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

Background: Microglia and macrophages ( MG/M Phi) 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/M Phi 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. 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. TNF alpha and Ym1 levels were monitored to determine the MG/M Phi activating phenotype. Primary cultures of MG were produced from adult mice, and were exposed to IFN gamma or IL-4 with and without IL-1 beta. Moreover, cultures were exposed to IL-4 and/or IL-13 in the presence and absence of IL-1 beta. Results: The locomotor activity and lesion area of IL-1 KO mice improved significantly after SCI compared with wild-type mice. TNF alpha production was significantly suppressed in IL-1 KO mice. Also, Ym1, an alternative activating MG/M Phi marker, did not increase in IL-1 KO mice, suggesting that IL-1 contributes to both the classical and alternative activation of MG/M Phi. We treated primary MG cultures with IFN gamma or IL-4 in the presence and absence of IL-1 beta. Increased nitric oxide and TNF alpha was present in the culture media and increased inducible NO synthase was detected in cell suspensions following co-treatment with IFN gamma and IL-1 beta. 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-1 beta. 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.