Lipocalin-2 Protein Deficiency Ameliorates Experimental Autoimmune Encephalomyelitis

Abstract

Background:The role of LCN2 in EAE is not clear. Results: LCN2 expression increased in EAE. Lcn2 deficiency attenuated EAE symptoms and pathology. LCN2 enhanced glial expression of inflammatory mediators and peripheral encephalitogenic T cell activation in vitro and in vivo. Conclusion: Both central and peripheral LCN2 contributed to EAE development. Significance: LCN2 can be targeted for treatment of multiple sclerosis.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. Multiple sclerosis (MS)5 is a chronic inflammatory disease of the central nervous system (CNS) characterized by immune cell infiltration and demyelination of the brain and spinal cord (1-3). In MS, inflammatory reactions involve complex interactions between infiltrating immune cells and resident CNS cells that lead to inflammatory lesion formation, demyelination, oligodendrocyte, and axonal damage (4, 5). Experimental autoimmune encephalomyelitis (EAE) is an animal model widely used to study neuroimmunologic responses in MS. The key players in MS, which include T cells (6 -8), B cells (9 -11), mast cells (12, 13), macrophages (14) Lipocalin 2 (LCN2), also termed 24p3 (21), uterocalin (22), and neutrophil gelatinase-associated lipocalin (NGAL) (23), is a member of the lipocalin family, a group of small extracellular proteins with great functional diversit...

Neutralization of Lipocalin-2 Diminishes Stroke-Reperfusion Injury

“…The LCN2 mAb may have wide applicability in multiple CNS disorders. Preclinical studies showed that LCN2 deficiency markedly decreased neuroinflammation and associated injuries in mouse models of traumatic brain injury [ 44 , 45 ], hemorrhagic stroke [ 46 , 47 , 48 ], spinal cord injury [ 49 ], and experimental autoimmune encephalomyelitis [ 50 ]. These findings suggest that LCN2 is a critical mediator of neuroinflammation in response to various CNS disorders.…”

Lipocalin-2 is increased in progressive multiple sclerosis and inhibits remyelination

“… 26 , 27 Therefore, the correlation between LCN2 and NFL is interesting because it is observed in a disease stage for which our knowledge about pathogenic processes is still limited. A detrimental effect of LCN2 on axonal degeneration in progressive MS can be induced by several mechanisms, as LCN2 has been shown to modulate CNS inflammation, induce neuronal cell death, regulate dendritic spine formation, and, importantly, modulate iron availability and transfer to the cells, which has been suggested to be of particular importance for demyelination and neurodegeneration in progressive MS. 6 , 13 , 20 , 28 – 31 …”

“… 11 , 12 Studies in experimental autoimmune encephalomyelitis (EAE) have suggested functional roles for LCN2, with regulatory effects on disease severity, proliferation of T cells, and demyelination. 13 – 16 Of note, LCN2 has been shown to be increased in a small cohort of patients with progressive disease (compared with RRMS). 15 …”

Lipocalin 2 Suppresses Ocular Inflammation by Inhibiting the Activation of NF-κβ Pathway in Endotoxin-Induced Uveitis

“…However, the specific roles of LCN2 in different inflammatory conditions are not always consistent. For example, Nam et al found that LCN2 acted in a proinflammatory manner in experimental autoimmune encephalomyelitis models of neuroinflammation [39], and Jang et al reported that Lcn2 –/– mice had reduced brain IL-12, TNF-α, and IL-23 mRNA levels after LPS injection, suggesting a proinflammatory role LCN2 in the central nervous system [32]. In contrast, Kang et al found that Lcn2 –/– mice treated with LPS had significantly elevated levels of proinflammatory cytokines and displayed worse behavioral performance than normal mice [19].…”