T cell infiltration after chronic constriction injury of mouse sciatic nerve is associated with interleukin-17 expression

Kleinschnitz, Christoph; Hofstetter, Harald H.; Meuth, Sven G.; Braeuninger, Stefan; Sommer, Claudia; Stoll, Guido

doi:10.1016/j.expneurol.2006.03.014

Cited by 142 publications

(131 citation statements)

References 38 publications

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“…Attenuation of neuropathic pain has been described in animals with reduced macrophage influx, genetic absence of T lymphocytes, depletion of neutrophils and macrophages, or in which mast cell degranulation is prevented (24,27,29,33,42,43). This has been attributed to lower levels of inflammatory cytokines or chemokines activating sensory neurons (1,2,21,22).…”

Section: Figurementioning

confidence: 99%

Immune cell–derived opioids protect against neuropathic pain in mice

Łabuz¹,

Schmidt²,

Schreiter³

et al. 2009

J. Clin. Invest.

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The analgesic effects of leukocyte-derived opioids have been exclusively demonstrated for somatic inflammatory pain, for example, the pain associated with surgery and arthritis. Neuropathic pain results from injury to nerves, is often resistant to current treatments, and can seriously impair a patient's quality of life. Although it has been recognized that neuronal damage can involve inflammation, it is generally assumed that immune cells act predominately as generators of neuropathic pain. However, in this study we have demonstrated that leukocytes containing opioids are essential regulators of pain in a mouse model of neuropathy. About 30%-40% of immune cells that accumulated at injured nerves expressed opioid peptides such as β-endorphin, Met-enkephalin, and dynorphin A. Selective stimulation of these cells by local application of corticotropin-releasing factor led to opioid peptide-mediated activation of opioid receptors in damaged nerves. This ultimately abolished tactile allodynia, a highly debilitating heightened response to normally innocuous mechanical stimuli, which is symptomatic of neuropathy. Our findings suggest that selective targeting of opioid-containing immune cells promotes endogenous pain control and offers novel opportunities for management of painful neuropathies. IntroductionWithin inflamed tissues, a plethora of molecules such as protons, adenosine triphosphate, glutamate, neuropeptides (e.g., calcitonin gene-related peptide [CGRP], substance P), prostaglandins, bradykinin, cytokines, and chemokines can induce pain (1, 2). Concurrently, however, endogenous counterregulatory mechanisms are mounted. It has been established that somatic inflammatory (e.g., postoperative and arthritic) pain can be effectively controlled by the immune system, in both animals and humans (3,4). This is mediated by extravasating leukocytes, which produce and liberate opioid peptides in inflamed tissues. The released opioids bind to opioid receptors on peripheral sensory neurons, resulting in the inhibition of noxious impulse propagation (5-17). Such effects are particularly interesting because they occur directly in peripheral tissues and, therefore, are free of side effects such as nausea, depression of breathing, cognitive impairment, dependence, and addiction mediated by opioid receptors in the CNS (3).Neuropathic pain is a common consequence of nerve injuries caused by trauma such as amputation, entrapment, or compression. It is characterized by persistent burning or shooting sensations and heightened responses to normally noxious (hyperalgesia) and innocuous stimuli (allodynia). Despite increasing efforts, such pain remains poorly controlled, severely impacting patients ' well-being (18-20), which makes new therapeutic approaches highly desirable. Research over the last decade has provided evidence on the association of traumatic peripheral nerve injuries with inflammatory reactions mobilizing the immune system (1,

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Section: Figurementioning

confidence: 99%

Immune cell–derived opioids protect against neuropathic pain in mice

Łabuz¹,

Schmidt²,

Schreiter³

et al. 2009

J. Clin. Invest.

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“…In rats, facial nerve transection was found to induce the expression of MCP-1 by neurons. Although the role of IL-15/15Rα in T cell chemoattraction in the brain has not been examined, IL-15 was found to be upregulated prior to T cell entry into the mouse sciatic nerve following constriction injury [10]. The present study therefore sought to test the hypothesis that T cell homing to the injured FMN following facial nerve axotomy would be impaired in IL-15 and IL-15Rα knockout mice, and to determine whether microglial responsiveness and motoneuron death are affected.…”

mentioning

confidence: 99%

IL-15 and IL-15Rα gene deletion: Effects on T lymphocyte trafficking and the microglial and neuronal responses to facial nerve axotomy

Huang

Petitto

2007

Neuroscience Letters

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IL-15 is a potent T cell chemoattractant, and this cytokine and its unique α subunits, IL-15Rα, can modify immune cell expression of several T cell chemokines and their receptors. Facial nerve axotomy in mice leads to T cell migration across an intact blood-brain-barrier (BBB), and under certain conditions T cells can provide neuroprotection to injured neurons in the facial motor nucleus (FMN). Although chemokines and chemoattractant cytokines are thought to be responsible for T cell migration to the injured cell bodies, data addressing this question are lacking. This study tested the hypothesis that T cell homing to the axotomized FMN would be impaired in knockout (KO) mice with the IL-15 and IL-15Rα genes deleted, and sought to determine if microglial responsiveness and motoneuron death are affected. Both IL-15KO and IL-15RαKO mice exhibited a marked reduction in CD3 + T cells and had fewer MHC2 + activated microglia in the injured FMN than their respective WT controls at day 14 post-axotomy. Although there was a relative absence of T cell recruitment into the axotomized FMN in both knockout strains, IL-15RαKO mice had five times more motoneuron death (characterized by perineuronal microglial clusters engulfing dead motoneurons) than their WT controls, whereas dead neurons in IL-15KO did not differ from their WT controls. Further studies are needed to dissect the mechanisms that underlie these observations (e.g., central vs. peripheral immune contributions).IL-15 and IL-2 are members of the 4α-helix bundle family of cytokines that share the same constitutively expressed pair of signal transducing β and γ receptor subunits, but exhibit high affinity binding to unique α subunits (e.g., IL-15Rα) that confer specificity for each cytokine. Mouse microglia express IL-15 and IL-15Rα [5], and human astrocytes and neural cell lines (e.g., neuroblastoma cells) also express IL-15 mRNA [11,20]. IL-15 is a potent T cell chemoattractant (Wilkinson and Liew, 1995). IL-15 and IL-15Rα can modify the expression of T cell chemoattractants including MCP-1, RANTES, and IP-10, chemokines and their receptors that have been implicated in autoimmune T cell infiltration of the CNS [1,2,8,15].T lymphocytes migrate in and out of the brain and other nonlymphoid organs, and can be found in very small numbers in the brain under normal physiological conditions [3,6,7]. Facial nerve axotomy in mice leads to T cell migration across an intact blood-brain-barrier (BBB) where

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“…That few T cells were observed in the FMN following re-injury does not preclude the possibility that T cells might exert their effects peripherally at the site of nerve injury, as T cells have been shown to accumulate at the nerve stump following peripheral nerve injury (Kleinschnitz, et al, 2006, Moalem, et al, 2004. Moreover, facial motor neurons showed an upregulated expression of the anti-apoptotic gene bcl-2 following induction of an inflammatory response in the facial muscles of the rat, indicating that facial motor neurons are able to respond to peripheral immune signals (Mariotti, et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Immunodeficiency impairs re-injury induced reversal of neuronal atrophy: Relation to T cell subsets and microglia

Ha¹,

Huang²,

Parikh³

et al. 2007

Experimental Neurology

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Following facial nerve resection in the mouse, a substantial number of neurons reside in an atrophied state (characterized by cell shrinkage and decreased ability to uptake Nissl stain), which can be reversed by re-injury. The mechanisms mediating the reversal of neuronal atrophy remain unclear. Although T cells have been shown to prevent neuronal loss following peripheral nerve injury, it was unknown whether T cells play a role in mediating the reversal of axotomy-induced neuronal atrophy. Thus, we used a facial nerve re-injury model to test the hypothesis that the reversal of neuronal atrophy would be impaired in recombinase activating gene-2 knockout (RAG-2 KO) mice, which lack functional T and B cells. Measures of neuronal survival were compared in the injured facial motor nucleus (FMN) of RAG-2 KO and wild-type (WT) mice that received a resection of the right facial nerve followed by re-injury of the same nerve 10 weeks later ("chronic resection + re-injury") or a resection of the right facial nerve followed by sham re-injury of the same nerve 10 weeks later ("chronic resection + sham"). We recently demonstrated that prior exposure to neuronal injury elicited a marked increase in T cell trafficking indicative of a T cell memory response when the contralateral FMN was injured later in adulthood. We examined if such a T cell memory response would also occur in the current re-injury model. RAG-2 KO mice showed no reversal of neuronal atrophy whereas WT mice showed a robust response. The reversal of atrophy in WT mice was not accompanied by a T cell memory response. Although the number of CD4 + and CD8 + T cells in the injured FMN did not differ from each other, double-negative T cells appear to be recruited in response to neuronal injury. Re-injury did not result in increased expression of MHC2 by microglia. Our findings suggest that T cells may be involved in reversing the axotomy-induced atrophy of injured neurons.

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T cell infiltration after chronic constriction injury of mouse sciatic nerve is associated with interleukin-17 expression

Cited by 142 publications

References 38 publications

Immune cell–derived opioids protect against neuropathic pain in mice

Immune cell–derived opioids protect against neuropathic pain in mice

IL-15 and IL-15Rα gene deletion: Effects on T lymphocyte trafficking and the microglial and neuronal responses to facial nerve axotomy

Immunodeficiency impairs re-injury induced reversal of neuronal atrophy: Relation to T cell subsets and microglia

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