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Low-Dose Interleukin-2 and Regulatory T Cell Treatments Attenuate Punctate and Dynamic Mechanical Allodynia in a Mouse Model of Sciatic Nerve Injury

Authors Hu R, Zhang J, Liu X, Huang D, Cao YQ

Received 10 January 2021

Accepted for publication 13 March 2021

Published 6 April 2021 Volume 2021:14 Pages 893—906

DOI https://doi.org/10.2147/JPR.S301343

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 5

Editor who approved publication: Professor E. Alfonso Romero-Sandoval


Rong Hu,1– 3 Jintao Zhang,1,2,4 Xuemei Liu,1,2 Dong Huang,3 Yu-Qing Cao1,2

1Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA; 2Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA; 3Department of Pain Management, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 4Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China

Correspondence: Yu-Qing Cao
Department of Anesthesiology, Washington University School of Medicine, 660 South Euclid, Box 8054, St. Louis, MO, 63110, USA
Tel +1 314 362 8726
Fax +1 314 362 8334
Email [email protected]

Purpose: Nerve injury-induced mechanical hyper-sensitivity, in particular stroking-induced dynamic allodynia, is highly debilitating and difficult to treat. Previous studies indicate that the immunosuppressive regulatory T (Treg) cells modulate the magnitude of punctate mechanical allodynia resulting from sciatic nerve injury. However, whether enhancing Treg-mediated suppression attenuates dynamic allodynia is not known. In the present study, we addressed this knowledge gap by treating mice with low-dose interleukin-2 (ld-IL2) injections or adoptive transfer of Treg cells.
Methods: Female Swiss Webster mice received daily injections of ld-IL2 (1 μg/mouse, intraperitoneally) either before or after unilateral spared nerve injury (SNI). Male C57BL/6J mice received adoptive transfer of 1 x 106 Treg cells 3 weeks post-SNI. The responses to punctate and dynamic mechanical stimuli on the hindpaw were monitored before and up to 4– 6 weeks post-SNI. We also compared the distribution of Treg cells and CD3+ total T cells after SNI and/or ld-IL2 treatment.
Results: Ld-IL2 pretreatment in female Swiss Webster mice completely blocked the development of SNI-induced dynamic mechanical allodynia and reduced the magnitude of punctate allodynia. Delayed ld-IL2 treatment in female mice significantly attenuated the morphine-resistant punctate and dynamic allodynia at 3– 5 weeks post-SNI. Adoptive transfer of Treg cells to male C57BL/6J mice 3 weeks post-SNI effectively reversed the persistent punctate and dynamic allodynia, supporting that the effect of ld-IL2 is mediated through endogenous Treg cells, and is likely independent of mouse strain and sex. Neither ld-IL2 treatment nor Treg transfer affected the basal responses to punctate or brush stimuli. Ld-IL2 significantly increased the frequency of Treg cells among total CD3+ T cells in the injured sciatic nerves but not in the uninjured nerves or the dorsal root ganglia, suggesting the injured nerve as ld-IL2’s site of action.
Conclusion: Collectively, results from the present study supports Treg as a cellular target and ld-IL2 as a potential therapeutic option for nerve injury-induced persistent punctate and dynamic mechanical allodynia.

Keywords: spared nerve injury, chronic pain, punctate allodynia, dynamic allodynia, low-dose interleukin-2, regulatory T cell

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