Interleukin-1 participates in the classical and alternative activation of microglia/macrophages after spinal cord injury

Abstract

BackgroundMicroglia 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 knock-out (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.MethodsSCI 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.ResultsThe 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.ConclusionsWe 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.

Bone Marrow Mesenchymal Stromal Cells Drive Protective M2 Microglia Polarization After Brain Trauma

“…A similar increase in IL-1β was reported in BV2 cells challenged with LPS after co-culturing of MSCs [45]. Furthermore, data from a model of spinal cord injury indicate that IL-1β may support the induction of alternative M activation [55], suggesting a role in injury resolution and brain repair, as well as being involved in the proinflammatory response. We also detected significant upregulation of CCL2 after infusion of MSCs in TBI mice at 7 d. CCL2 promotes chemotaxis of monocytes and hematopoietic progenitors to inflammation sites [56,57] and may therefore indicate increased mobilization and infiltration of peripheral immune cells by MSCs.…”

VEGF inhibits the inflammation in spinal cord injury through activation of autophagy

“…Expression of the pro-inflammatory markers IL-6, IL-1β, TNF-α and IL-12 increases acutely in response to SCI [24,25], the inflammatory response leads to a release of vasoactive mediators, such as IL-1β, leading to BSCB disruption [26]. Evidence suggests that the endothelium transport systems may be modified due to SCI demonstrated by the upregulation of the specific transporter for TNF-α [27].…”

High-mobility group box1 protein promotes neuroinflammation after intracerebral hemorrhage in rats

“…Increasing evidence indicates that microglia are the innate immune cells of the central nervous system, and that they respond quickly to various injuries, even to minor pathological changes (Ransohoff et al, 2012;Sato et al, 2012;Zhang et al, 2012b). Microglia are known to initiate cerebral inflammation and induce brain cell apoptosis after various brain insults; they do so by releasing cytotoxic products, such as reactive oxygen and nitrogen species, proinflammatory cytokines, and proteases (Kreutzberg, 1996;Khasnavis et al, 2012).…”