Abstract
Lipocalin-2 (LCN2) plays an important role in cellular processes as diverse as cell growth, migration/invasion, differentiation, and death/survival. Furthermore, recent studies indicate that LCN2 expression and secretion by glial cells are induced by inflammatory stimuli in the central nervous system. The present study was undertaken to examine the regulation of LCN2 expression in experimental autoimmune encephalomyelitis (EAE) and to determine the role of LCN2 in the disease process. LCN2 expression was found to be strongly increased in spinal cord and secondary lymphoid tissues after EAE induction. In spinal cords astrocytes and microglia were the major cell types expressing LCN2 and its receptor 24p3R, respectively, whereas in spleens, LCN2 and 24p3R were highly expressed in neutrophils and dendritic cells, respectively. Furthermore, disease severity, inflammatory infiltration, demyelination, glial activation, the expression of inflammatory mediators, and the proliferation of MOG-specific T cells were significantly attenuated in Lcn2-deficient mice as compared with wild-type animals. Myelin oligodendrocyte glycoprotein-specific T cells in culture exhibited an increased expression of Il17a, Ifng, Rorc, and Tbet after treatment with recombinant LCN2 protein. Moreover, LCN2-treated glial cells expressed higher levels of proinflammatory cytokines, chemokines, and MMP-9. Adoptive transfer and recombinant LCN2 protein injection experiments suggested that LCN2 expression in spinal cord and peripheral immune organs contributes to EAE development. Taken together, these results imply LCN2 is a critical mediator of autoimmune inflammation and disease development in EAE and suggest that LCN2 be regarded a potential therapeutic target in multiple sclerosis.
Highlights
The role of LCN2 in EAE is not clear
LCN2 Levels in Peripheral Immune Organs and in Spinal Cords after EAE Induction—To determine the role played by LCN2 in autoimmune neuroinflammation, we first investigated LCN2 expression in an EAE mouse model
Days 10 and 17 after EAE induction were selected as time points for Lcn2 expression analysis in the spinal cord and in peripheral lymphoid organs, respectively; these values were chosen based on peak times for encephalitogenic immune responses in the spinal cord and peripheral lymphoid organs [52]
Summary
The role of LCN2 in EAE is not clear. Results: LCN2 expression increased in EAE. Adoptive transfer and recombinant LCN2 protein injection experiments suggested that LCN2 expression in spinal cord and peripheral immune organs contributes to EAE development. Taken together, these results imply LCN2 is a critical mediator of autoimmune inflammation and disease development in EAE and suggest that LCN2 be regarded a potential therapeutic target in multiple sclerosis. Recombinant LCN2 protein enhanced the activation of encephalitogenic T cells and CNS-resident glial cells, and adoptive transfer and LCN2 protein injection experiments showed that LCN2 expression in the CNS and peripheral lymphoid tissues is critically involved in the development of EAE
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