Role of Lipocalin-2-Chemokine Axis in the Development of Neuropathic Pain following Peripheral Nerve Injury

Jeon, Sangmin; Jha, Mithilesh Kumar; Ock, Jiyeon; Seo, Jung-Wan; Jin, Myungwon; Cho, Hee-Jung; Lee, Won Ha; Suk, Kyoungho

doi:10.1074/jbc.m113.454140

Cited by 50 publications

(50 citation statements)

References 66 publications

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“…Because we issued our first report on the glial expression of LCN2 (41, 55), several studies have demonstrated the potentially important roles played by LCN2 in the physiology and pathology of the CNS (38,44,47,56). Nevertheless, its functional roles in neuroinflammation and related diseases of the CNS are far from clear, and the results of some previous studies have been contradictory.…”

Section: Discussionmentioning

confidence: 83%

Lipocalin-2 Protein Deficiency Ameliorates Experimental Autoimmune Encephalomyelitis

Nam

Kim

Seo

et al. 2014

Journal of Biological Chemistry

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109

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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...

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Section: Discussionmentioning

confidence: 83%

Lipocalin-2 Protein Deficiency Ameliorates Experimental Autoimmune Encephalomyelitis

Nam

Kim

Seo

et al. 2014

Journal of Biological Chemistry

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109

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“…LCN2 knockout (KO) mice were provided by Dr. Shizou Akira (Osaka University, Japan). The breeding and genotyping of LCN2 KO mice were performed as described previously [32]. All animal procedures were approved by the Committee on the Ethics of Animal Experiments of the Kyungpook National University.…”

Section: Reagents and Micementioning

confidence: 99%

“…Recombinant mouse LCN2 protein was prepared as described previously [32,33]. Briefly, recombinant LCN2 protein was expressed as a glutathione S-transferase (GST) fusion protein in BL21 strain E. coli, which does not synthesize siderophore.…”

Section: Reagents and Micementioning

confidence: 99%

Lipocalin-2 inhibits osteoclast formation by suppressing the proliferation and differentiation of osteoclast lineage cells

Kim

Yoon

et al. 2015

Experimental Cell Research

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“…In rat brain, LCN2 mRNA and protein were upregulated after neuronal injury induced by kainite (Chia et al 2011) or after neuroinflammation induced by systemic LPS injections (Ip et al 2011). Some papers showed that astrocytes produced LCN2 (Bi et al 2013), but other papers showed that LCN2 colocalized with neurons, not astrocytes or microglia (Jeon et al 2013; Mucha et al 2011; Skrzypiec et al 2013). Our data suggest that ischemic neurons (not glia) produced LCN2 in rat and human stroke brains (Xing et al 2014).…”

Section: Neuronal Help-me Signals and Neuron-immune Interactionsmentioning

confidence: 99%

Help-me signaling: Non-cell autonomous mechanisms of neuroprotection and neurorecovery

Xing

2017

Progress in Neurobiology

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Self-preservation is required for life. At the cellular level, this fundamental principle is expressed in the form of molecular mechanisms for preconditioning and tolerance. When the cell is threatened, internal cascades of survival signaling become triggered to protect against cell death and defend against future insults. Recently, however, emerging findings suggest that this principle of self-preservation may involve not only intracellular signals; the release of extracellular signals may provide a way to recruit adjacent cells into an amplified protective program. In the central nervous system where multiple cell types co-exist, this mechanism would allow threatened neurons to “ask for help” from glial and vascular compartments. In this review, we describe this new concept of help-me signaling, wherein damaged or diseased neurons release signals that may shift glial and vascular cells into potentially beneficial phenotypes, and help remodel the neurovascular unit. Understanding and dissecting these non-cell autonomous mechanisms of self-preservation in the CNS may lead to novel opportunities for neuroprotection and neurorecovery.

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Role of Lipocalin-2-Chemokine Axis in the Development of Neuropathic Pain following Peripheral Nerve Injury

Cited by 50 publications

References 66 publications

Lipocalin-2 Protein Deficiency Ameliorates Experimental Autoimmune Encephalomyelitis

Lipocalin-2 Protein Deficiency Ameliorates Experimental Autoimmune Encephalomyelitis

Lipocalin-2 inhibits osteoclast formation by suppressing the proliferation and differentiation of osteoclast lineage cells

Help-me signaling: Non-cell autonomous mechanisms of neuroprotection and neurorecovery

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