Abstract
Background: Neuroinflammation and cytokines play critical roles in neuropathic pain and axon degeneration/regeneration. Cytokines of transforming growth factor-β superfamily have implications in pain and injured nerve repair processing. However, the transcriptional profiles of the transforming growth factor-β superfamily members in dorsal root ganglia under neuropathic pain and axon degeneration/regeneration conditions remain elusive.
Objective: We aimed to plot the transcriptional profiles of transforming growth factor-β superfamily components in lumbar dorsal root ganglia of sciatic nerve-axotomized rats and to further verify the profiles by testing the analgesic effect of activin C, a representative cytokine, on neuropathic pain.
Methods: Adult male rats were axotomized in sciatic nerves, and lumbar dorsal root ganglia were isolated for total RNA extraction or section. A custom microarray was developed and employed to plot the gene expression profiles of transforming growth factor-β superfamily components. Realtime RT-PCR was used to confirm changes in the expression of activin/inhibin family genes, and then in situ hybridization was performed to determine the cellular locations of inhibin α, activin βC, BMP-5 and GDF-9 mRNAs. The rat spared nerve injury model was performed, and a pain test was employed to determine the effect of activin C on neuropathic pain.
Results: The expression of transforming growth factor-β superfamily cytokines and their signaling, including some receptors and signaling adaptors, were robustly upregulated. Activin βC subunit mRNAs were expressed in the small-diameter dorsal root ganglion neurons and upregulated after axotomy. Single intrathecal injection of activin C inhibited neuropathic pain in spared nerve injury model.
Conclusion: This is the first report to investigate the transcriptional profiles of members of transforming growth factor-β superfamily in axotomized dorsal root ganglia. The distinct cytokine profiles observed here might provide clues toward further study of the role of transforming growth factor-β superfamily in the pathogenesis of neuropathic pain and axon degeneration/regeneration after peripheral nerve injury.
Keywords: transforming growth factor-β (TGF-β), transcriptional profile, dorsal root ganglion (DRG), axotomy, neuropathic pain, microarray, activin C
Graphical Abstract
[http://dx.doi.org/10.1038/nm.2231] [PMID: 20948531]
[http://dx.doi.org/10.1097/j.pain.0000000000001032] [PMID: 28837503]
[http://dx.doi.org/10.1097/WCO.0000000000000621] [PMID: 30320612]
[http://dx.doi.org/10.1159/000435932] [PMID: 26437375]
[http://dx.doi.org/10.1016/j.sjpain.2017.08.002] [PMID: 29229214]
[http://dx.doi.org/10.1007/s12264-018-0204-z] [PMID: 29340868]
[http://dx.doi.org/10.1016/j.neuroscience.2014.09.027] [PMID: 25242643]
[http://dx.doi.org/10.1007/s12264-020-00608-1] [PMID: 33196963]
[http://dx.doi.org/10.2174/1871528114666150114170004] [PMID: 25587846]
[http://dx.doi.org/10.1016/j.ejphar.2018.07.040] [PMID: 30036535]
[http://dx.doi.org/10.1016/j.phrs.2016.11.019] [PMID: 27894923]
[http://dx.doi.org/10.1007/s12264-021-00697-6] [PMID: 34003466]
[http://dx.doi.org/10.1016/j.pneurobio.2018.12.001] [PMID: 30579784]
[http://dx.doi.org/10.1093/neuros/nyx362] [PMID: 28973496]
[http://dx.doi.org/10.1093/brain/awr350] [PMID: 22275428]
[http://dx.doi.org/10.1016/j.jpain.2013.08.010] [PMID: 24290447]
[http://dx.doi.org/10.4103/1673-5374.193223] [PMID: 27904475]
[http://dx.doi.org/10.1007/s12035-011-8221-1] [PMID: 22125199]
[http://dx.doi.org/10.1007/s12264-021-00709-5] [PMID: 34076854]
[http://dx.doi.org/10.1096/fasebj.13.15.2105] [PMID: 10593858]
[http://dx.doi.org/10.1016/j.devcel.2009.02.012] [PMID: 19289080]
[http://dx.doi.org/10.1007/978-3-642-80481-6_10] [PMID: 9401209]
[http://dx.doi.org/10.1111/j.1478-3231.2005.01192.x] [PMID: 16420505]
[http://dx.doi.org/10.1093/abbs/gmx124] [PMID: 29190314]
[http://dx.doi.org/10.1038/nm944] [PMID: 14528299]
[http://dx.doi.org/10.1186/s10194-016-0665-2] [PMID: 27541934]
[http://dx.doi.org/10.3727/096368916X693824] [PMID: 27983926]
[http://dx.doi.org/10.1007/s10753-013-9727-7] [PMID: 24014115]
[PMID: 22275431]
[http://dx.doi.org/10.1016/j.neuroscience.2007.09.041] [PMID: 17964731]
[http://dx.doi.org/10.1016/j.neuron.2015.05.005] [PMID: 26004914]
[http://dx.doi.org/10.1111/bph.15284] [PMID: 33095918]
[http://dx.doi.org/10.1517/14728222.2016.1085972] [PMID: 26863504]
[http://dx.doi.org/10.1523/JNEUROSCI.1726-06.2006] [PMID: 16914685]
[http://dx.doi.org/10.1523/JNEUROSCI.2584-09.2010] [PMID: 20107078]
[http://dx.doi.org/10.1007/s12264-017-0147-9] [PMID: 28612318]
[http://dx.doi.org/10.1073/pnas.122231899] [PMID: 12060780]
[http://dx.doi.org/10.1038/cr.2008.327] [PMID: 19114991]
[http://dx.doi.org/10.1038/cr.2011.43] [PMID: 21423271]
[http://dx.doi.org/10.1016/j.pharep.2017.09.009] [PMID: 29475003]
[http://dx.doi.org/10.3389/fnmol.2017.00284] [PMID: 28932184]
[http://dx.doi.org/10.1002/ana.23928] [PMID: 23686636]
[http://dx.doi.org/10.1016/0165-0270(94)90144-9] [PMID: 7990513]
[http://dx.doi.org/10.1016/S0149-7634(05)80090-9] [PMID: 2052197]
[http://dx.doi.org/10.1006/dbio.2002.0779] [PMID: 12376100]
[http://dx.doi.org/10.1016/j.drudis.2018.12.001] [PMID: 30529762]
[http://dx.doi.org/10.1111/micc.12099] [PMID: 25279424]
[http://dx.doi.org/10.1016/j.pneurobio.2013.07.002] [PMID: 23891815]
[http://dx.doi.org/10.1159/000057359] [PMID: 9525694]
[http://dx.doi.org/10.1016/j.neuroscience.2015.01.059] [PMID: 25662509]
[http://dx.doi.org/10.1172/JCI80883] [PMID: 26168219]
[http://dx.doi.org/10.1523/JNEUROSCI.3051-05.2005] [PMID: 16207882]
[http://dx.doi.org/10.1523/JNEUROSCI.3822-07.2007] [PMID: 18077689]
[http://dx.doi.org/10.3390/cells3040981] [PMID: 25317929]
[http://dx.doi.org/10.1016/j.ydbio.2016.07.005] [PMID: 27432514]
[http://dx.doi.org/10.1007/s00441-015-2219-3] [PMID: 26077927]
[http://dx.doi.org/10.1111/joor.12286] [PMID: 25757091]
[http://dx.doi.org/10.1097/WNR.0000000000000785] [PMID: 28394782]
[http://dx.doi.org/10.1007/s00586-019-05878-6] [PMID: 30661198]
[http://dx.doi.org/10.1016/j.cyto.2019.01.011] [PMID: 30776685]
[http://dx.doi.org/10.1177/1744806918802703] [PMID: 30259786]
[http://dx.doi.org/10.1016/j.ydbio.2019.04.008] [PMID: 31026439]
[http://dx.doi.org/10.1186/s13041-017-0342-7] [PMID: 29282074]
[http://dx.doi.org/10.1007/s00441-012-1493-6] [PMID: 22955564]
[http://dx.doi.org/10.1007/s00441-013-1634-6] [PMID: 23640134]
[http://dx.doi.org/10.30802/AALAS-JAALAS-19-000081] [PMID: 32156325]
[http://dx.doi.org/10.1038/nrm2297] [PMID: 18000526]