Absence of IL-1β positively affects neurological outcome, lesion development and axonal plasticity after spinal cord injury (original) (raw)
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Journal of neuroscience research, 2014
Secondary damage after spinal cord injury (SCI) induces neuronal demise through neurotoxicity and inflammation, and interleukin (IL)-1β is a key inflammatory mediator. We hypothesized that IL-1β is released in spinal cord slice cultures (SCSC) and aimed at preventing the potentially neurotoxic effects of IL-1β by using interleukin-1 receptor antagonist (IL1RA). We hypothesized that IL1RA treatment enhances neuronal survival and suppresses microglial activation. SCSC were cultured up to 8 days in vitro (DIV) in the presence of IL1RA or without, either combined with trophic support using neurotrophin (NT)-3 or not. Four groups were studied: negative control, IL1RA, NT-3, and IL1RA + NT-3. IL-1β concentrations in supernatants were measured by ELISA. SCSC were immunohistochemically stained for NeuN and α-neurofilament, and microglial cells were visualized with isolectin B4 . After 8 DIV, ventral horn neurons were significantly more numerous in the IL1RA, NT-3, and IL1RA + NT-3 groups co...
Journal of Neuroinflammation, 2012
Background: Microglia and macrophages (MG/MΦ) have a diverse range of functions depending on unique cytokine stimuli, and contribute to neural cell death, repair, and remodeling during central nervous system diseases. While IL-1 has been shown to exacerbate inflammation, it has also been recognized to enhance neuroregeneration. We determined the activating phenotype of MG/MΦ and the impact of IL-1 in an in vivo spinal cord injury (SCI) model of IL-1 knockout (KO) mice. Moreover, we demonstrated the contribution of IL-1 to both the classical and alternative activation of MG in vitro using an adult MG primary culture. Methods: SCI was induced by transection of the spinal cord between the T9 and T10 vertebra in wild-type and IL-1 KO mice. Locomotor activity was monitored and lesion size was determined for 14 days. TNFα and Ym1 levels were monitored to determine the MG/MΦ activating phenotype. Primary cultures of MG were produced from adult mice, and were exposed to IFNγ or IL-4 with and without IL-1β. Moreover, cultures were exposed to IL-4 and/or IL-13 in the presence and absence of IL-1β. Results: The locomotor activity and lesion area of IL-1 KO mice improved significantly after SCI compared with wild-type mice. TNFα production was significantly suppressed in IL-1 KO mice. Also, Ym1, an alternative activating MG/MΦ marker, did not increase in IL-1 KO mice, suggesting that IL-1 contributes to both the classical and alternative activation of MG/MΦ. We treated primary MG cultures with IFNγ or IL-4 in the presence and absence of IL-1β. Increased nitric oxide and TNFα was present in the culture media and increased inducible NO synthase was detected in cell suspensions following co-treatment with IFNγ and IL-1β. Expression of the alternative activation markers Ym1 and arginase-1 was increased after exposure to IL-4 and further increased after co-treatment with IL-4 and IL-1β. The phenotype was not observed after exposure of cells to IL-13. Conclusions: We demonstrate here in in vivo experiments that IL-1 suppressed SCI in a process mediated by the reduction of inflammatory responses. Moreover, we suggest that IL-1 participates in both the classical and alternative activation of MG in in vivo and in vitro systems.
Brain Research, 1997
. Interleukin-1 beta IL-1b is a major mediator of inflammation and a growth promoter for many cell types that could play an important Ž . role in the consequences of traumatic spinal cord injury SCI . In the present study, the expression of IL-1b and its mRNA was determined in the rat spinal cord following a standardized contusion injury. IL-1b mRNA, measured with quantitative RT-PCR, was Ž . significantly increased in the lesion site by 1 h after SCI 35.2 " 5.9 vs. 9.1 " 2.1 pgrmg RNA, n s 3, P -0.05 and remained Ž . significantly higher than in the normal spinal cord for at least 72 h post-injury p.i. . IL-1b mRNA levels in tissue immediately caudal to the lesion site did not change after the injury. IL-1b protein levels, measured by an ELISA, were determined at the lesion site and in Ž . cerebrospinal fluid CSF and serum samples. IL-1b levels in the CSF and serum were much lower than in the spinal cord. At the lesion Ž . site, IL-1b was increased significantly by 1 h p.i., peaked at 8 h 32.3 " 0.1 vs. 7.6 " 1.9, ngrg tissue, n s 5, P -0.05 and remained significantly higher than normal through at least 7 days p.i. These results suggest that the increased IL-1b mRNA and protein levels are an early and local response at the lesion site that could trigger other, later, responses to traumatic SCI.
Brain Behavior and Immunity, 2010
a b s t r a c t CNS injury stimulates the expression of several proinflammatory cytokines and chemokines, some of which including MCP-1 (also known as CCL2), KC (CXCL1), and MIP-2 (CXCL2) act to recruit Gr-1 + leukocytes at lesion sites. While earlier studies have reported that neutrophils and monocytes/macrophages contribute to secondary tissue loss after spinal cord injury (SCI), recent work has shown that depletion of Gr-1 + leukocytes compromised tissue healing and worsened functional recovery. Here, we demonstrate that astrocytes distributed throughout the spinal cord initially contribute to early neuroinflammation by rapidly synthesizing MCP-1, KC, and MIP-2, from 3 up to 12 h post-SCI. Chemokine expression by astrocytes was followed by the infiltration of blood-derived immune cells, such as type I ''inflammatory" monocytes and neutrophils, into the lesion site and nearby damaged areas. Interestingly, astrocytes from mice deficient in MyD88 signaling produced significantly less MCP-1 and MIP-2 and were unable to synthesize KC. Analysis of the contribution of MyD88-dependent receptors revealed that the astrocytic expression of MCP-1, KC, and MIP-2 was mediated by the IL-1 receptor (IL-1R1), and not by TLR2 or TLR4. Flow cytometry analysis of cells recovered from the spinal cord of MyD88-and IL-1R1-knockout mice confirmed the presence of significantly fewer type I ''inflammatory" monocytes and the almost complete absence of neutrophils at 12 h and 4 days post-SCI. Together, these results indicate that MyD88/IL-1R1 signals regulate the entry of neutrophils and, to a lesser extent, type I ''inflammatory" monocytes at sites of SCI.
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...
Pain, 2006
Peripheral nerve injury may lead to neuropathic pain, which is often associated with mechanical and thermal allodynia, ectopic discharge of from injured nerves and from the dorsal root ganglion neurons, and elevated levels of proinflammatory cytokines, particularly interleukin-1 (IL-1). In the present study, we tested the role of IL-1 in neuropathic pain models using two mouse strains impaired in IL-1 signaling: Deletion of the IL-1 receptor type I (IL-1rKO) and transgenic over-expression of the IL-1 receptor antagonist (IL-1raTG). Neuropathy was induced by cutting the L5 spinal nerve on one side, following which mechanical and thermal pain sensitivity was measured. Wild-type (WT) mice and the parent strains developed significant allodynia and hyperalgesia in the hindpaw ipsilateral to the injury compared with the contralateral hind-paw. The mutant strains, however, did not display decreased pain threshold in either hind-paw. Pain behavior was also assessed by cutting the sciatic and saphenous nerves and measuring autotomy scores. WT mice developed progressive autotomy, beginning at 7 days post-injury, whereas the mutant strains displayed delayed onset of autotomy and markedly reduced severity of the autotomy score. Electrophysiological assessment revealed that in WT mice a significant proportion of the dorsal root axons exhibited spontaneous ectopic activity at 1, 3, and 7 days following spinal nerve injury, whereas in IL-1rKO and IL-1raTG mice only a minimal number of axons exhibited such activity. Taken together, these results suggest that IL-1 signaling plays an important role in neuropathic pain and in the altered neuronal activity that underlies its development.
Effects of pro-inflammatory cytokines in experimental spinal cord injury
Brain Research, 1997
Following injury to the spinal cord, secondary tissue damage leading to massive additional tissue loss and inflammatory reactions as well as scar formation takes place. The precise functions and effects of the inflammatory cells and their secreted factors are largely unclear. The present study investigates whether the exogenous local administration of pro-inflammatory cytokines to mice after spinal Ž . Ž . cord injury can influence these intrinsic processes. A mixture of murine recombinant interleukin-1b IL-1b , interleukin-6 IL-6 and Ž . tumour necrosis factor a TNFa was administered to the lesioned spinal cord of adult mice. These cytokines provoked an increased recruitment and activation of macrophages and microglial cells in the lesion area when administered 1 day post lesion. In contrast, when administered 4 days after the lesion, recruitment of macrophages was slightly increased while activation of microglia was decreased as compared to controls. The amount of tissue loss 7 days after trauma was smaller in the animals receiving the cytokine mixture than in the mice receiving Ringer control solution on day 4 after lesion. Thus the role of the inflammatory response in spinal cord injury seems to be complex and well regulated. Anti-inflammatory cytokines and factors probably also contribute to the outcome of the damage following injury to the spinal cord. q 1997 Elsevier Science B.V.
Cytokine, 2007
Interleukin-1b (IL-1b) is an important trophic factor in the nervous system (NS). IL-1b is ubiquitously expressed from very early stages during the development of the amphibian NS and its action has been demonstrated in vitro on survival, proliferation and differentiation in mammalian embryos. In this report, we show that IL-1b is immunocytochemically expressed in embryonic spinal cord from early stages, both in rat (embryonic day 12) and in chicken (stage 17-HH), in neuroepithelial cells and nerve fibres, dorsal root ganglia, anterior and posterior roots of the spinal nerves, and in the fibres of these nerves. Our in vivo experiments on chick embryos, with microbeads impregnated with IL-1b implanted laterally to the spinal cord at the level of the wing anlage, demonstrate that this cytokine produces a statistically significant increase in nuclear incorporation of BrdU at the dorsal level and a reduction of this at the ventral level, whereas local immunoblocking with anti-IL-1b antibodies causes a dorsal reduction of BrdU incorporation and alters ventral differentiation. These data demonstrate that IL-1b plays a part in controlling proliferation and early differentiation during the development of the spinal cord in chick embryos.