Effects of pro-inflammatory cytokines in experimental spinal cord injury (original) (raw)
Related papers
The Inflammatory Response after Moderate Contusion Spinal Cord Injury: A Time Study
Biology
Spinal cord injury (SCI) initiates detrimental cellular and molecular events that lead to acute and delayed neuroinflammation. Understanding the role of the inflammatory response in SCI requires insight into the temporal and cellular synthesis of inflammatory mediators. We subjected C57BL/6J mice to SCI and investigated inflammatory reactions. We examined activation, recruitment, and polarization of microglia and infiltrating immune cells, focusing specifically on tumor necrosis factor (TNF) and its receptors TNFR1 and TNFR2. In the acute phase, TNF expression increased in glial cells and neuron-like cells, followed by infiltrating immune cells. TNFR1 and TNFR2 levels increased in the delayed phase and were found preferentially on neurons and glial cells, respectively. The acute phase was dominated by the infiltration of granulocytes and macrophages. Microglial/macrophage expression of Arg1 increased from 1–7 days after SCI, followed by an increase in Itgam, Cx3cr1, and P2ry12, whic...
Brain, 2010
Traumatic injury to the central nervous system results in the disruption of the blood brain/spinal barrier, followed by the invasion of cells and other components of the immune system that can aggravate injury and affect subsequent repair and regeneration. Although studies of chronic neuroinflammation in the injured spinal cord of animals are clinically relevant to most patients living with traumatic injury to the brain or spinal cord, very little is known about chronic neuroinflammation, though several studies have tested the role of neuroinflammation in the acute period after injury. The present study characterizes a novel cell preparation method that assesses, quickly and effectively, the changes in the principal immune cell types by flow cytometry in the injured spinal cord, daily for the first 10 days and periodically up to 180 days after spinal cord injury. These data quantitatively demonstrate a novel time-dependent multiphasic response of cellular inflammation in the spinal cord after spinal cord injury and are verified by quantitative stereology of immunolabelled spinal cord sections at selected time points. The early phase of cellular inflammation is comprised principally of neutrophils (peaking 1 day post-injury), macrophages/microglia (peaking 7 days post-injury) and T cells (peaking 9 days post-injury). The late phase of cellular inflammation was detected after 14 days post-injury, peaked after 60 days post-injury and remained detectable throughout 180 days post-injury for all three cell types. Furthermore, the late phase of cellular inflammation (14-180 days post-injury) did not coincide with either further improvements, or new decrements, in open-field locomotor function after spinal cord injury. However, blockade of chemoattractant C5a-mediated inflammation after 14 days post-injury reduced locomotor recovery and myelination in the injured spinal cord, suggesting that the late inflammatory response serves a reparative function. Together, these data provide new insight into cellular inflammation of spinal cord injury and identify a surprising and extended multiphasic response of cellular inflammation.
Rats and mice exhibit distinct inflammatory reactions after spinal cord injury
The Journal of Comparative Neurology, 2003
Spinal contusion pathology in rats and mice is distinct. Cystic cavities form at the impact site in rats while a dense connective tissue matrix occupies the injury site in mice. Because inflammatory cells coordinate mechanisms of tissue injury and repair, we evaluated whether the unique anatomical presentation in spinally injured rats and mice is associated with a species-specific inflammatory response. Immunohistochemistry was used to compare the leukocytic infiltrate between rats and mice. Microglia/macrophage reactions were similar between species; however, the onset and magnitude of lymphocyte and dendritic cell (DC) infiltration were markedly different. In rats, T-cell numbers were highest between 3 and 7 days postinjury and declined by 50% over the next 3 weeks. In mice, significant T-cell entry was not evident until 14 days postinjury, with T-cell numbers doubling between 2 and 6 weeks. Dendritic cell influx paralleled T-cell infiltration in rats but was absent in mouse spinal cord. De novo expression of major histocompatability class II molecules was increased in both species but to a greater extent in mice. Unique to mice were cells that resembled lymphocytes but did not express lymphocyte-specific markers. These cells extended from blood vessels within the fibrotic tissue matrix and expressed fibronectin, collagen I, CD11b, CD34, CD13, and CD45. This phenotype is characteristic of fibrocytes, specialized bloodborne cells involved in wound healing and immunity. Thus, species-specific neuroinflammation may contribute to the formation of distinct tissue environments at the site of spinal cord injury in mice and rats.
Characterization of the early neuroinflammation after spinal cord injury in mice
Journal of neuropathology and experimental neurology, 2007
The occurrence of neuroinflammation after spinal cord injury (SCI) is well established, but its function is debated, with both beneficial and detrimental consequences ascribed. A discriminate of the role of neuroinflammation may be the time period after SCI, and there is evidence to favor early neuroinflammation being undesirable, whereas the later evolving phase may have useful roles. Here, we have focused on the inflammatory response in the first 24 hours of SCI in mice. We found elevation of interleukin (IL)-1beta and other cytokines and chemokines within 15 minutes to 3 hours of injury. The early neuroinflammation in SCI is likely to be CNS-derived and involves microglia, as demonstrated by in situ hybridization for IL-1beta in microglia, by an in vitro model of SCI in which elevation of inflammatory cytokines occurs in the absence of a dynamic source of infiltrating leukocytes, and by the correlation of decreased levels of inflammatory molecules and microglia activity in IL-1be...
Journal of Neuroscience Research, 2002
Injury of the spinal cord leads to an inflammatory tissue response, probably mediated in part by cytokines. Because a common therapy for acute spinal cord injury is the use of an antiinflammatory synthetic glucocorticoid (methylprednisolone), we sought to determine mechanisms contributing to inflammation shortly after acute injury. Cytokine mRNAs [interleukin (IL)-1␣, IL-1, tumor necrosis factor (TNF)-␣, and IL-6] were increased during the first 2 hr following weight-drop compression injury by RNase protection assay, prior to the reported appearance of circulating lymphocytes. This immediate pattern of cytokine mRNA induction could be replicated in cultured, explanted spinal cord slices but not in whole blood of injured animals, which is consistent with a tissue source of cytokine mRNAs. Western blotting detected IL-1-like immunoreactivity released into culture medium following explantation and pro-IL-1-like immunoreactivity in freshly dissected spinal cord tissue. Pharmacologically blocking IL-1 and TNF-␣ receptors significantly reduced expression of IL-1␣, IL-1, and TNF-␣ mRNAs. Finally, mice lacking both IL-1 and TNF-␣ receptors exhibited diminished induction of TNF-␣, IL-6, and IL-1ra mRNAs following injury. Therefore, we conclude that contusion injury induces an immediate release of cytokines, which then contributes to the induction of cytokine mRNAs.
Journal of Clinical Neuroscience, 2005
The post-traumatic inflammatory response in acute spinal cord contusion injury was studied in the rat. Mild and severe spinal cord injury (SCI) was produced by dropping a 10 g weight from 3 and 12 cm at the T12 vertebral level. Increased immunoreactivity of TNF-a in mild and severe SCI was detected in neurons at 1 h post-injury, and in neurons and microglia at 6 h post-injury, with a less significant increase in mild SCI. Expression was short-lived and declined sharply by 1 d post-injury. RT-PCR showed an early significant up-regulation of IL-1b, IL-6 and TNF-a mRNAs, maximal at 6 h post-injury with return to control levels by 24 h post-injury, the changes being less statistically significantly in mild SCI. Western blot showed early transient increases of IL-1b, IL-6 and TNF-a proteins in severe SCI but not mild SCI. Immunocytochemical, western blotting and RT-PCR analyses suggest that endogenous cells (neurons and microglia) in the spinal cord, not blood-borne leucocytes, contribute to IL-1b, IL-6 and TNF-a production in the post-traumatic inflammatory response and that their up-regulation is greater in severe than mild SCI. ª Summary Global changes in gene expression were analyzed in pericontusional tissue taken during surgery from 4 patients with traumatic brain injury (TBI), in cerebral infarction tissue from a patient with vasculitis and in normal brain tissue resected during craniotomy for meningioma. Of approximately 1200 genes showing some level of expression by cDNA microarray hybridization, 104 ($8%) showed differential expression in traumatized tissue. Genes controlling transcriptional regulation, intermediary and energy metabolism, signal transduction, and intercellular adhesion and recognition were differentially affected most often. Four genes previously shown to be associated with TBI (c-Fos, Jun B, HSP70, and Zif/268) were all found to be up-regulated in at least one TBI patient. Thus, the robust response to TBI of several immediate early genes is confirmed, and a longer list of candidate genes from other functional categories is suggested for further studies aimed at understanding the molecular and cellular consequences of TBI. ª
The Role of Interleukins after Spinal Cord Injury
Interleukins - The Immune and Non-Immune Systems’ Related Cytokines, 2021
In skin wound healing the injured tissue goes through a normal progression, inflammation subsides and remodeling occurs. However after spinal cord injury inflammation persists and there is less progression into a regenerative/rebuilding phase. This inflammatory process after spinal cord injury is orchestrated by many cell types and numerous cytokines. Although there are several positive effects of inflammation after spinal cord injury, such as the removal of debris, the substantial upregulation of immune cells has been shown to contribute to neural degeneration. Several chemokines and cytokines including many interleukins are involved in guiding these immune cells to the lesion. While there are many inflammatory cytokines acting on these immune cells after SCI, there are also several anti-inflammatory interleukins that have shown beneficial effects in reducing inflammation. After SCI in a rat model, interleukin-10 and interleukin-19 have been shown to downregulate the synthesis of p...
Turkish neurosurgery, 2009
A rat model of spinal cord ischemia/reperfusion was conducted and the serum cytokine levels and histopathological changes were assessed. Twenty-four male Sprague-Dawley rats were assigned into four experimental groups. Group-A (the sham operated rats) and group-B (the spinal ischemia/reperfusion group) were sacrificed at 24 hours postoperatively while group-C (the sham operated rats) and group-D (the spinal ischemia/reperfusion group) were sacrificed at 48 hours. Histopathological changes in the spinal cords and serum cytokine levels were analysed. All three proinflammatory cytokine levels reached significantly higher levels compared to the sham operated groups in both the 24-hour and 48-hour spinal cord ischemia/reperfusion groups. Inflammation is a plausible pathway in spinal cord ishemia/reperfusion injury. However clinical treatment of the damage does not currently include antiinflammatory therapy. The results of our study supported the hypothesis that inflammatory responses cou...