A significant percentage (40-50%) of individuals with spinal cord injury (SCI) exhibit central neuropathic pain (CNP), a condition of persistent discomfort involving often unbearable burning, pricking, shooting and/or evoked types of pain in response to light touch. CNP appears more frequently in females, who also exhibit a greater sensitivity to pain than males. CNP develops in response to a dysregulation of somatosensory signaling and is largely refractory to conventional therapeutic interventions with only 40-60% of people achieving partial relief. Therefore CNP remains a major unmet clinical challenge, not only for SCI but numerous other neurological conditions, including Multiple Sclerosis, stroke and traumatic brain injury where its prevalence has been observed. Though the activation of cells comprising the innate immune system, microglia and macrophages, has been identified as key effector in the development and persistence of CNP, through their production of a repertoire of pain and plasticity modulating factors, the immunophenotypical identity of these cells remains poorly characterized in SCI under conditions in which there is the presence or absence of CNP. Recent work has highlighted the importance of the classically-activated M1 microglia-macrophage phenotype in the deleterious processes associated with injury including inflammation, cell death and abortive axon regeneration, while the alternatively-activated M2 form, which functionally promotes tissue remodeling, angiogenesis, axon growth and remyelination, is largely absent from chronic lesions. The phenotypic identity of activated microglia and macrophages within regions of the neural axis outside of the immediate injury, such as the lumbar spinal cord, where physiological changes in nociceptive and anti-nociceptive system processing occurs, including increased hyperexcitability of dorsal horn neurons and the loss/inhibition of GABAnergic neurotransmission, however, is unknown. Furthermore, the characterization of microglia and macrophage phenotype after SCI in animals where there is an absence or presence of CNP has not been investigated nor has the therapeutic targeting of M1 to M2 phenotypic conversion as an approach to preventing CNP development or persistence been evaluated. The proposed investigation will employ a clinically-relevant contusion paradigm to study temporally and spatially M1 and M2 population dynamics in SCI animals in which CNP is present and absent as evidenced by pain behaviors (Specific Aim 1). This paradigm will allow us to begin to understand the involvement of specific microglia phenotypes in the development and persistence of CNP as well as the influence of gender on these responses. Subsequently, through the use of a novel and potent M1 to M2 conversion protocols established in our laboratory, we will further address this question by examining if the conversion of M1 microglia to a M2a or M2c phenotype can either prevent the development of CNP or reduce its severity (Specific Aim 2). Collectively these studies will provide novel insight into the role specific phenotypic forms of microglia and macrophages play in CNP, how gender influences these immune responses and the development of CNP as well as offer a putative therapeutic direction for attenuating CNP after SCI.
Central neuropathic pain (CNP) involves unbearable sensations of burning, pricking or shooting pain that occurs in 40-50% of people with spinal cord injury (SCI); unfortunately CNP remains largely refractory to conventional therapeutic interventions and is a major unmet clinical challenge as only 40-60% of people achieve partial relief. Although activated cells of the innate immune system, microglia and macrophages, play an important role in the development and persistence of CNP, their immunophenotypical profile after SCI remains poorly characterized. These studies seek to understand the temporal and spatial population dynamics of M1 and M2 microglia and macrophages after SCI, at and below the level of the lesion, the impact of gender on these responses as well as evaluate the therapeutic potential of M1-M2 phenotypic conversion for preventing the development/severity of SCI-induced CNP.
|Pearse, Damien D; Bastidas, Johana; Izabel, Sarah S et al. (2018) Schwann Cell Transplantation Subdues the Pro-Inflammatory Innate Immune Cell Response after Spinal Cord Injury. Int J Mol Sci 19:|