Abstract
Background
Systemic inflammation has been implicated in the pathogenesis of moyamoya disease (MMD). Sortilin is a critical regulator of proinflammatory cytokine secretion in several cell types. The present study investigated the association between circulating sortilin and proinflammatory cytokine levels and the occurrence of MMD.
Methods
Forty-two MMD cases and 76 age- and sex-matched controls were enrolled in this study between January 2018 and June 2019 at the Affiliated Hospital of Jining Medical University. The demographic and clinical characteristics were evaluated, and the circulating serum and cerebrospinal fluid (CSF) levels of sortilin, sortilin-related receptor with A-type repeats (SorLA), and proinflammatory cytokines including C-reactive protein (CRP), interleukin (IL)-6, interferon (IFN)-γ were measured by enzyme-linked immunosorbent assay. Linear regression and correlation analyses were used to estimate the associations between sortilin, SorLA, and proinflammatory cytokine levels.
Results
MMD patients had higher serum levels of sortilin (P = 0.012), CRP (P = 0.013), IL-6 (P = 0.004), and IFN-γ (P = 0.033) than healthy controls. In MMD patients, serum sortilin was positively correlated with serum proinflammatory cytokines (CRP: r = 0.459, P = 0.0022; IL-6: r = 0.445, P = 0.0032; and IFN-γ: r = 0.448, P = 0.0029) and CSF sortilin (r = 0.440, P = 0.0035); the latter was positively correlated with CSF levels of CRP (r = 0.542, P = 0.0002), IL-6 (r = 0.440, P = 0.0036), and IFN-γ (r = 0.443, P = 0.0033).
Conclusions
Elevated sortilin level is associated MMD onset and may be a clinically useful biomarker along with proinflammatory cytokine levels.
Similar content being viewed by others
References
Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7:41–53. https://doi.org/10.1038/nrn1824
Aragon MJ et al (2017) Serum-borne bioactivity caused by pulmonary multiwalled carbon nanotubes induces neuroinflammation via blood-brain barrier impairment. Proc Natl Acad Sci U S A 114:E1968–E1976. https://doi.org/10.1073/pnas.1616070114
Calkin AC, Tontonoz P (2010) Genome-wide association studies identify new targets in cardiovascular disease. Sci Transl Med 2:48ps46. https://doi.org/10.1126/scitranslmed.3001557
Carlo AS et al (2013) The pro-neurotrophin receptor sortilin is a major neuronal apolipoprotein E receptor for catabolism of amyloid-beta peptide in the brain. J Neurosci 33:358–370. https://doi.org/10.1523/jneurosci.2425-12.2013
Dai D et al (2014) Serum miRNA signature in Moyamoya disease. PLoS One 9:e102382. https://doi.org/10.1371/journal.pone.0102382
Fujimura M et al (2018) Increased serum production of soluble CD163 and CXCL5 in patients with moyamoya disease: Involvement of intrinsic immune reaction in its pathogenesis. Brain Res 1679:39–44. https://doi.org/10.1016/j.brainres.2017.11.013
Fukui M (1997) Guidelines for the diagnosis and treatment of spontaneous occlusion of the circle of Willis (‘moyamoya’ disease). Research committee on spontaneous occlusion of the circle of Willis (Moyamoya Disease) of the Ministry of Health and Welfare, Japan. Clin Neurol Neurosurg 99(Suppl 2):S238–S240
Hu F et al (2010) Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron 68:654–667. https://doi.org/10.1016/j.neuron.2010.09.034
Jacobsen L et al (1996) Molecular characterization of a novel human hybrid-type receptor that binds the alpha2-macroglobulin receptor-associated protein. J Biol Chem 271:31379–31383. https://doi.org/10.1074/jbc.271.49.31379
Kang HS et al (2010) Plasma matrix metalloproteinases, cytokines and angiogenic factors in moyamoya disease. J Neurol Neurosurg Psychiatry 81:673–678. https://doi.org/10.1136/jnnp.2009.191817
Kjolby M et al (2010) Sort1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export. Cell Metab 12:213–223. https://doi.org/10.1016/j.cmet.2010.08.006
Kleinloog R, Regli L, Rinkel GJ, Klijn CJ (2012) Regional differences in incidence and patient characteristics of moyamoya disease: a systematic review. J Neurol Neurosurg Psychiatry 83:531–536. https://doi.org/10.1136/jnnp-2011-301387
Larsen JV, Petersen CM (2017) SorLA in Interleukin-6 Signaling and Turnover. Mol Cell Biol 37. https://doi.org/10.1128/mcb.00641-16
Ma W et al (2019) Serum uric acid and triglycerides in Chinese patients with newly diagnosed moyamoya disease: A cross-sectional study. Biomed Res Int 2019:9792412. https://doi.org/10.1155/2019/9792412
Mikami T, Suzuki H, Komatsu K, Mikuni N (2019) Influence of inflammatory disease on the pathophysiology of moyamoya disease and quasi-moyamoya disease. Neurol Med Chir (Tokyo). https://doi.org/10.2176/nmc.ra.2019-0059
Mortensen MB et al (2014) Targeting sortilin in immune cells reduces proinflammatory cytokines and atherosclerosis. J Clin Invest 124:5317–5322. https://doi.org/10.1172/jci76002
Mufson EJ, Wuu J, Counts SE, Nykjaer A (2010) Preservation of cortical sortilin protein levels in MCI and Alzheimer’s disease. Neurosci Lett 471:129–133. https://doi.org/10.1016/j.neulet.2010.01.023
Narducci A, Yasuyuki K, Onken J, Blecharz K, Vajkoczy P (2019) In vivo demonstration of blood-brain barrier impairment in Moyamoya disease. Acta Neurochir (Wien) 161:371–378. https://doi.org/10.1007/s00701-019-03811-w
Nielsen MS, Jacobsen C, Olivecrona G, Gliemann J, Petersen CM (1999) Sortilin/neurotensin receptor-3 binds and mediates degradation of lipoprotein lipase. J Biol Chem 274:8832–8836. https://doi.org/10.1074/jbc.274.13.8832
Nilsson SK, Christensen S, Raarup MK, Ryan RO, Nielsen MS, Olivecrona G (2008) Endocytosis of apolipoprotein A-V by members of the low density lipoprotein receptor and the VPS10p domain receptor families. J Biol Chem 283:25920–25927. https://doi.org/10.1074/jbc.M802721200
Nykjaer A, Willnow TE (2012) Sortilin: a receptor to regulate neuronal viability and function. Trends Neurosci 35:261–270. https://doi.org/10.1016/j.tins.2012.01.003
Ohkubo K et al (2015) Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells. Sci Rep 5:13191. https://doi.org/10.1038/srep13191
Patel KM et al (2015) Macrophage sortilin promotes LDL uptake, foam cell formation, and atherosclerosis. Circ Res 116:789–796. https://doi.org/10.1161/circresaha.116.305811
Patel AB, Tsilioni I, Leeman SE (2016) Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism. Proc Natl Acad Sci U S A 113:E7049–E7058. https://doi.org/10.1073/pnas.1604992113
Petersen CM et al (1997) Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography. J Biol Chem 272:3599–3605. https://doi.org/10.1074/jbc.272.6.3599
Rogaeva E et al (2007) The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 39:168–177. https://doi.org/10.1038/ng1943
Rosenberg GA (2012) Neurological diseases in relation to the blood-brain barrier. J Cereb Blood Flow Metab 32:1139–1151. https://doi.org/10.1038/jcbfm.2011.197
Scott RM, Smith ER (2009) Moyamoya disease and moyamoya syndrome. N Engl J Med 360:1226–1237. https://doi.org/10.1056/NEJMra0804622
Soriano SG, Cowan DB, Proctor MR, Scott RM (2002) Levels of soluble adhesion molecules are elevated in the cerebrospinal fluid of children with moyamoya syndrome. Neurosurgery 50:544–549. https://doi.org/10.1097/00006123-200203000-00022
Sugihara M et al (2019) The AAA + ATPase/ubiquitin ligase mysterin stabilizes cytoplasmic lipid droplets. J Cell Biol 218:949–960. https://doi.org/10.1083/jcb.201712120
Sullivan SE et al (2019) Candidate-based screening via gene modulation in human neurons and astrocytes implicates FERMT2 in Abeta and TAU proteostasis. Hum Mol Genet 28:718–735. https://doi.org/10.1093/hmg/ddy376
Sung HY et al (2018) Aberrant promoter hypomethylation of sortilin 1: A moyamoya disease biomarker. J Stroke 20:350–361. https://doi.org/10.5853/jos.2018.00962
Suzuki J, Takaku A (1969) Cerebrovascular “moyamoya” disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol 20:288–299. https://doi.org/10.1001/archneur.1969.00480090076012
Wang J et al (2019) Blood-brain barrier disruption and inflammation reaction in mice after chronic exposure to Microcystin-LR. Sci Total Environ 689:662–678. https://doi.org/10.1016/j.scitotenv.2019.06.387
Yabe-Wada T et al (2016) TLR signals posttranscriptionally regulate the cytokine trafficking mediator sortilin. Sci Rep 6:26566. https://doi.org/10.1038/srep26566
Acknowledgements
The study was supported by the National Natural Science Foundation of China (81602846) and Taishan Scholar Project of Shandong Province (tsqn201812159).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors have no conflicts of interest to declare.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Supplementary Fig. 1
Correlations between CSF levels of sortilin and CRP, IL-6, and IFN-γ in MMD patients with low sortilin CSF level (≤ 400 ng/L) (A, B, C) and high sortilin CSF level (> 400 ng/L) (D, E, F). ***P < 0.001. CSF: cerebrospinal fluid. (DOCX 142 KB)
Rights and permissions
About this article
Cite this article
Han, W., Qiao, Y., Zhang, H. et al. Circulating sortilin levels are associated with inflammation in patients with moyamoya disease. Metab Brain Dis 36, 103–109 (2021). https://doi.org/10.1007/s11011-020-00616-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-020-00616-0