Attenuation of mechanical pain hypersensitivity by treatment with Peptide5, a connexin-43 mimetic peptide, involves inhibition of NLRP3 inflammasome in nerve-injured mice

Tonkin, Ryan S.; Bowles, Callum; Perera, Chamini J.; Keating, Brooke A.; Makker, Preet G S; Duffy, Samuel S.; Lees, Justin G.; Tran, Collin; Don, Anthony S.; Fath, Thomas; Liu, Lu; O’Carroll, Simon J.; Nicholson, Louise; Green, Colin; Gorrie, Catherine A.; Moalem‐Taylor, Gila

doi:10.1016/j.expneurol.2017.10.016

Cited by 103 publications

(68 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, TAT-Gap19 significantly suppressed the radiationinduced increases in SA-β gal activity, mainly at 5 Gy at 7 and 9 days and from 0.1 Gy at 14 days, and GDF-15 levels from 0.1 Gy in TICAE and TIME cells suggesting a role for Cx43 hemichannels. Chronic Cx43 hemichannel opening, as reported in our previous study at 72 h after irradiation in TICAE and TIME cells (Ramadan et al, 2019), may result in ATP leakage that in turn can activate downstream cellular processes including propagation of intercellular Ca 2+ waves, ROS production, activation of the NLRP3 inflammasome pathway and inflammation (De Bock et al, 2012;Mugisho et al, 2018;Tonkin et al, 2018), which are all known to stimulate premature cellular senescence (Kurz et al, 2004;Acosta et al, 2013;Tchkonia et al, 2013). In addition, senescence can be communicated to neighboring cells in a paracrine manner involving secretion of the senescence-associated secretory phenotype (SASP) and inflammasome activation (Acosta et al, 2013).…”

Section: Discussionmentioning

confidence: 85%

Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage

et al. 2020

View full text Add to dashboard Cite

Background: Emerging evidence indicates an excess risk of late occurring cardiovascular diseases, especially atherosclerosis, after thoracic cancer radiotherapy. Ionizing radiation (IR) induces cellular effects which may induce endothelial cell dysfunction, an early marker for atherosclerosis. In addition, intercellular communication through channels composed of transmembrane connexin proteins (Cxs), i.e. Gap junctions (direct cell-cell coupling) and hemichannels (paracrine release/uptake pathway) can modulate radiation-induced responses and therefore the atherosclerotic process. However, the role of endothelial hemichannel in IR-induced atherosclerosis has never been described before. Materials and Methods: Telomerase-immortalized human Coronary Artery/ Microvascular Endothelial cells (TICAE/TIME) were exposed to X-rays (0.1 and 5 Gy). Production of reactive oxygen species (ROS), DNA damage, cell death, inflammatory responses, and senescence were assessed with or without applying a Cx43 hemichannel blocker (TAT-Gap19). Results: We report here that IR induces an increase in oxidative stress, cell death, inflammatory responses (IL-8, IL-1β, VCAM-1, MCP-1, and Endothelin-1) and premature cellular senescence in TICAE and TIME cells. These effects are significantly reduced in the presence of the Cx43 hemichannel-targeting peptide TAT-Gap19. Conclusion: Our findings suggest that endothelial Cx43 hemichannels contribute to various IR-induced processes, such as ROS, cell death, inflammation, and senescence, resulting in an increase in endothelial cell damage, which could be protected by blocking these hemichannels. Thus, targeting Cx43 hemichannels may potentially exert radioprotective effects.

show abstract

Section: Discussionmentioning

confidence: 85%

Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In a study by Curto-Reyes et al [ 68 ], spared nerve injury (SNI) induces the development of mechanical allodynia and thermal hyperalgesia but does not change mRNA levels of the NLRP3 inflammasome components, such as ASC, caspase-1, or IL-1β in the spinal cord. The other studies find that CCI-induced neuropathic pain [ 69 ], or a brief course of morphine given following CCI-prolonged pain [ 31 ], increases the expression of NLRP3 inflammasome protein in the mouse or rat ipsilateral spinal dorsal horn. Additionally, the cellular distribution of NLRP3 in the nervous system is still debatable.…”

Section: Discussionmentioning

confidence: 99%

miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis

Pan

Shan

et al. 2018

J Neuroinflammation

148

107

View full text Add to dashboard Cite

BackgroundChemokine CXC receptor 4 (CXCR4) in spinal glial cells has been implicated in neuropathic pain. However, the regulatory cascades of CXCR4 in neuropathic pain remain elusive. Here, we investigated the functional regulatory role of miRNAs in the pain process and its interplay with CXCR4 and its downstream signaling.MethodsmiRNAs and CXCR4 and its downstream signaling molecules were measured in the spinal cords of mice with sciatic nerve injury via partial sciatic nerve ligation (pSNL). Immunoblotting, immunofluorescence, immunoprecipitation, and mammal two-hybrid and behavioral tests were used to explore the downstream CXCR4-dependent signaling pathway.ResultsCXCR4 expression increased in spinal glial cells of mice with pSNL-induced neuropathic pain. Blocking CXCR4 alleviated the pain behavior; contrarily, overexpressing CXCR4 induced pain hypersensitivity. MicroRNA-23a-3p (miR-23a) directly bounds to 3′ UTR of CXCR4 mRNA. pSNL-induced neuropathic pain significantly reduced mRNA expression of miR-23a. Overexpression of miR-23a by intrathecal injection of miR-23a mimics or lentivirus reduced spinal CXCR4 and prevented pSNL-induced neuropathic pain. In contrast, knockdown of miR-23a by intrathecal injection of miR-23a inhibitor or lentivirus induced pain-like behavior, which was reduced by CXCR4 inhibition. Additionally, miR-23a knockdown or CXCR4 overexpression in naïve mice could increase the thioredoxin-interacting protein (TXNIP), which was associated with induction of NOD-like receptor protein 3 (NLRP3) inflammasome. Indeed, CXCR4 and TXNIP were co-expressed. The mammal two-hybrid assay revealed the direct interaction between CXCR4 and TXNIP, which was increased in the spinal cord of pSNL mice. In particular, inhibition of TXNIP reversed pain behavior elicited by pSNL, miR-23a knockdown, or CXCR4 overexpression. Moreover, miR-23a overexpression or CXCR4 knockdown inhibited the increase of TXNIP and NLRP3 inflammasome in pSNL mice.ConclusionsmiR-23a, by directly targeting CXCR4, regulates neuropathic pain via TXNIP/NLRP3 inflammasome axis in spinal glial cells. Epigenetic interventions against miR-23a, CXCR4, or TXNIP may potentially serve as novel therapeutic avenues in treating peripheral nerve injury-induced nociceptive hypersensitivity.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1073-0) contains supplementary material, which is available to authorized users.

show abstract

“…Of particular interest is the growing body of evidence that suggests that one member of this pathway (i.e., NOD-like receptor protein 3 (NLRP3)) is involved in various types of neuropathic pain. (Khan et al, 2018;Li et al, 2018;Pan et al, 2018;Pu et al, 2018;Tonkin et al, 2018;Xu et al, 2019) Of note, in a recent preclinical study of PIPN in rats, (Jia et al, 2017) paclitaxel increased the expression of and activated fragments of caspase-1 and IL1β which suggests activation of the NLRP3 inflammasome. The expression of NLRP3 was located in CD68 macrophages that infiltrated the L4-5 DRG and sciatic nerve.…”

Section: Perturbed Neuroinflammation-related Pathways Associated Withmentioning

confidence: 99%

Perturbations in neuroinflammatory pathways are associated with paclitaxel-induced peripheral neuropathy in breast cancer survivors

Miaskowski

Topp

Conley

et al. 2019

Journal of Neuroimmunology

View full text Add to dashboard Cite

A B S T R A C TPaclitaxel is a common chemotherapy drug associated with the development of chronic paclitaxel-induced peripheral neuropathy (PIPN). PIPN is associated with neuroinflammatory mechanisms in pre-clinical studies. Here, we evaluated for differential gene expression (DGE) in peripheral blood between breast cancer survivors with and without PIPN and for neuroinflammatory (NI) related signaling pathways and whole-transcriptome profiles from other experiments. Pathway impact analysis identified 8 perturbed NI related pathways. Expression profile analysis found 15 experiments having similar whole-transcriptome profiles of DGE related to neuroinflammation and PIPN. These findings suggest that perturbations in pathways associated with neuroinflammation are found in cancer survivors with PIPN.

show abstract

Attenuation of mechanical pain hypersensitivity by treatment with Peptide5, a connexin-43 mimetic peptide, involves inhibition of NLRP3 inflammasome in nerve-injured mice

Cited by 103 publications

References 82 publications

Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage

Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage

miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis

Perturbations in neuroinflammatory pathways are associated with paclitaxel-induced peripheral neuropathy in breast cancer survivors

Contact Info

Product

Resources

About