An HDAC6 inhibitor reverses chemotherapy-induced mechanical hypersensitivity via an IL-10 and macrophage dependent pathway

Zhang, Jixiang; Ma, Jiacheng; Trinh, Ronnie T.; Heijnen, Cobi J.; Kavelaars, Annemieke

doi:10.1016/j.bbi.2021.12.005

Cited by 17 publications

(19 citation statements)

References 43 publications

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“…Minimum group sizes were based on power analysis of results of previous experiments ( Krukowski et al, 2017 ; Ma et al, 2019 ; J. Zhang et al, 2022 ). Statistical analysis of the differences between groups was performed in Prism GraphPad9 using one- or two-way ANOVA with Dunnett, Tukey, or Sidak post hoc tests as appropriate.…”

Section: Methodsmentioning

confidence: 99%

“…With limited treatment options available, new approaches to alleviate the symptoms of CIPN are urgently needed ( Cavaletti et al, 2019 ; Colvin, 2019 ). Histone deacetylase 6 (HDAC6) inhibition has potential as a novel strategy to prevent or reverse peripheral neuropathies induced by cisplatin, paclitaxel, or vincristine ( Krukowski et al, 2017 ; Van Helleputte et al, 2018 ; Ma et al, 2019 ; J. Zhang et al, 2022 ); reversal is especially attractive as it does not interfere with the primary cancer treatment. HDAC6 is predominantly a cytosolic deacetylase that deacetylates nonhistone proteins, including tubulin and heat shock proteins, ultimately regulating processes, such as intracellular protein trafficking and degradation ( Hubbert et al, 2002 ; Bali et al, 2005 ).…”

Section: Introductionmentioning

confidence: 99%

“…HDAC6 is predominantly a cytosolic deacetylase that deacetylates nonhistone proteins, including tubulin and heat shock proteins, ultimately regulating processes, such as intracellular protein trafficking and degradation ( Hubbert et al, 2002 ; Bali et al, 2005 ). Consequently, HDAC6 inhibitors restore axonal mitochondrial content and function after treatment with cisplatin or vincristine ( Krukowski et al, 2017 ; Van Helleputte et al, 2018 ; Ma et al, 2019 ; J. Zhang et al, 2022 ). In contrast to other agents that suppress CIPN in preclinical models (for review, see Flatters et al, 2017 ), a 2 week course of dosing with an HDAC6 inhibitor persistently reverses peripheral neuropathy induced by cisplatin and paclitaxel ( Krukowski et al, 2017 ; Ma et al, 2019 ; J. Zhang et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, HDAC6 inhibitors restore axonal mitochondrial content and function after treatment with cisplatin or vincristine ( Krukowski et al, 2017 ; Van Helleputte et al, 2018 ; Ma et al, 2019 ; J. Zhang et al, 2022 ). In contrast to other agents that suppress CIPN in preclinical models (for review, see Flatters et al, 2017 ), a 2 week course of dosing with an HDAC6 inhibitor persistently reverses peripheral neuropathy induced by cisplatin and paclitaxel ( Krukowski et al, 2017 ; Ma et al, 2019 ; J. Zhang et al, 2022 ). We have shown that conditional KO of Hdac6 in advillin + sensory neurons only partially attenuates mechanical hypersensitivity ( Ma et al, 2019 ), indicating that the pain-resolving effects of HDAC6 inhibitors rely on as yet to be elucidated intercellular communication.…”

Section: Introductionmentioning

confidence: 99%

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HDAC6 Inhibition Reverses Cisplatin-Induced Mechanical Hypersensitivity via Tonic Delta Opioid Receptor Signaling

et al. 2022

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Peripheral neuropathic pain induced by the chemotherapeutic cisplatin can persist for months to years after treatment. Histone deacetylase 6 (HDAC6) inhibitors have therapeutic potential for cisplatin-induced neuropathic pain since they persistently reverse mechanical hypersensitivity and spontaneous pain in rodent models. Here, we investigated the mechanisms underlying reversal of mechanical hypersensitivity in male and female mice by a 2 week treatment with an HDAC6 inhibitor, administered 3 d after the last dose of cisplatin. Mechanical hypersensitivity in animals of both sexes treated with the HDAC6 inhibitor was temporarily reinstated by a single injection of the neutral opioid receptor antagonist 6β-naltrexol or the peripherally restricted opioid receptor antagonist naloxone methiodide. These results suggest that tonic peripheral opioid ligand-receptor signaling mediates reversal of cisplatin-induced mechanical hypersensitivity after treatment with an HDAC6 inhibitor. Pointing to a specific role for δ opioid receptors (DORs), Oprd1 expression was decreased in DRG neurons following cisplatin administration, but normalized after treatment with an HDAC6 inhibitor. Mechanical hypersensitivity was temporarily reinstated in both sexes by a single injection of the DOR antagonist naltrindole. Consistently, HDAC6 inhibition failed to reverse cisplatin-induced hypersensitivity when DORs were genetically deleted from advillin + neurons. Mechanical hypersensitivity was also temporarily reinstated in both sexes by a single injection of a neutralizing antibody against the DOR ligand met-enkephalin. In conclusion, we reveal that treatment with an HDAC6 inhibitor induces tonic enkephalin-DOR signaling in peripheral sensory neurons to suppress mechanical hypersensitivity. SIGNIFICANCE STATEMENT Over one-fourth of cancer survivors suffer from intractable painful chemotherapy-induced peripheral neuropathy (CIPN), which can last for months to years after treatment ends. HDAC6 inhibition is a novel strategy to reverse CIPN without negatively interfering with tumor growth, but the mechanisms responsible for persistent reversal are not well understood. We built on evidence that the endogenous opioid system contributes to the spontaneous, apparent resolution of pain caused by nerve damage or inflammation, referred to as latent sensitization. We show that blocking the δ opioid receptor or its ligand enkephalin unmasks CIPN in mice treated with an HDAC6 inhibitor (latent sensitization). Our work provides insight into the mechanisms by which treatment with an HDAC6 inhibitor apparently reverses CIPN.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HDAC6 Inhibition Reverses Cisplatin-Induced Mechanical Hypersensitivity via Tonic Delta Opioid Receptor Signaling

et al. 2022

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“…The results ( Figure 4, A and B ) demonstrated that intrathecal administration of m-clodrosome delayed resolution of mechanical allodynia in cisplatin-treated male and female mice. Intrathecal administration of m-clodrosome reduced the percentage of M2 macrophages in the DRG without affecting M1 macrophages ( Figure 4, C and D , and Supplemental Figure 8 ) and did not affect microglia in the spinal cord ( 29 , 30 ). These findings identified a critical role of M2 macrophages in resolution of CIPN.…”

Section: Resultsmentioning

confidence: 93%

CD8+ T cell–derived IL-13 increases macrophage IL-10 to resolve neuropathic pain

Singh¹,

Krukowski²,

Laumet³

et al. 2022

JCI Insight

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Understanding the endogenous mechanisms regulating resolution of pain may identify novel targets for treatment of chronic pain. Resolution of chemotherapy-induced peripheral neuropathy (CIPN) after treatment completion depends on CD8 + T cells and on IL-10 produced by other cells. Using Rag2 –/– mice lacking T and B cells and adoptive transfer of Il13 –/– CD8 + T cells, we showed that CD8 + T cells producing IL-13 were required for resolution of CIPN. Intrathecal administration of anti–IL-13 delayed resolution of CIPN and reduced IL-10 production by dorsal root ganglion macrophages. Depleting local CD206 + macrophages also delayed resolution of CIPN. In vitro, TIM3 + CD8 + T cells cultured with cisplatin, apoptotic cells, or phosphatidylserine liposomes produced IL-13, which induced IL-10 in macrophages. In vivo, resolution of CIPN was delayed by intrathecal administration of anti-TIM3. Resolution was also delayed in Rag2 –/– mice reconstituted with Havcr2 (TIM3) –/– CD8 + T cells. Our data indicated that cell damage induced by cisplatin activated TIM3 on CD8 + T cells, leading to increased IL-13 production, which in turn induced macrophage IL-10 production and resolution of CIPN. Development of exogenous activators of the IL-13/IL-10 pain resolution pathway may provide a way to treat the underlying cause of chronic pain.

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Cisplatin

Akther¹,

Hussain²,

Ray³

2024

Encyclopedia of Toxicology

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An HDAC6 inhibitor reverses chemotherapy-induced mechanical hypersensitivity via an IL-10 and macrophage dependent pathway

Cited by 17 publications

References 43 publications

HDAC6 Inhibition Reverses Cisplatin-Induced Mechanical Hypersensitivity via Tonic Delta Opioid Receptor Signaling

HDAC6 Inhibition Reverses Cisplatin-Induced Mechanical Hypersensitivity via Tonic Delta Opioid Receptor Signaling

CD8+ T cell–derived IL-13 increases macrophage IL-10 to resolve neuropathic pain

Cisplatin

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