title: Depletion of Foxp3+ regulatory T cells increases severity of mechanical allodynia and significantly alters systemic cytokine levels following peripheral nerve injury.
abstract: Neuropathic pain is a debilitating condition caused by damage to the somatosensory nervous system, such as peripheral nerve injury. The immune system, and in particular the adaptive T cell response, plays a key role in mediating such pain. Regulatory T (Treg) cells are a small subpopulation of inhibitory T cells that prevent autoimmunity, limit immunopathology and maintain immune homeostasis. Here, we investigated the effects of conditional depletion of Treg cells on mechanical allodynia and serum cytokines in mice with chronic constriction injury (CCI) of the sciatic nerve, an animal model of neuropathic pain. We demonstrate that CCI induced the infiltration of small numbers of Treg cells within effected neuronal tissue. Utilising the transgenic DEREG (DEpletion of REGulatory T cells) mice, we confirmed effective depletion of Foxp3+ Treg cells by diphtheria toxin injections. Following CCI we observed a transient, though significant, increase in pain hypersensitivity for Treg-depleted DEREG mice compared to non-Treg-depleted mice. Analysis of systemic cytokine levels demonstrated significant changes in serum cytokine expression profiles. In particular, we observed significant increases in systemic concentration of RANTES, IL-2 and IL-5, and significant decreases in IL-12 and IFN-γ in nerve-injured Treg-depleted DEREG mice. Further analysis indicated a substantial increase in the serum concentration of IL-12p40 as a direct result of Treg cell depletion. These results suggest that depletion of Foxp3+ Treg cells promote nerve injury-induced pain hypersensitivity, partially by inducing altered systemic concentrations of cytokines, which may act to regulate neuropathic pain.
authors.affiliation: School of Medical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Justin G
authors.initials: JG
authors.lastname: Lees
authors.affiliation: School of Medical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Duffy
authors.affiliation: School of Medical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Chamini J
authors.initials: CJ
authors.lastname: Perera
authors.affiliation: School of Medical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: gila@unsw.edu.au.
authors.forename: Gila
authors.initials: G
authors.lastname: Moalem-Taylor
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018946:Chemokine CCL5 / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D004167:Diphtheria Toxin / Q000633:toxicity; D004195:Disease Models, Animal; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006930:Hyperalgesia / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D015848:Interleukin-5 / Q000276:immunology / Q000378:metabolism; D008212:Lymphocyte Depletion / Q000379:methods; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009437:Neuralgia / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D059348:Peripheral Nerve Injuries / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D012584:Sciatic Nerve / Q000276:immunology / Q000293:injuries / Q000503:physiopathology; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D018946:Chemokine CCL5; D016207:Cytokines; D004167:Diphtheria Toxin; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D015848:Interleukin-5; D018664:Interleukin-12; D007371:Interferon-gamma
keywords: Chronic constriction injury; DEREG; Neuropathic pain; Systemic cytokines; Treg