Plasma soluble L-selectin in medicated patients with schizophrenia and healthy controls

Satyajit Mohite, Fang Yang, Pooja A Amin, Giovana Zunta-Soares, Gabriela D Colpo, Laura Stertz, Ajaykumar N Sharma, Gabriel R Fries, Consuelo Walss-Bass, Jair C Soares, Olaoluwa O Okusaga, Satyajit Mohite, Fang Yang, Pooja A Amin, Giovana Zunta-Soares, Gabriela D Colpo, Laura Stertz, Ajaykumar N Sharma, Gabriel R Fries, Consuelo Walss-Bass, Jair C Soares, Olaoluwa O Okusaga

Abstract

Immune dysfunction has been implicated in the pathophysiology of schizophrenia. Leukocyte migration to the site of inflammation is a fundamental step of immune response which involves P-, E-, and L-selectins. Elevated selectin levels have been reported in un-medicated first-episode patients with schizophrenia but not in medicated patients with multi-episode schizophrenia. We measured fasting plasma soluble P-, E-, and L-selectin in 39 medicated patients with multi-episode schizophrenia and 19 healthy controls. In patients, psychotic symptom severity and cognitive function were assessed with the Positive and Negative Syndrome Scale (PANSS) and the NIH Toolbox Cognitive Test Battery respectively. C-reactive protein (CRP) and Body Mass Index (BMI) were measured in patients and controls. Comparison of selectin levels between patients and controls was done with t-tests and linear regression. Pearson correlation coefficients between plasma selectins and PANSS and cognitive measures were calculated. Geometric mean plasma soluble L-selectin level was lower in patients compared to controls from unadjusted (606.7 ± 1.2 ng/ml vs. 937.7 ± 1.15 ng/ml, p < 0.001) and adjusted analyses (β = 0.59; CI 0.41 to 0.88, p = 0.011). There was a trend towards higher plasma soluble P-selectin in patients compared to controls (90.4 ± 1.2ng/ml vs. 71.8 ± 1.2ng/ml, p = 0.059) in the unadjusted analysis. There was no association between the selectins and psychotic symptoms or cognitive function in the patients. In addition, the selectins were not significantly associated with CRP or BMI. The limitations of this study include small sample size and unavailability of information on medications and blood cell counts. The potential utility of soluble L-selectin as a biomarker of antipsychotic exposure in patients with schizophrenia and the concomitant change in immune response with the use of antipsychotics should be further evaluated.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1
Plasma soluble L-selectin (A), P-selectin (B) and E-selectin (C) levels in patients with schizophrenia and healthy controls. Error bars are representing 95% confidence intervals, and the little circle stands for the mean of the log-transformed value of each selectin. Plasma soluble P-, E- and L-selectin concentration were log transformed to normalize the data. Geometric means reported in the text were calculated by exponentiating mean log-transformed P-, E- and L-selectin for adjusted and unadjusted comparisons of patients and controls.

References

    1. Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS injury and disease. Br J Pharmacol. 2006;147(S1):S232–S40.
    1. Raghavendra V, Tanga FY, DeLeo JA. Complete Freunds adjuvant‐induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS. Eur J Neurosci. 2004;20(2):467–73. 10.1111/j.1460-9568.2004.03514.x
    1. Patterson P. Brain–Immune Connections in Autism, Schizophrenia, and Depression. Infectious Behavior. Cambridge, MA: MIT Press; 2011.
    1. Riazi K, Galic MA, Kuzmiski JB, Ho W, Sharkey KA, Pittman QJ. Microglial activation and TNFα production mediate altered CNS excitability following peripheral inflammation. Proceedings of the National Academy of Sciences. 2008;105(44):17151–6.
    1. Kirkpatrick B, Miller BJ. Inflammation and schizophrenia. Schizophr Bull. 2013;39(6):1174–9. 10.1093/schbul/sbt141
    1. van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, Caspers E, et al. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11 C] PK11195 positron emission tomography study. Biol Psychiatry. 2008;64(9):820–2. 10.1016/j.biopsych.2008.04.025
    1. Hirose M, Matsumura R, Sato K, Murai T, Kawashima H. Binding of L-selectin to its vascular and extravascular ligands is differentially regulated by pH. Biochem Biophys Res Commun. 2011;414(2):437–42. 10.1016/j.bbrc.2011.09.123
    1. Marki A, Esko JD, Pries AR, Ley K. Role of the endothelial surface layer in neutrophil recruitment. J Leukoc Biol. 2015;98(4):503–15. 10.1189/jlb.3MR0115-011R
    1. Parish CR. The role of heparan sulphate in inflammation. Nature Reviews Immunology. 2006;6(9):633–43. 10.1038/nri1918
    1. D’Mello C, Swain MG. Liver–brain interactions in inflammatory liver diseases: implications for fatigue and mood disorders. Brain Behav Immun. 2014;35:9–20. 10.1016/j.bbi.2013.10.009
    1. Engelhardt B, Ransohoff RM. Capture, crawl, cross: the T cell code to breach the blood–brain barriers. Trends Immunol. 2012;33(12):579–89. 10.1016/j.it.2012.07.004
    1. McEver RP. Selectins: initiators of leukocyte adhesion and signaling at the vascular wall. Cardiovasc Res. 2015:cvv154.
    1. Cella G, Marchetti M, Vignoli A, Randi M, Saggiorato G, Pasetto L, et al. Blood oxidative status and selectins plasma levels in healthy donors receiving granulocyte-colony stimulating factor. Leukemia. 2006;20(8):1430–4. 10.1038/sj.leu.2404271
    1. Impellizzeri D, Cuzzocrea S. Targeting selectins for the treatment of inflammatory diseases. Expert Opin Ther Targets. 2014;18(1):55–67. 10.1517/14728222.2013.841140
    1. Jackson LA, Drevets DA, Dong Z-M, Greenfield RA, Murphy JW. Levels of L-selectin (CD62L) on human leukocytes in disseminated cryptococcosis with and without associated HIV-1 infection. J Infect Dis. 2005;191(8):1361–7. 10.1086/428949
    1. Ferri LE, Pascual J, Seely AJ, Chaudhury P, Christou NV. Soluble L-selectin attenuates tumor necrosis factor-α-mediated leukocyte adherence and vascular permeability: A protective role for elevated soluble L-selectin in sepsis*. Critical care medicine. 2002;30(8):1842–7.
    1. Shimada Y, Sato S, Hasegawa M, Tedder TF, Takehara K. Elevated serum L-selectin levels and abnormal regulation of L-selectin expression on leukocytes in atopic dermatitis: soluble L-selectin levels indicate disease severity. J Allergy Clin Immunol. 1999;104(1):163–8.
    1. MacKinnon J, Knott R, Forrester J. Altered L-selectin expression in lymphocytes and increased adhesion to endothelium in patients with diabetic retinopathy. Br J Ophthalmol. 2004;88(9):1137–41. 10.1136/bjo.2003.040329
    1. Choudhary D, Hegde P, Voznesensky O, Choudhary S, Kopsiaftis S, Claffey KP, et al., editors. Increased expression of L-selectin (CD62L) in high-grade urothelial carcinoma: A potential marker for metastatic disease. Urologic Oncology: Seminars and Original Investigations; 2015: Elsevier.
    1. Iwata Y, Tsuchiya KJ, Mikawa S, Nakamura K, Takai Y, Suda S, et al. Serum levels of P-selectin in men with high-functioning autism. Br J Psychiatry. 2008;193(4):338–9. 10.1192/bjp.bp.107.043497
    1. Masopust J, Malý R, Andrýs C, Vališ M, Bažant J, Hosák L. Markers of thrombogenesis are activated in unmedicated patients with acute psychosis: a matched case control study. BMC Psychiatry. 2011;11(1):1.
    1. Iwata Y, Suzuki K, Nakamura K, Matsuzaki H, Sekine Y, Tsuchiya KJ, et al. Increased levels of serum soluble L-selectin in unmedicated patients with schizophrenia. Schizophr Res. 2007;89(1):154–60.
    1. Matsumoto A, Ohta N, Goto Y, Kashiwa Y, Yamamoto S, Fujino Y. Haloperidol Suppresses Murine Dendritic Cell Maturation and Priming of the T Helper 1–Type Immune Response. Anesth Analg. 2015;120(4):895–902. 10.1213/ANE.0000000000000606
    1. Noto C, Ota VK, Gouvea ES, Rizzo LB, Spindola LM, Honda PH, et al. Effects of risperidone on cytokine profile in drug-naive first-episode psychosis. Int J Neuropsychopharmacol. 2015:pyu042.
    1. Kay SR, Flszbein A, Opfer LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261.
    1. Casaletto KB, Umlauf A, Beaumont J, Gershon R, Slotkin J, Akshoomoff N, et al. Demographically corrected normative standards for the English version of the NIH Toolbox Cognition Battery. J Int Neuropsychol Soc. 2015;21(05):378–91.
    1. Armstrong RA. When to use the Bonferroni correction. Ophthalmic Physiol Opt. 2014;34(5):502–8. 10.1111/opo.12131
    1. Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70(7):663–71. 10.1016/j.biopsych.2011.04.013
    1. Lai C-Y, Scarr E, Udawela M, Everall I, Chen WJ, Dean B. Biomarkers in schizophrenia: A focus on blood based diagnostics and theranostics. World journal of psychiatry. 2016;6(1):102 10.5498/wjp.v6.i1.102
    1. Rothermundt M, Ponath G, Glaser T, Hetzel G, Arolt V. S100B serum levels and long-term improvement of negative symptoms in patients with schizophrenia. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology. 2004;29(5):1004–11.
    1. Librizzi L, Mazzetti S, Pastori C, Frigerio S, Salmaggi A, Buccellati C, et al. Activation of cerebral endothelium is required for mononuclear cell recruitment in a novel in vitro model of brain inflammation. Neuroscience. 2006;137(4):1211–9. 10.1016/j.neuroscience.2005.10.041
    1. Bergink V, Gibney SM, Drexhage HA. Autoimmunity, inflammation, and psychosis: a search for peripheral markers. Biol Psychiatry. 2014;75(4):324–31. 10.1016/j.biopsych.2013.09.037
    1. Bloomfield PS, Selvaraj S, Veronese M, Rizzo G, Bertoldo A, Owen DR, et al. Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [11C] PBR28 PET Brain Imaging Study. Am J Psychiatry. 2015.

Source: PubMed

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