CD3+ T cells are critical for the resolution of comorbid inflammatory pain and depression-like behavior

Geoffroy Laumet,Jules D Edralin,Robert Dantzer,Cobi J Heijnen,Annemieke Kavelaars

doi:10.1016/j.ynpai.2020.100043

Geoffroy Laumet, Jules D Edralin + Show 3 more

Open Access

https://doi.org/10.1016/j.ynpai.2020.100043

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Abstract

BackgroundChronic pain and depression often co-occur. The mechanisms underlying this comorbidity are incompletely understood. Here, we investigated the role of CD3+ T cells in an inflammatory model of comorbid persistent mechanical allodynia, spontaneous pain, and depression-like behavior in mice. MethodsC57Bl/6 wt and Rag2−/− mice were compared in their response to intraplantar administration of complete Freund’s adjuvant (CFA). Mechanical allodynia, spontaneous pain and depression-like behavior were assessed by von Frey, conditioned place preference and forced swim test respectively. ResultsResolution of mechanical allodynia, spontaneous pain, and depression-like behavior was markedly delayed in Rag2−/− mice that are devoid of adaptive immune cells. Reconstitution of Rag2−/− mice with CD3+ T cells from WT mice before CFA injection normalized the resolution of indicators of pain and depression-like behavior. T cells did not contribute to onset or severity of indicators of pain and depression-like behavior. The lack of T cells did not affect cytokine expression in the paw, spinal cord and brain, indicating that the delayed resolution was not resulting from prolonged (neuro)inflammation. ConclusionsOur findings show that T cells are critical for the natural resolution of mechanical allodynia, spontaneous pain, and depression-like behavior after an inflammatory challenge. Dysregulation of this T cell-mediated resolution pathway could contribute to the comorbidity of chronic pain and depression. SignificanceChronic pain and depression are frequently associated with signs of inflammation. However, general immunosuppression is not sufficient to resolve comorbid pain and depression. Here we demonstrate that T cells are required for resolution of comorbid persistent mechanical allodynia, spontaneous pain, and depression in a model of peripheral inflammation, indicating the immune system can contribute to both onset and resolution of these comorbidities. Enhancing pro-resolution effects of T cells may have a major impact to treat patients with comorbid persistent pain and depression.

Highlights

Chronic pain is a leading health problem in North America with a lifetime prevalence of up to 20% of the U.S and 30% of the Canadian population (Johannes et al, 2010; Schopflocher et al, 2011)
There were no group differences in prefrontal cortex (PFC) cytokine mRNA levels (Fig. 5E,F). These findings indicate that the prolonged allodynia, spontaneous pain, and depression-like behavior in T celldeficient mice did not result from differences in acute or persistent upregulation of Tnf or Il1b expression in paw, spinal cord and PFC
The present findings demonstrate for the first time that CD3+ T cells are required for the resolution of comorbid persistent mechanical allodynia, spontaneous pain, and depression-like behavior in response to peripheral inflammation

Summary

Introduction

Chronic pain is a leading health problem in North America with a lifetime prevalence of up to 20% of the U.S and 30% of the Canadian population (Johannes et al, 2010; Schopflocher et al, 2011). We investigated the role of CD3+ T cells in an inflammatory model of comorbid persistent mechanical allodynia, spontaneous pain, and depression-like behavior in mice. Conclusions: Our findings show that T cells are critical for the natural resolution of mechanical allodynia, spontaneous pain, and depression-like behavior after an inflammatory challenge. Dysregulation of this T cellmediated resolution pathway could contribute to the comorbidity of chronic pain and depression. We demonstrate that T cells are required for resolution of comorbid persistent mechanical allodynia, spontaneous pain, and depression in a model of peripheral inflammation, indicating the immune system can contribute to both onset and resolution of these comorbidities. Enhancing pro-resolution effects of T cells may have a major impact to treat patients with comorbid persistent pain and depression

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Discussion

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