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Lipocalin 2 as a Putative Modulator of Local Inflammatory Processes in the Spinal Cord and Component of Organ Cross talk After Spinal Cord Injury

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Abstract

Lipocalin 2 (LCN2), an immunomodulator, regulates various cellular processes such as iron transport and defense against bacterial infection. Under pathological conditions, LCN2 promotes neuroinflammation via the recruitment and activation of immune cells and glia, particularly microglia and astrocytes. Although it seems to have a negative influence on the functional outcome in spinal cord injury (SCI), the extent of its involvement in SCI and the underlying mechanisms are not yet fully known. In this study, using a SCI contusion mouse model, we first investigated the expression pattern of Lcn2 in different parts of the CNS (spinal cord and brain) and in the liver and its concentration in blood serum. Interestingly, we could note a significant increase in LCN2 throughout the whole spinal cord, in the brain, liver, and blood serum. This demonstrates the diversity of its possible sites of action in SCI. Furthermore, genetic deficiency of Lcn2 (Lcn2−/−) significantly reduced certain aspects of gliosis in the SCI-mice. Taken together, our studies provide first valuable hints, suggesting that LCN2 is involved in the local and systemic effects post SCI, and might modulate the impairment of different peripheral organs after injury.

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Data Availability

The datasets generated and analyzed during this study are available from the corresponding author upon reasonable request.

Code Availability

Not applicable.

Abbreviations

ALDH1L1:

Aldehyde dehydrogenase 1 family member L1

Bax:

Bcl-2-associated X protein

Bcl2:

B-Cell lymphoma 2

BSA:

Bovine serum albumin

C3:

Complement component 3

CD31:

Cluster of differentiation 31

CD44:

Cluster of differentiation 44

CNS:

Central nervous system

EDTA:

Ethylenediaminetetraacetic acid

ELISA:

Enzyme-linked immunosorbent assay

FCS:

Fetal calf serum

GFAP:

Glial fibrillary acidic protein

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

Hsp90:

Heat shock protein 90

IBA1:

Ionized calcium binding adaptor molecule 1

IgG:

Immunoglobulin G

LCN2:

Lipocalin 2

M-MLV:

Moloney murine leukemia virus

NGAL:

Neutrophil gelatinase-associated lipocalin

PBS:

Phosphate-buffered saline

PCR:

Polymerase chain reaction

PFA:

Paraformaldehyde

PVDF:

Polyvinylidene difluoride

RIPA:

Radioimmunoprecipitation assay

RT:

Room temperature

SC :

Spinal cord

SCI:

Spinal cord injury

SDS:

Sodium dodecyl sulfate

SPHK1:

Sphingosine kinase 1

TBS:

Tris-buffered saline

WT:

Wild-type

References

  1. Westgren N, Levi R (1998) Quality of life and traumatic spinal cord injury. Arch Phys Med Rehabil 79(11):1433–1439. https://doi.org/10.1016/s0003-9993(98)90240-4

    Article  CAS  PubMed  Google Scholar 

  2. Torregrossa F, Salli M, Grasso G (2020) Emerging therapeutic strategies for traumatic spinal cord injury. World Neurosurg 140:591–601. https://doi.org/10.1016/j.wneu.2020.03.199

    Article  PubMed  Google Scholar 

  3. Ahuja CS et al (2017) Traumatic spinal cord injury-repair and regeneration. Neurosurgery 80(3S):S9–S22. https://doi.org/10.1093/neuros/nyw080

    Article  PubMed  Google Scholar 

  4. Fleming JC et al (2006) The cellular inflammatory response in human spinal cords after injury. Brain 129(Pt 12):3249–3269. https://doi.org/10.1093/brain/awl296

    Article  PubMed  Google Scholar 

  5. Gattlen C et al (2016) Spinal cord T-cell infiltration in the rat spared nerve injury model: a time course study. Int J Mol Sci 17(3):352. https://doi.org/10.3390/ijms17030352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Faulkner JR et al (2004) Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 24(9):2143–2155. https://doi.org/10.1523/JNEUROSCI.3547-03.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sekhon LH, Fehlings MG (2001) Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine (Phila Pa 1976) 26(24 Suppl):S2-12. https://doi.org/10.1097/00007632-200112151-00002

    Article  CAS  Google Scholar 

  8. Ducker TB, Assenmacher DR (1969) Microvascular response to experimental spinal cord trauma. Surg Forum 20:428–430

    CAS  PubMed  Google Scholar 

  9. Guha A, Tator CH (1988) Acute cardiovascular effects of experimental spinal cord injury. J Trauma 28(4):481–490. https://doi.org/10.1097/00005373-198804000-00011

    Article  CAS  PubMed  Google Scholar 

  10. Pineau I et al (2010) Astrocytes initiate inflammation in the injured mouse spinal cord by promoting the entry of neutrophils and inflammatory monocytes in an IL-1 receptor/MyD88-dependent fashion. Brain Behav Immun 24(4):540–553. https://doi.org/10.1016/j.bbi.2009.11.007

    Article  CAS  PubMed  Google Scholar 

  11. David S, Kroner A (2011) Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 12(7):388–399. https://doi.org/10.1038/nrn3053

    Article  CAS  PubMed  Google Scholar 

  12. Taoka Y et al (1997) Role of neutrophils in spinal cord injury in the rat. Neuroscience 79(4):1177–1182. https://doi.org/10.1016/s0306-4522(97)00011-0

    Article  CAS  PubMed  Google Scholar 

  13. Popovich PG et al (1999) Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol 158(2):351–365. https://doi.org/10.1006/exnr.1999.7118

    Article  CAS  PubMed  Google Scholar 

  14. Cregg JM et al (2014) Functional regeneration beyond the glial scar. Exp Neurol 253:197–207. https://doi.org/10.1016/j.expneurol.2013.12.024

    Article  PubMed  Google Scholar 

  15. Kroner AJ (2019) Rosas Almanza, Role of microglia in spinal cord injury. Neurosci Lett 709:134370. https://doi.org/10.1016/j.neulet.2019.134370

    Article  CAS  PubMed  Google Scholar 

  16. Haydon PG, Carmignoto G (2006) Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev 86(3):1009–1031. https://doi.org/10.1152/physrev.00049.2005

    Article  CAS  PubMed  Google Scholar 

  17. Bush TG et al (1999) Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23(2):297–308. https://doi.org/10.1016/s0896-6273(00)80781-3

    Article  CAS  PubMed  Google Scholar 

  18. Firkins SS, Bates CA, Stelzner DJ (1993) Corticospinal tract plasticity and astroglial reactivity after cervical spinal injury in the postnatal rat. Exp Neurol 120(1):1–15. https://doi.org/10.1006/exnr.1993.1036

    Article  CAS  PubMed  Google Scholar 

  19. Davies SJ et al (1997) Regeneration of adult axons in white matter tracts of the central nervous system. Nature 390(6661):680–683. https://doi.org/10.1038/37776

    Article  CAS  PubMed  Google Scholar 

  20. Okada S et al (2006) Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat Med 12(7):829–834. https://doi.org/10.1038/nm1425

    Article  CAS  PubMed  Google Scholar 

  21. Bellver-Landete V et al (2019) Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury. Nat Commun 10(1):518. https://doi.org/10.1038/s41467-019-08446-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zamanian JL et al (2012) Genomic analysis of reactive astrogliosis. J Neurosci 32(18):6391–6410. https://doi.org/10.1523/JNEUROSCI.6221-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Brambilla R et al (2005) Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury. J Exp Med 202(1):145–156. https://doi.org/10.1084/jem.20041918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liddelow SA et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541(7638):481–487. https://doi.org/10.1038/nature21029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jang E et al (2013) Phenotypic polarization of activated astrocytes: the critical role of lipocalin-2 in the classical inflammatory activation of astrocytes. J Immunol 191(10):5204–5219. https://doi.org/10.4049/jimmunol.1301637

    Article  CAS  PubMed  Google Scholar 

  26. Rathore KI et al (2011) Lipocalin 2 plays an immunomodulatory role and has detrimental effects after spinal cord injury. J Neurosci 31(38):13412–13419. https://doi.org/10.1523/jneurosci.0116-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Flo TH et al (2004) Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432(7019):917–921. https://doi.org/10.1038/nature03104

    Article  CAS  PubMed  Google Scholar 

  28. Al Nimer F et al (2016) Lipocalin-2 is increased in progressive multiple sclerosis and inhibits remyelination. Neurol Neuroimmunol Neuroinflamm 3(1):e191. https://doi.org/10.1212/NXI.0000000000000191

    Article  PubMed  PubMed Central  Google Scholar 

  29. Ni W et al (2015) Role of lipocalin-2 in brain injury after intracerebral hemorrhage. J Cereb Blood Flow Metab 35(9):1454–1461. https://doi.org/10.1038/jcbfm.2015.52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ranjbar Taklimie F et al (2019) Hypoxia induces astrocyte-derived lipocalin-2 in ischemic stroke. Int J Mol Sci 20(6).https://doi.org/10.3390/ijms20061271

  31. Moschen AR et al (2017) Lipocalin-2: a master mediator of intestinal and metabolic inflammation. Trends Endocrinol Metab 28(5):388–397. https://doi.org/10.1016/j.tem.2017.01.003

    Article  CAS  PubMed  Google Scholar 

  32. Yang J et al (2002) An iron delivery pathway mediated by a lipocalin. Mol Cell 10(5):1045–1056. https://doi.org/10.1016/s1097-2765(02)00710-4

    Article  CAS  PubMed  Google Scholar 

  33. Bi F et al (2013) Reactive astrocytes secrete lcn2 to promote neuron death. Proc Natl Acad Sci U S A 110(10):4069–4074. https://doi.org/10.1073/pnas.1218497110

    Article  PubMed  PubMed Central  Google Scholar 

  34. Jang E et al (2013) Secreted protein lipocalin-2 promotes microglial M1 polarization. FASEB J 27(3):1176–1190. https://doi.org/10.1096/fj.12-222257

    Article  CAS  PubMed  Google Scholar 

  35. Wu J et al (2014) Spinal cord injury causes brain inflammation associated with cognitive and affective changes: role of cell cycle pathways. J Neurosci 34(33):10989–11006. https://doi.org/10.1523/JNEUROSCI.5110-13.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Davidoff G et al (1985) Cognitive dysfunction and mild closed head injury in traumatic spinal cord injury. Arch Phys Med Rehabil 66(8):489–491

    CAS  PubMed  Google Scholar 

  37. Davidoff GN, Roth EJ, Richards JS (1992) Cognitive deficits in spinal cord injury: epidemiology and outcome. Arch Phys Med Rehabil 73(3):275–284

    CAS  PubMed  Google Scholar 

  38. Campbell SJ et al (2005) Central nervous system injury triggers hepatic CC and CXC chemokine expression that is associated with leukocyte mobilization and recruitment to both the central nervous system and the liver. Am J Pathol 166(5):1487–1497. https://doi.org/10.1016/S0002-9440(10)62365-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cheng RD et al (2020) Spinal cord injury causes insulin resistance associated with PI3K signaling pathway in hypothalamus. Neurochem Int 140:104839. https://doi.org/10.1016/j.neuint.2020.104839

    Article  CAS  PubMed  Google Scholar 

  40. Berger T et al (2006) Lipocalin 2-deficient mice exhibit increased sensitivity to Escherichia coli infection but not to ischemia-reperfusion injury. Proc Natl Acad Sci U S A 103(6):1834–1839. https://doi.org/10.1073/pnas.0510847103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gasterich N et al (2021) Inflammatory responses of astrocytes are independent from lipocalin 2. J Mol Neurosci 71(5):933–942. https://doi.org/10.1007/s12031-020-01712-7

    Article  CAS  PubMed  Google Scholar 

  42. Basso DM, Beattie MS, Bresnahan JC (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12(1):1–21. https://doi.org/10.1089/neu.1995.12.1

    Article  CAS  PubMed  Google Scholar 

  43. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402–408. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  PubMed  Google Scholar 

  44. Neal M et al (2018) Prokineticin-2 promotes chemotaxis and alternative A2 reactivity of astrocytes. Glia 66(10):2137–2157. https://doi.org/10.1002/glia.23467

    Article  PubMed  PubMed Central  Google Scholar 

  45. Dekens DW et al (2017) Neutrophil gelatinase-associated lipocalin and its receptors in Alzheimer’s disease (AD) brain regions: differential findings in AD with and without depression. J Alzheimers Dis 55(2):763–776. https://doi.org/10.3233/JAD-160330

    Article  CAS  PubMed  Google Scholar 

  46. Berard JL et al (2012) Lipocalin 2 is a novel immune mediator of experimental autoimmune encephalomyelitis pathogenesis and is modulated in multiple sclerosis. Glia 60(7):1145–1159. https://doi.org/10.1002/glia.22342

    Article  PubMed  Google Scholar 

  47. O’Shea TM, Burda JE, Sofroniew MV (2017) Cell biology of spinal cord injury and repair. J Clin Invest 127(9):3259–3270. https://doi.org/10.1172/JCI90608

    Article  PubMed  PubMed Central  Google Scholar 

  48. Freeman KA et al (2015) Spinal cord protection via alpha-2 agonist-mediated increase in glial cell-line-derived neurotrophic factor. J Thorac Cardiovasc Surg 149(2):578–84 discussion 584-6.https://doi.org/10.1016/j.jtcvs.2014.10.037

    Article  PubMed  Google Scholar 

  49. Sofroniew MV (2014) Multiple roles for astrocytes as effectors of cytokines and inflammatory mediators. Neuroscientist 20(2):160–172. https://doi.org/10.1177/1073858413504466

    Article  CAS  PubMed  Google Scholar 

  50. Siebert JR, Osterhout DJ (2011) The inhibitory effects of chondroitin sulfate proteoglycans on oligodendrocytes. J Neurochem 119(1):176–188. https://doi.org/10.1111/j.1471-4159.2011.07370.x

    Article  CAS  PubMed  Google Scholar 

  51. Tran AP, Warren PM, Silver J (2018) The biology of regeneration failure and success after spinal cord injury. Physiol Rev 98(2):881–917. https://doi.org/10.1152/physrev.00017.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Liu LR et al (2020) Interaction of microglia and astrocytes in the neurovascular unit. Front Immunol 11:1024. https://doi.org/10.3389/fimmu.2020.01024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hyvarinen T et al (2019) Co-stimulation with IL-1beta and TNF-alpha induces an inflammatory reactive astrocyte phenotype with neurosupportive characteristics in a human pluripotent stem cell model system. Sci Rep 9(1):16944. https://doi.org/10.1038/s41598-019-53414-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lee S, Jha MK, Suk K (2015) Lipocalin-2 in the inflammatory activation of brain astrocytes. Crit Rev Immunol 35(1):77–84. https://doi.org/10.1615/critrevimmunol.2015012127

    Article  PubMed  Google Scholar 

  55. Mondal A et al (2020) Lipocalin 2 induces neuroinflammation and blood-brain barrier dysfunction through liver-brain axis in murine model of nonalcoholic steatohepatitis. J Neuroinflammation 17(1):201. https://doi.org/10.1186/s12974-020-01876-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rashad NM et al (2017) Lipocalin-2 expression and serum levels as early predictors of type 2 diabetes mellitus in obese women. IUBMB Life 69(2):88–97. https://doi.org/10.1002/iub.1594

    Article  CAS  PubMed  Google Scholar 

  57. Shashidharamurthy R et al (2013) Differential role of lipocalin 2 during immune complex-mediated acute and chronic inflammation in mice. Arthritis Rheum 65(4):1064–1073. https://doi.org/10.1002/art.37840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lee S et al (2011) Lipocalin-2 Is a chemokine inducer in the central nervous system: role of chemokine ligand 10 (CXCL10) in lipocalin-2-induced cell migration. J Biol Chem 286(51):43855–43870. https://doi.org/10.1074/jbc.M111.299248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Bachman MA, Miller VL, Weiser JN (2009) Mucosal lipocalin 2 has pro-inflammatory and iron-sequestering effects in response to bacterial enterobactin. PLoS Pathog 5(10):e1000622. https://doi.org/10.1371/journal.ppat.1000622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hamzic N, Blomqvist A, Nilsberth C (2013) Immune-induced expression of lipocalin-2 in brain endothelial cells: relationship with interleukin-6, cyclooxygenase-2 and the febrile response. J Neuroendocrinol 25(3):271–280. https://doi.org/10.1111/jne.12000

    Article  CAS  PubMed  Google Scholar 

  61. Noble LJ et al (2002) Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events. J Neurosci 22(17):7526–7535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Johnson P et al (2000) A role for the cell adhesion molecule CD44 and sulfation in leukocyte-endothelial cell adhesion during an inflammatory response? Biochem Pharmacol 59(5):455–465. https://doi.org/10.1016/s0006-2952(99)00266-x

    Article  CAS  PubMed  Google Scholar 

  63. Lee S et al (2007) A dual role of lipocalin 2 in the apoptosis and deramification of activated microglia. J Immunol 179(5):3231–3241. https://doi.org/10.4049/jimmunol.179.5.3231

    Article  CAS  PubMed  Google Scholar 

  64. Ouali Alami N et al (2018) NF-kappaB activation in astrocytes drives a stage-specific beneficial neuroimmunological response in ALS. EMBO J 37(16). https://doi.org/10.15252/embj.201798697

  65. Abella V et al (2015) The potential of lipocalin-2/NGAL as biomarker for inflammatory and metabolic diseases. Biomarkers 20(8):565–571. https://doi.org/10.3109/1354750X.2015.1123354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gris D, Hamilton EF, Weaver LC (2008) The systemic inflammatory response after spinal cord injury damages lungs and kidneys. Exp Neurol 211(1):259–270. https://doi.org/10.1016/j.expneurol.2008.01.033

    Article  CAS  PubMed  Google Scholar 

  67. Zhang C et al (2018) Gut microbiota dysbiosis in male patients with chronic traumatic complete spinal cord injury. J Transl Med 16(1):353. https://doi.org/10.1186/s12967-018-1735-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Campbell IL (2005) Cytokine-mediated inflammation, tumorigenesis, and disease-associated JAK/STAT/SOCS signaling circuits in the CNS. Brain Res Brain Res Rev 48(2):166–177. https://doi.org/10.1016/j.brainresrev.2004.12.006

    Article  CAS  PubMed  Google Scholar 

  69. Sundman MH et al (2017) The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease. Brain Behav Immun 66:31–44. https://doi.org/10.1016/j.bbi.2017.05.009

    Article  CAS  PubMed  Google Scholar 

  70. Zhang Y et al (2014) Lipocalin 2 expression and secretion is highly regulated by metabolic stress, cytokines, and nutrients in adipocytes. PLoS One 9(5):e96997. https://doi.org/10.1371/journal.pone.0096997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Mukhamedshina YO et al (2017) Systemic and local cytokine profile following spinal cord injury in rats: a multiplex analysis. Front Neurol 8:581. https://doi.org/10.3389/fneur.2017.00581

    Article  PubMed  PubMed Central  Google Scholar 

  72. Molina L et al (2018) Hepatocyte-derived lipocalin 2 is a potential serum biomarker reflecting tumor burden in hepatoblastoma. Am J Pathol 188(8):1895–1909. https://doi.org/10.1016/j.ajpath.2018.05.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Li H et al (2018) Hepatocytes and neutrophils cooperatively suppress bacterial infection by differentially regulating lipocalin-2 and neutrophil extracellular traps. Hepatology 68(4):1604–1620. https://doi.org/10.1002/hep.29919

    Article  CAS  PubMed  Google Scholar 

  74. Jayaraman A et al (2005) Identification of neutrophil gelatinase-associated lipocalin (NGAL) as a discriminatory marker of the hepatocyte-secreted protein response to IL-1beta: a proteomic analysis. Biotechnol Bioeng 91(4):502–515. https://doi.org/10.1002/bit.20535

    Article  CAS  PubMed  Google Scholar 

  75. Cowland JB et al (2003) Neutrophil gelatinase-associated lipocalin is up-regulated in human epithelial cells by IL-1 beta, but not by TNF-alpha. J Immunol 171(12):6630–6639. https://doi.org/10.4049/jimmunol.171.12.6630

    Article  CAS  PubMed  Google Scholar 

  76. Borkham-Kamphorst E, Drews F, Weiskirchen R (2011) Induction of lipocalin-2 expression in acute and chronic experimental liver injury moderated by pro-inflammatory cytokines interleukin-1beta through nuclear factor-kappaB activation. Liver Int 31(5):656–665. https://doi.org/10.1111/j.1478-3231.2011.02495.x

    Article  CAS  PubMed  Google Scholar 

  77. Fleming JC et al (2012) Remote inflammatory response in liver is dependent on the segmental level of spinal cord injury. J Trauma Acute Care Surg 72(5):1194–201 discussion 1202.https://doi.org/10.1097/TA.0b013e31824d68bd

    Article  CAS  PubMed  Google Scholar 

  78. Ferreira AC et al (2015) From the periphery to the brain: Lipocalin-2, a friend or foe? Prog Neurobiol 131:120–136. https://doi.org/10.1016/j.pneurobio.2015.06.005

    Article  CAS  PubMed  Google Scholar 

  79. Jin M et al (2014) Lipocalin-2 deficiency attenuates neuroinflammation and brain injury after transient middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 34(8):1306–1314. https://doi.org/10.1038/jcbfm.2014.83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Borkham-Kamphorst E et al (2013) Protective effects of lipocalin-2 (LCN2) in acute liver injury suggest a novel function in liver homeostasis. Biochim Biophys Acta 1832(5):660–673. https://doi.org/10.1016/j.bbadis.2013.01.014

    Article  CAS  PubMed  Google Scholar 

  81. Asimakopoulou A et al (2014) Lipocalin-2 (LCN2) regulates PLIN5 expression and intracellular lipid droplet formation in the liver. Biochim Biophys Acta 1842(10):1513–1524. https://doi.org/10.1016/j.bbalip.2014.07.017

    Article  CAS  PubMed  Google Scholar 

  82. Wieser V et al (2016) Lipocalin 2 drives neutrophilic inflammation in alcoholic liver disease. J Hepatol 64(4):872–880. https://doi.org/10.1016/j.jhep.2015.11.037

    Article  CAS  PubMed  Google Scholar 

  83. Li T et al (2019) An update on reactive astrocytes in chronic pain. J Neuroinflammation 16(1):140. https://doi.org/10.1186/s12974-019-1524-2

    Article  PubMed  PubMed Central  Google Scholar 

  84. Lee S et al (2009) Lipocalin-2 is an autocrine mediator of reactive astrocytosis. J Neurosci 29(1):234–249. https://doi.org/10.1523/JNEUROSCI.5273-08.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhao N et al (2019) Lipocalin-2 may produce damaging effect after cerebral ischemia by inducing astrocytes classical activation. J Neuroinflammation 16(1):168. https://doi.org/10.1186/s12974-019-1556-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Franklin KBJ, Paxinos G (2019) Paxinos and Franklin’s the mouse brain in stereotaxic coordinates. Academic Press, Cambridge, United States

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Acknowledgements

We thank Uta Zahn, Petra Ibold, and Helga Helten for their technical support. Furthermore, we would like to acknowledge Tak W Mak, (University of Toronto, Canada) for providing Lcn2 knockout animals.

Funding

This project was supported by an internal grant from RWTH Aachen University (A. Zendedel, START- 101/18).

Author information

Authors and Affiliations

  1. Institute of Neuroanatomy, RWTH Aachen University, 52074, Aachen, Germany

    Victoria Behrens, Clara Voelz, Nina Müller, Weiyi Zhao, Natalie Gasterich, Tim Clarner, Cordian Beyer & Adib Zendedel

  2. Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Adib Zendedel

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  1. Victoria Behrens
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  2. Clara Voelz
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  3. Nina Müller
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  4. Weiyi Zhao
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  5. Natalie Gasterich
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  6. Tim Clarner
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  7. Cordian Beyer
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  8. Adib Zendedel
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Contributions

The study was conceptualized and designed by Adib Zendedel, Cordian Beyer, Tim Clarner, and Victoria Behrens. Material preparation, data collection, and analysis were performed by Victoria Behrens, Weiyi Zhao, Clara Voelz, Nina Müller, and Natalie Gasterich. The first draft of the manuscript was written by Victoria Behrens, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Adib Zendedel was responsible for the overall supervision of this study.

Corresponding author

Correspondence to Adib Zendedel.

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Ethics Approval

All animals used in this study were acquired and cared for in accordance with the Federation of European Laboratory Associations (FELASA) recommendations. All experimental procedures and animal care were approved by the Review board for the Care of Animal Subjects of the district government (LANUV, Recklinghausen, North Rhine-Westphalia, Germany) or by the Review Board for the Care of Animal Subjects of the district government (ethic No. 962055, Tehran, Iran) respectively.

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12035_2021_2530_MOESM1_ESM.pptx

Supplementary file1 Supplementary figure 1 Gene expression of astrogliosis markers Gfap (a), vimentin (b) and serpina3n (c) in central region of SC in WT mice (n=6; 72 h n=5). Ratio of Bax/Bcl2 in WT and Lcn2−/−mice in rostral (d) (n=5; Lcn2−/−control, 24 h n=4) and caudal (e) (n=5) region of SC. Data represent means ± SEM. ****p<0.0001, ***p<0.001, **p<0.01, *p<0.05 indicate control vs time point. Wherever a tendency towards a significant difference between WT and Lcn2−/−might be assumed, p values are given (PPTX 150 KB)

12035_2021_2530_MOESM2_ESM.pptx

Supplementary file2 Supplementary figure 2 IHC staining against astrogliosis marker ALDH1L1 of representative sections of the central SC from the groups control (a/d), 7 days WT (b/e) and 7 days Lcn2−/−(c/f) (PPTX 36552 KB)

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Behrens, V., Voelz, C., Müller, N. et al. Lipocalin 2 as a Putative Modulator of Local Inflammatory Processes in the Spinal Cord and Component of Organ Cross talk After Spinal Cord Injury. Mol Neurobiol 58, 5907–5919 (2021). https://doi.org/10.1007/s12035-021-02530-7

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  • DOI: https://doi.org/10.1007/s12035-021-02530-7

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