The transcription factor C/EBPβ in the dorsal root ganglion contributes to peripheral nerve trauma–induced nociceptive hypersensitivity

Li, Zhisong; Mao, Yuanyuan; Liang, Lingli; Wu, Shaogen; Yuan, Jingjing; Mo, Kai; Cai, Wei; Mao, Qingxiang; Cao, Jing; Bekker, Alex; Zhang, Wei; Tao, Yuan‐Xiang

doi:10.1126/scisignal.aam5345

Cited by 57 publications

(57 citation statements)

References 36 publications

(130 reference statements)

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“…These nociceptive hypersensitivities occurred 4 weeks post-microinjection and persisted for at least 8 weeks (Fig. 5d-g), consistent with the 3-4-week lag period of AAV5 expression, which lasts for at least 3 months [27,30,31]. Neither virus affected locomotor function (Table 2) or basal contralateral paw withdrawal responses (Fig.…”

Section: Drg Overexpression Of Creb Leads To Nociceptive Hypersensitivitysupporting

confidence: 76%

“…In the present study, we for the first time showed the CREB is widely expressed throughout the brain, spinal cord, and DRG [36]. Like other transcription factors such as myeloid zinc finger 1, CCAAT/enhancer binding protein β, and OCT1 [28][29][30]32], CREB may be upregulated in painprocessing regions under neuropathic pain conditions. The expression of p-CREB in the DRG and spinal cord dorsal horn neurons was significantly increased in a rat model of type II diabetic neuropathic pain [15].…”

Section: Discussionmentioning

confidence: 48%

“…Mechanical, cold, and heat tests, as well as the conditional place preference (CPP) test and locomotor performance assessments, were performed as previously described [30][31][32]. Each behavioral test for evoked pain was carried out at 30-60min intervals.…”

Section: Behavioral Testingmentioning

confidence: 99%

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CREB Participates in Paclitaxel-Induced Neuropathic Pain Genesis Through Transcriptional Activation of Dnmt3a in Primary Sensory Neurons

et al. 2021

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Chemotherapy-induced peripheral neuropathic pain (CIPNP) often occurs in cancer patients treated with antineoplastic drugs. Therapeutic management of CIPNP is very limited, at least in part due to the largely unknown mechanisms that underlie CIPNP genesis. Here, we showed that systemic administration of the chemotherapeutic drug paclitaxel significantly and timedependently increased the levels of cyclic AMP response element-binding protein (CREB) in dorsal root ganglion (DRG) neurons. Blocking this increase through DRG microinjection of Creb siRNA attenuated paclitaxel-induced mechanical, heat, and cold nociceptive hypersensitivities. Mimicking this increase through DRG microinjection of the adeno-associated virus 5 expressing full-length Creb mRNA led to enhanced responses to basal mechanical, heat, and cold stimuli in mice in absence of paclitaxel treatment. Mechanically, paclitaxel-induced increase of DRG CREB protein augmented Dnmt3a promoter activity and participated in the paclitaxel-induced upregulation of DNMT3a protein in the DRG. CREB overexpression also elevated the expression of DNMT3a in in vivo and in vitro DRG neurons of naïve mice. Given that DNMT3a is an endogenous instigator of CIPNP and that CREB co-expresses with DNMT3a in DRG neurons, CREB may be a key player in CIPNP through transcriptional activation of the Dnmt3a gene in primary sensory neurons. CREB is thus a likely potential target for the therapeutic management of this disorder.

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Section: Drg Overexpression Of Creb Leads To Nociceptive Hypersensitivitysupporting

confidence: 76%

Section: Discussionmentioning

confidence: 48%

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CREB Participates in Paclitaxel-Induced Neuropathic Pain Genesis Through Transcriptional Activation of Dnmt3a in Primary Sensory Neurons

et al. 2021

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“…The present study demonstrated that SNL persistently enhanced the C/EBPβ protein level in the ipsilateral L4 DRG, rather than the intact/adjacent L3 DRG, ipsilateral and contralateral L4 DRGs. Based on these results, such increase only occurs in the damaged DRG neurons, as C/EBPβmRNA was identi ed in small, medium, and large DRG neurons, rather than satellite glial cells, of naive mice [24]. In addition, in the CCI mouse model, in the ipsilateral L3/4 DRGs, many neurons labeled with C/EBPβmRNA were positive for ATF3, the injury marker [24].…”

Section: Discussionmentioning

confidence: 92%

“…A previous study revealed that chronic sciatic nerve construction injury upregulated C/EBPβexpression at protein and mRNA levels in ipsilateral L3/4 DRGs [24]. However, whether C/EBPβ expression in intact/adjoining DRG was altered following peripheral nerve trauma is unclear.…”

Section: Discussionmentioning

confidence: 97%

C/EBPβ Participates in Nerve Trauma-Induced TLR7 Upregulation in Primary Sensory Neurons

He¹,

Cao²,

Jiang³

et al. 2021

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Nerve trauma-induced toll-like receptor 7 (TLR7) expression level increase in primary sensory neurons in the damaged dorsal root ganglion (DRG) avails to neuropathic pain, but the reason is still unknown. In the current study, we showed that unilateral lumbar 4 (L4) spinal nerve ligation (SNL) upregulated CCAAT/enhancer-binding protein-β (C/EBPβ) expression in ipsilateral L4 DRG. Preventing this elevation attenuated the SNL-induced upregulation of TLR7 in the ipsilateral L4 DRG and inhibited cold/thermal hyperalgesia and mechanical allodynia. Mimicking nerve trauma-induced C/EBPβ upregulation generated an elevated level of TLR7 in injected DRG, augmented responses to cold/thermal/mechanical stimuli while causing ipsilateral spontaneous pain with no SNL. Mechanistically, SNL upregulated binding of increased C/EBPβ to Tlr7 promoter in ipsilateral L4 DRG. Accorded that C/EBPβ could trigger the activation of Tlr7 promoter and co-expressed with Tlr7 mRNA in individual DRG neurons, our findings strongly suggest the role of C/EBPβ in nerve trauma-mediated TLR7 upregulation in damaged primary sensory neurons.

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N⁶‐Methyladenosine Demethylase FTO Contributes to Neuropathic Pain by Stabilizing G9a Expression in Primary Sensory Neurons

et al. 2020

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Nerve injury‐induced change in gene expression in primary sensory neurons of dorsal root ganglion (DRG) is critical for neuropathic pain genesis. N 6 ‐methyladenosine (m 6 A) modification of RNA represents an additional layer of gene regulation. Here, it is reported that peripheral nerve injury increases the expression of the m 6 A demethylase fat‐mass and obesity‐associated proteins (FTO) in the injured DRG via the activation of Runx1, a transcription factor that binds to the Fto gene promoter. Mimicking this increase erases m 6 A in euchromatic histone lysine methyltransferase 2 ( Ehmt2 ) mRNA (encoding the histone methyltransferase G9a) and elevates the level of G9a in DRG and leads to neuropathic pain symptoms. Conversely, blocking this increase reverses a loss of m 6 A sites in Ehmt2 mRNA and destabilizes the nerve injury‐induced G9a upregulation in the injured DRG and alleviates nerve injury‐associated pain hypersensitivities. FTO contributes to neuropathic pain likely through stabilizing nerve injury‐induced upregulation of G9a, a neuropathic pain initiator, in primary sensory neurons.

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The transcription factor C/EBPβ in the dorsal root ganglion contributes to peripheral nerve trauma–induced nociceptive hypersensitivity

Abstract: The transcription factor C/EBPβ may be a master regulator of neuropathic pain caused by peripheral nerve injury.

Cited by 57 publications

References 36 publications

CREB Participates in Paclitaxel-Induced Neuropathic Pain Genesis Through Transcriptional Activation of Dnmt3a in Primary Sensory Neurons

CREB Participates in Paclitaxel-Induced Neuropathic Pain Genesis Through Transcriptional Activation of Dnmt3a in Primary Sensory Neurons

C/EBPβ Participates in Nerve Trauma-Induced TLR7 Upregulation in Primary Sensory Neurons

N⁶‐Methyladenosine Demethylase FTO Contributes to Neuropathic Pain by Stabilizing G9a Expression in Primary Sensory Neurons

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The transcription factor C/EBPβ in the dorsal root ganglion contributes to peripheral nerve trauma–induced nociceptive hypersensitivity

Abstract: The transcription factor C/EBPβ may be a master regulator of neuropathic pain caused by peripheral nerve injury.

Cited by 57 publications

References 36 publications

CREB Participates in Paclitaxel-Induced Neuropathic Pain Genesis Through Transcriptional Activation of Dnmt3a in Primary Sensory Neurons

CREB Participates in Paclitaxel-Induced Neuropathic Pain Genesis Through Transcriptional Activation of Dnmt3a in Primary Sensory Neurons

C/EBPβ Participates in Nerve Trauma-Induced TLR7 Upregulation in Primary Sensory Neurons

N6‐Methyladenosine Demethylase FTO Contributes to Neuropathic Pain by Stabilizing G9a Expression in Primary Sensory Neurons

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N⁶‐Methyladenosine Demethylase FTO Contributes to Neuropathic Pain by Stabilizing G9a Expression in Primary Sensory Neurons