PMC:4136538 / 2051-6755
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4136538","sourcedb":"PMC","sourceid":"4136538","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4136538","text":"Introduction\nAs one of the most devastating kinds of chronic pain, neuropathic pain, defined as pain caused by a lesion or disease of the somatosensory system [1], is a great challenge to physicians [2]. Decades of investigation using pre-clinical models has provided ample evidence of the contribution of the adaptive immune system (lymphocyte-mediated immune responses), to the development of neuropathic pain [3]. Specifically, using a well-established murine model, spinal nerve L5 transection (L5Tx), our laboratory has demonstrated that spinal cord-infiltrating CD4+ T lymphocytes contribute to the maintenance of L5Tx-induced mechanical hypersensitivity [4], indicating the involvement of helper CD4+ T lymphocyte-mediated immune responses in neuropathic pain. It is well known that helper CD4+ T lymphocytes can be classified into several functional subtypes, including type 1 (Th1, mediating primarily cell-mediated immunity), type 2 (Th2, mediating primarily humoral responses), and type 17 (Th17, mediating primarily inflammatory responses) helper T cells [5]. Each subtype of helper T cells has a distinct transcription factor and cytokine profile that drives the downstream responses they mediate. Previously, a limited number of studies that used indirect approaches suggested that Th1 is the dominant helper T cell subtype in mediating the development of neuropathic pain. First, Moalem et al. demonstrated that the passive transfer of in vitro maintained Th1, but not Th2, cells promoted nerve injury-induced behavioral hypersensitivity [6]. Others have subsequently shown the close association between increased spinal cord interferon IFN-γ (the signature cytokine produced by Th1 cells) and behavioral hypersensitivity, as well as an association between increased interleukin (IL)-4 (the signature cytokine produced by Th2 cells) expression and a reduction in nerve injury-induced sensory hypersensitivity [7,8]. More recently, the involvement of IL-17 (the signature cytokine produced by Th17 cells) in the development of peripheral nerve injury-induced neuropathic pain was described, suggesting a role of Th17 in neuropathic pain [9–11]. However, there have been no studies that directly examined the phenotype(s) of the infiltrating CD4+ T lymphocytes following peripheral nerve injury, which may in part be due to the technical difficulty of isolating the small number of lumbar spinal cord-infiltrating T cells. Thus, in the current study, we directly evaluated spinal cord-infiltrating CD4+ T lymphocytes based on their intracellular expression profiles of subtype-specific transcription factors and cytokines via flow cytometric analysis using the L5Tx model of neuropathic pain. As we did not detect significant changes in IL-17 expression in the lumbar spinal cord post-L5Tx in preliminary studies, we focused our investigation on the Th1 and Th2 subtypes.\nFurther, the underlying mechanism through which selected infiltrating helper T cell subtypes contribute to peripheral nerve injury-induced sensory hypersensitivity is still unclear. It has been proposed that infiltrating T lymphocytes interact with central nervous system (CNS) resident glial cells, including both astrocytes and microglia, to promote CNS pro-inflammatory responses that further contribute to central sensitization and persistent pain behaviors [3,12]. It is well-known that Th1 cells further activate macrophages through several co-stimulatory pathways. Previously, we have reported that microglial CD40 plays a critical role in the development of L5Tx-induced mechanical hypersensitivity [13]. As the ligation between CD40 expressed by macrophages and CD40 ligand (CD154) expressed by Th1 cells plays a key role in enhancing macrophage function in the peripheral immune system and microglia are the monocyte/macrophage lineage cells in the CNS, it is possible that infiltrating T lymphocytes play their pro-nociceptive role by interacting with microglia through the CD40–CD154 pathway. In fact, this very interaction has been linked to the pathogenesis of various CNS diseases, including multiple sclerosis and Alzheimer’s disease [14–19]. Thus, in this current study, we investigated whether CD154+CD4+ T lymphocytes contribute to the maintenance of long-term behavioral hypersensitivity with CD154 knockout (KO) mice. In addition, to examine whether lumbar spinal cord-infiltrating CD4+ T lymphocytes contribute to the maintenance of L5Tx-induced mechanical hypersensitivity through the regulation of spinal cord astrocytic activity, we also examined lumbar spinal cord astrocytic glial fibillary acidic protein (GFAP) immunoreactivity in time course studies in both wild type (WT) and CD4 KO 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