Lipocalin‐2 mediates the rejection of neural transplants

Weng, Yi-Chinn; Huang, Yuting; Chiang, I-Chen; Tsai, Pei‐Ju; Y, Su; Chou, Wen‐Hai

doi:10.1096/fj.202001018r

Cited by 7 publications

(8 citation statements)

References 47 publications

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“…LCN2 is expressed at the primary cilium ( 28 , 29 ). It encodes NGAL (neutrophil gelatinase-associated lipocalin), an iron-trafficking protein involved in multiple immunological processes ( 30 – 32 ), including common variable immunodeficiency ( 33 ), but its role in transplantation remains obscure ( 34 , 35 ). Furthermore, HOMER2, IQCH, and NGAL are all cilia-associated proteins.…”

Section: Discussionmentioning

confidence: 99%

An exome-wide study of renal operational tolerance

Massart¹,

Danger²,

Olsen³

et al. 2023

Front. Med.

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BackgroundRenal operational tolerance is a rare and beneficial state of prolonged renal allograft function in the absence of immunosuppression. The underlying mechanisms are unknown. We hypothesized that tolerance might be driven by inherited protein coding genetic variants with large effect, at least in some patients.MethodsWe set up a European survey of over 218,000 renal transplant recipients and collected DNAs from 40 transplant recipients who maintained good allograft function without immunosuppression for at least 1 year. We performed an exome-wide association study comparing the distribution of moderate to high impact variants in 36 tolerant patients, selected for genetic homogeneity using principal component analysis, and 192 controls, using an optimal sequence-kernel association test adjusted for small samples.ResultsWe identified rare variants of HOMER2 (3/36, FDR 0.0387), IQCH (5/36, FDR 0.0362), and LCN2 (3/36, FDR 0.102) in 10 tolerant patients vs. 0 controls. One patient carried a variant in both HOMER2 and LCN2. Furthermore, the three genes showed an identical variant in two patients each. The three genes are expressed at the primary cilium, a key structure in immune responses.ConclusionRare protein coding variants are associated with operational tolerance in a sizable portion of patients. Our findings have important implications for a better understanding of immune tolerance in transplantation and other fields of medicine.ClinicalTrials.gov, identifier: NCT05124444.

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Section: Discussionmentioning

confidence: 99%

An exome-wide study of renal operational tolerance

Massart¹,

Danger²,

Olsen³

et al. 2023

Front. Med.

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“…Lcn-2 can also induce astrocytes to phagocytose molecules such as iron and myelin phospholipids, resulting in iron accumulation and demyelination. At the transplant site, astrocyte Lcn-2 interacts with its receptor BOCT, leading to iron deficiency and apoptosis of transplanted neurons ( 78 ). Following ischemic stroke, reactive astrocytes in nonischemic areas of the corpus callosum upon injury express Lcn-2 and acquire a phagocytic phenotype capable of uptaking myelin phospholipids.…”

Section: Interaction Between Astrocytes and Lcn-2 In Neuroinflammationmentioning

confidence: 99%

The interaction of lipocalin-2 and astrocytes in neuroinflammation: mechanisms and therapeutic application

Tan,

Zhang,

Rao

et al. 2024

Front. Immunol.

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Neuroinflammation is a common pathological process in various neurological disorders, including stroke, Alzheimer’s disease, Parkinson’s disease, and others. It involves the activation of glial cells, particularly astrocytes, and the release of inflammatory mediators. Lipocalin-2 (Lcn-2) is a secretory protein mainly secreted by activated astrocytes, which can affect neuroinflammation through various pathways. It can also act as a pro-inflammatory factor by modulating astrocyte activation and polarization through different signaling pathways, such as NF-κB, and JAK-STAT, amplifying the inflammatory response and aggravating neural injury. Consequently, Lcn-2 and astrocytes may be potential therapeutic targets for neuroinflammation and related diseases. This review summarizes the current knowledge on the role mechanisms, interactions, and therapeutic implications of Lcn-2 and astrocytes in neuroinflammation.

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“…Total RNA was extracted from the hippocampus at 4, 24, and 72 h, and 7 days after tGCI using TRIzol reagent (Invitrogen, Carlsbad, CA, USA) [46,47]. Isolated RNA was quantified using a NanoDrop 2000 Spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) and reverse transcribed into cDNA using a RevertAid H Minus First Strand cDNA Synthesis Kit (Thermo) and a Veriti 96-Well Thermal Cycler (Thermo).…”

Section: Real-time Rt-pcrmentioning

confidence: 99%

“…Mice were anesthetized deeply with 4% isoflurane in N 2 O/O 2 (70%/30%) at 4, 24, and 48 h after tGCI, and transcardially perfused with saline [44,[46][47][48]. Mouse brains were isolated, sectioned using a brain matrix (Braintree Scientific, Braintree, MA, USA) to generate 1 mm-thick coronal sections, and fixed overnight in 10% neutral buffered Formalin solution (Sigma-Aldrich, St. Louis, MO, USA, Cat# HT501128) for paraffin embedding.…”

Section: Immunofluorescence Stainingmentioning

confidence: 99%

DUSP6 Deficiency Attenuates Neurodegeneration after Global Cerebral Ischemia

Weng

Huang

Chiang

et al. 2023

IJMS

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Transient global cerebral ischemia (tGCI) resulting from cardiac arrest causes selective neurodegeneration in hippocampal CA1 neurons. Although the effect is clear, the underlying mechanisms directing this process remain unclear. Previous studies have shown that phosphorylation of Erk1/2 promotes cell survival in response to tGCI. DUSP6 (also named MKP3) serves as a cytosolic phosphatase that dephosphorylates Erk1/2, but the role of DUSP6 in tGCI has not been characterized. We found that DUSP6 was specifically induced in the cytoplasm of hippocampal CA1 neurons 4 to 24 h after tGCI. DUSP6-deficient mice showed normal spatial memory acquisition and retention in the Barnes maze. Impairment of spatial memory acquisition and retention after tGCI was attenuated in DUSP6-deficient mice. Neurodegeneration after tGCI, revealed by Fluoro-Jade C and H&E staining, was reduced in the hippocampus of DUSP6-deficient mice and DUSP6 deficiency enhanced the phosphorylation and nuclear translocation of Erk1/2 in the hippocampal CA1 region. These data support the role of DUSP6 as a negative regulator of Erk1/2 signaling and indicate the potential of DUSP6 inhibition as a novel therapeutic strategy to treat neurodegeneration after tGCI.

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Lipocalin‐2 mediates the rejection of neural transplants

Cited by 7 publications

References 47 publications

An exome-wide study of renal operational tolerance

An exome-wide study of renal operational tolerance

The interaction of lipocalin-2 and astrocytes in neuroinflammation: mechanisms and therapeutic application

DUSP6 Deficiency Attenuates Neurodegeneration after Global Cerebral Ischemia

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