Lipocalin-2 Is a Chemokine Inducer in the Central Nervous System

Lee, Shinrye; Kim, Jong‐Heon; Kim, Jae Hong; Seo, Jung-Wan; Han, Hyung-Soo; Lee, Won‐Ha; Mori, Kiyoshi; Nakao, Kazuwa; Barasch, Jonathan; Suk, Kyoungho

doi:10.1074/jbc.m111.299248

Cited by 139 publications

(82 citation statements)

References 99 publications

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“…Once activated, STAT3 mediates GFAP upregulation, as observed in our study and demonstrated previously 27, 30. According to recent studies 28, activated STAT3 is also involved in secretion of chemokines such as CCL2–3 and CXCL‐10, found to be highly upregulated in retinal tissue in response to BM‐MSC transplantation. Chemokines play a central role in macrophage recruitment.…”

Section: Discussionsupporting

confidence: 88%

“…The MAPK cascade may lead to further chemokine secretion 44, GFAP expression through the AP1/CREB complex 45, 46, and LCN2 expression 29, which we found to be significantly upregulated in the host retina in vivo but not ex vivo. Thus, we propose that LCN2 plays a central role in maintaining reactive gliosis 41 and neuroinflammation 28.…”

Section: Discussionmentioning

confidence: 95%

“…There is wealth of evidence that in response to upstream cytokines and growth factors, including IL6, CNTF, IL1β, and PDGF, both JAK and MAPK kinases induce STAT3 transcriptional activity by phosphorylating STAT3 on its tyrosine 705 and serine 727 residue, respectively 23, 26. Phosphorylated STAT3 dimers migrate into the nucleus and transcribe target genes, such as GFAP 27 and CxCl10 28. These results confirm that following BM‐MSC transplantation, the downstream effector of MAPK and JAK/STAT pathways STAT3 is significantly upregulated in retinal Muller glia.…”

Section: Resultsmentioning

confidence: 99%

“…Using gene expression profiling, we identified LCN2, with a 125‐fold induction in gene expression in BM‐MSC recipient retina, as a potential new marker of retinal reactive gliosis. There is increasing evidence correlating astrocyte‐mediated LCN2 secretion to neuroinflammation 28, 40, reactive gliosis 41, and neuronal death 40. Although the mechanism through which LCN2 signals is not yet clear, its expression has been reported to be mediated by the ERK1/2 and INFγ/STAT1 signaling cascade 29.…”

Section: Discussionmentioning

confidence: 99%

“…Although the mechanism through which LCN2 signals is not yet clear, its expression has been reported to be mediated by the ERK1/2 and INFγ/STAT1 signaling cascade 29. Moreover, in different models of neurodegeneration, LCN2 acts as chemokine inducer by promoting the upregulation of chemokines, such as CCL2 and CXCL10, through the JAK2/STAT3 pathway 28. There is evidence that under degenerative conditions reactive astrocyte gain neurotoxic properties and recent studies have identified LCN2 as an inducible neurotoxic mediator secreted by astrocytes to promote neuronal death 40.…”

Section: Discussionmentioning

confidence: 99%

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Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation

et al. 2015

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A variety of diseases lead to degeneration of retinal ganglion cells (RGCs) and their axons within the optic nerve resulting in loss of visual function. Although current therapies may delay RGC loss, they do not restore visual function or completely halt disease progression. Regenerative medicine has recently focused on stem cell therapy for both neuroprotective and regenerative purposes. However, significant problems remain to be addressed, such as the long‐term impact of reactive gliosis occurring in the host retina in response to transplanted stem cells. The aim of this work was to investigate retinal glial responses to intravitreally transplanted bone marrow mesenchymal stem cells (BM‐MSCs) to help identify factors able to modulate graft‐induced reactive gliosis. We found in vivo that intravitreal BM‐MSC transplantation is associated with gliosis‐mediated retinal folding, upregulation of intermediate filaments, and recruitment of macrophages. These responses were accompanied by significant JAK/STAT3 and MAPK (ERK1/2 and JNK) cascade activation in retinal Muller glia. Lipocalin‐2 (Lcn‐2) was identified as a potential new indicator of graft‐induced reactive gliosis. Pharmacological inhibition of STAT3 in BM‐MSC cocultured retinal explants successfully reduced glial fibrillary acidic protein expression in retinal Muller glia and increased BM‐MSC retinal engraftment. Inhibition of stem cell‐induced reactive gliosis is critical for successful transplantation‐based strategies for neuroprotection, replacement, and regeneration of the optic nerve. Stem Cells 2015;33:3006–3016

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation

et al. 2015

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Differential Role of Lipocalin 2 During Immune Complex–Mediated Acute and Chronic Inflammation in Mice

Shashidharamurthy¹,

Machiah²,

Aitken³

et al. 2013

Arthritis & Rheumatism

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Objectives Lipocalin-2 (Lcn2) is an innate immune protein expressed by a variety of cells and is highly upregulated during several pathological conditions including immune-complex (IC) mediated inflammatory/autoimmune disorders. However, the function of Lcn2 during IC-mediated inflammation is largely unknown. Therefore our objective was to investigate the role of Lcn2 in IC-mediated diseases. Methods The upregulation of Lcn2 was determined by ELISA in three different mouse models of IC-mediated autoimmune disease: systemic lupus erythematosus, collagen-induced arthritis and serum-induced arthritis. The in vivo role of Lcn2 during IC-mediated inflammation was investigated using Lcn2 knockout (Lcn2KO) mice and their wild type (WT) littermates. Results Lcn2 levels were significantly elevated in all the three autoimmune disease models. Further, in an acute skin inflammation model, Lcn2KO mice demonstrated a 50% reduction in inflammation with histopathological analysis revealing strikingly reduced immune cell infiltration compared to WT mice. Administration of recombinant Lcn2 to Lcn2KO mice restored inflammation to levels observed in WT mice. Neutralization of Lcn2 using a monoclonal antibody significantly reduced inflammation in WT mice. In contrast, Lcn2KO mice developed more severe serum-induced arthritis compared to WT mice. Histological analysis revealed extensive tissue and bone destruction with significantly reduced neutrophil infiltration but considerably more macrophage migration in Lcn2KO mice when compared to WT. Conclusion These results demonstrate that Lcn2 may regulate immune cell recruitment to the site of inflammation, a process essential for the controlled initiation, perpetuation and resolution of inflammatory processes. Thus, Lcn2 may present a promising target in the treatment of IC-mediated inflammatory/autoimmune diseases.

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Purines regulate adult brain subventricular zone cell functions: Contribution of reactive astrocytes

Boccazzi

Rolando

Abbracchio

et al. 2013

Glia

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Brain injuries modulate activation of neural stem cells (NSCs) in the adult brain. In pathological conditions, the concentrations of extracellular nucleotides (eNTs) raise several folds, contribute to reactive gliosis, and possibly directly affect subventricular zone (SVZ) cell functioning. Among eNTs and derived metabolites, the P2Y1 receptor agonist ADP strongly promotes astrogliosis and might also influence SVZ progenitor activity. Here, we tested the ability of the stable P2Y1 agonist adenosine 5'-O-(2-thiodiphosphate) (ADPβS) to control adult NSC functions both in vitro and in vivo, with a focus on the possible effects exerted by reactive astrocytes. In the absence of growth factors, ADPβS promoted proliferation and differentiation of SVZ progenitors. Moreover, ADPβS-activated astrocytes markedly changed the pattern of released cytokines and chemokines, and strongly modulated neurosphere-forming capacity of SVZ progenitors. Notably, a significant enhancement in proliferation was observed when SVZ cells, initially grown in the supernatant of astrocytes exposed to ADPβS, were shifted to normal medium. In vivo, ADPβS administration in the lateral ventricle of adult mice by osmotic minipumps caused diffused reactive astrogliosis, and a strong response of SVZ progenitors. Indeed, proliferation of glial fibrillary acidic protein-positive NSCs increased and led to a significant expansion of SVZ transit-amplifying progenitors and neuroblasts. Lineage tracing experiments performed in the GLAST::CreERT2;Rosa-YFP transgenic mice further demonstrated that ADPβS promoted proliferation of glutamate/aspartate transporter-positive progenitors and sustained their progression toward the generation of rapidly dividing progenitors. Altogether, our results show that the purinergic system crucially affects SVZ progenitor activities both directly and through the involvement of reactive astrocytes.

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Lipocalin-2 Is a Chemokine Inducer in the Central Nervous System

Cited by 139 publications

References 99 publications

Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation

Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation

Differential Role of Lipocalin 2 During Immune Complex–Mediated Acute and Chronic Inflammation in Mice

Purines regulate adult brain subventricular zone cell functions: Contribution of reactive astrocytes

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