormalities provide induction of molecular changes, which in advanced skin lesions might resemble immune-mediated tissue injury and engage psoriatic keratinocytes in transmission of itch [ 20 – 24 ].…”

Section: Introductionmentioning

confidence: 99%

UCHL1/PGP 9.5 Dynamic in Neuro-Immune-Cutaneous Milieu: Focusing on Axonal Nerve Terminals and Epidermal Keratinocytes in Psoriatic Itch

Kupczyk

Reich

Gajda

et al. 2018

BioMed Research International

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Psoriasis is an immunogenetic skin disease manifesting as plaque lesions on the skin. Patients with psoriasis frequently suffer from itch, an unpleasant sensation causing a desire to scratch. Psoriatic itch is mainly transmitted by unmyelinated C-fibers; however, the exact molecular mechanism of psoriatic itch is still unexplained. Protein gene product 9.5 (PGP 9.5) is a panneurological marker commonly used for analysis of peripheral peptidergic and nonpeptidergic nerves and identification of cutaneous neuro-immune-endocrine cells. However, some studies suggested that nonneuronal cells, like keratinocytes, may also express PGP 9.5. This phenomenon might be linked with impaired axonal transport, keratinocyte injury, or dysfunctions of neuro-immune-cutaneous connections. The aim of this study was to analyze the expression of PGP 9.5 in psoriatic skin. We observed significantly altered density of PGP 9.5-positive axonal nerve terminals in pruritic lesional (p=0.04) and nonlesional psoriatic skin (p>0.001) compared with controls. In contrast, no significant differences were observed between psoriatic skin without itch and controls. Furthermore, PGP 9.5 expression by suprabasal keratinocytes (SBKs) was significantly increased in itchy skin lesions (p=0.007) compared to skin without itch, and a positive correlation was observed between PGP 9.5 expression and itch intensity (r=0.64; p=0.02). Our findings indicate changes in peripheral innervations and psoriatic keratinocytes, which may influence neuro-immune-cutaneous homeostasis and modulate itch transmission.

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“…However, the mechanisms remain largely unknown. Rau et al demonstrated that ATF-3 expression was a strong predictor of single cells displaying pain-related electrophysiological properties in a cutaneous tissue damage model [ 32 ]. The decrease of ATF-3 expression in DRG neurons by silencing of TNF-α was associated with the amelioration of mechanical allodynia after L5 spinal nerve transection [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

ATF3-Expressing Large-Diameter Sensory Afferents at Acute Stage as Bio-Signatures of Persistent Pain Associated with Lumbar Radiculopathy

Lin

Chuang

et al. 2021

Cells

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The mechanism of pain chronicity is largely unknown in lumbar radiculopathy (LR). The anatomical location of nerve injury is one of the important factors associated with pain chronicity of LR. Accumulating evidence has shown constriction distal to the dorsal root ganglion (DRG) caused more severe radiculopathy than constriction proximal to the DRG; thereby, the mechanism of pain chronicity in LR could be revealed by comparing the differences in pathological changes of DRGs between nerve constriction distal and proximal to the DRG. Here, we used 2 rat models of LR with nerve constriction distal or proximal to the DRG to probe how the different nerve injury sites could differentially affect pain chronicity and the pathological changes of DRG neuron subpopulations. As expected, rats with nerve constriction distal to the DRG showed more persistent pain behaviors than those with nerve constriction proximal to the DRG in 50% paw withdraw threshold, weight-bearing test, and acetone test. One day after the operation, distal and proximal nerve constriction showed differential pathological changes of DRG. The ratios of activating transcription factor3 (ATF3)-positive DRG neurons were significantly higher in rats with nerve constriction distal to DRG than those with nerve constriction proximal to DRG. In subpopulation analysis, the ratios of ATF3-immunoreactivity (IR) in neurofilament heavy chain (NFH)-positive DRG neurons significantly increased in distal nerve constriction compared to proximal nerve constriction; although, both distal and proximal nerve constriction presented increased ratios of ATF3-IR in calcitonin gene-related peptide (CGRP)-positive DRG neurons. Moreover, the nerve constriction proximal to DRG caused more hypoxia than did that distal to DRG. Together, ATF3 expression in NHF-positive DRG neurons at the acute stage is a potential bio-signature of persistent pain in rat models of LR.

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Cutaneous tissue damage induces long-lasting nociceptive sensitization and regulation of cellular stress- and nerve injury-associated genes in sensory neurons

Cited by 15 publications

References 92 publications

Activating transcription factor 3 modulates protein kinase C epsilon activation in diabetic peripheral neuropathy

Activating transcription factor 3 modulates protein kinase C epsilon activation in diabetic peripheral neuropathy

UCHL1/PGP 9.5 Dynamic in Neuro-Immune-Cutaneous Milieu: Focusing on Axonal Nerve Terminals and Epidermal Keratinocytes in Psoriatic Itch

ATF3-Expressing Large-Diameter Sensory Afferents at Acute Stage as Bio-Signatures of Persistent Pain Associated with Lumbar Radiculopathy

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