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Impaired monocyte activation in schizophrenia: ultrastructural abnormalities and increased IL-1β production

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Abstract

Monocyte activation is consistently reported in patients with schizophrenia (SZ). We aimed to study the ultrastructure of monocytes and monocyte production of IL-1β in drug-free patients with SZ and controls. Monocytes from young (18–30 y.o.) healthy and SZ men in relapse were studied. Electron microscopy and morphometry were applied to estimate areas of monocytes, volume density (Vv), areas, and number of organelles. The production IL-1β by monocytes was estimated by the ELISA method. Group differences were examined using ANCOVA. Pearson’s correlation coefficients were used to examine the effects of possible confounding variables. Correlation analyses were applied to detect the relationships between the parameters of monocytes measured and between the parameters measured and the IL-1β production. Area of nucleolus, Vv and area of mitochondria and lysosomes, and the number of lysosomes were significantly increased in patients as compared to controls. Area of mitochondria was correlated significantly with Vv and area of lysosomes, and the number of lysosomes was significantly correlated with area of monocyte and Vv of vacuoles only in the control group. The production of IL-1β by monocytes was higher in patients than in controls (p = 0.01) and was correlated with Vv of lysosomes (r = 0.68, p = 0.04) and area of lysosomes (r = 0.78, p = 0.013). The data provide new evidence for over activation of monocytes in SZ and disturbed metabolic relationships between lysosomes, mitochondria, and vacuoles.

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References

  1. Beumer W, Gibney SM, Drexhage RC, Pont-Lezica L, Doorduin J, Klein HC (2012) The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. J Leukoc Biol 92:959–975. doi:10.1189/jlb.0212100

    Article  CAS  PubMed  Google Scholar 

  2. Bergink V, Gibney SM, Drexhage HA (2014) Autoimmunity, inflammation, and psychosis: a search for peripheral markers. Biol Psychiatry 75:324–331. doi:10.1016/j.biopsych.2013.09.037

    Article  CAS  PubMed  Google Scholar 

  3. Takahashi Y, Yu Z, Sakai M, Tomita H (2016) Linking activation of microglia and peripheral monocytic cells to the pathophysiology of psychiatric disorders. Front Cell Neurosci 10:144. doi:10.3389/fncel.2016.00144.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Rothermundt M, Arolt V, Weitzsch C, Eckhoff D, Kirchner H (1998) Immunological dysfunction in schizophrenia: a systematic approach. NeuropsychoBiology 37:186–193. doi:10.1159/000026501

    Article  CAS  PubMed  Google Scholar 

  5. Theodoropoulou S, Spanakos G, Baxevanis CN, Economou M, Gritzapis AD, Papamichail MP et al (2001) Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients. Schizophr Res 47:13–25. doi:10.1016/s0920-9964(00)00007

    Article  CAS  PubMed  Google Scholar 

  6. Drexhage RC, van der Heul-Nieuwenhuijsen L, Padmos RC, van Beveren N, Cohen D, Versnel MA et al (2010) Inflammatory gene expression in monocytes of patients with schizophrenia: overlap and difference with bipolar disorder. A study in naturalistically treated patients. Int J Neuropsychopharmacol 13:1369–1381. doi:10.1017/S1461145710000799

    Article  CAS  PubMed  Google Scholar 

  7. Nikkilä HV, Müller K, Ahokas A, Miettinen K, Rimón R, Andersson LC (1999) Accumulation of macrophages in the CSF of schizophrenic patients during acute psychotic episodes. Am J Psychiatry 156:1725–1729

    PubMed  Google Scholar 

  8. Müller N, Myint AM, Schwarz MJ (2012) Inflammation in schizophrenia. Adv Protein Chem Struct Biol 88:49–68. doi:10.1016/B978-0-12-398314-5.00003-9. Review.

    Article  PubMed  Google Scholar 

  9. Müller N, Wagner JK, Krause D, Weidinger E, Wildenauer A, Obermeier M, Dehning S, Gruber R, Schwarz MJ (2012) Impaired monocyte activation in schizophrenia. Psychiatry Res 198:341–346. doi:10.1016/j.psychres.2011.12.049

    Article  PubMed  Google Scholar 

  10. Kowalski J, Blad P, Kucia K, Madej A, Herman ZS (2001) Neuroleptics normalize increased release of interleukin-1 beta and tumor necrosis factor-alpha from monocytes in schizophrenia. Schizophr Res 50:169–175

    Article  CAS  PubMed  Google Scholar 

  11. Androsova LV, Kaleda VG, Barkhatova AN, Tsutsul’kovskaia MIa, Koliaskina GI (2007) The effect of treatment on interleukin-1beta production in patients with first episode of juvenile psychosis. Zh Nevrol Psikhiatr Im S S Korsakova 107:50–54 (Article in Russian).

    CAS  PubMed  Google Scholar 

  12. Kolyaskina GI, Sekirina TP, Androsova LV, Kushner SG, Vasil’eva EF, Burbaeva OA et al (2007) [The influence of atypical neuroleptics on the immune system of patients with schizophrenia]. Vestn Ross Akad Med Nauk 3:14–19 (ArticleRussian)

    Google Scholar 

  13. Eder C (2009) Mechanisms of interleukin-1beta release. Immunobiology 214:543–553. doi:10.1016/j.imbio.2008.11.007

    Article  CAS  PubMed  Google Scholar 

  14. Andrei C, Margiocco P, Poggi A, Lotti LV, Torrisi MR, Rubartelli A (2004) Phospholipases C and A2 control lysosome-mediated IL-1 beta secretion: Implications for inflammatory processes. Proc Natl Acad Sci USA 101:9745–9750. doi:10.1073/pnas.0308558101

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Uranova N, Bonartsev P, Brusov O, Morozova M, Rachmanova V, Orlovskaya D (2007) The ultrastructure of lymphocytes in schizophrenia. World J Biol Psychiatry 8:30–37. doi:10.1080/15622970600960207

    Article  PubMed  Google Scholar 

  16. Roitt I, Brostoff J, Male D (1998) Immunology. Mosby International Ltd

  17. Gundersen HJ, Bagger P, Bendtsen TF, Evans SM, Korbo L, Marcussen N et al (1988) The new stereological tools: disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis. APMIS 96(10):857–881

    Article  CAS  PubMed  Google Scholar 

  18. Russell J, Zomerdijk J (2005) RNA-polymerase-I-directed rDNA transcription, life and works. Trends Biochem Sci 30(2):87–96. doi:10.1016/j.tibs.2004.12.008

    Article  CAS  PubMed  Google Scholar 

  19. Schedle A, Willheim M, Zeitelberger A, Gessl A, Frauendorfer K, Schöfer C et al (1992) Nucleolar morphology and rDNA in situ hybridisation in monocytes. Cell Tissue Res 269(3):473–480

    Article  CAS  PubMed  Google Scholar 

  20. Krause DL, Wagner JK, Wildenauer A, Matz J, Weidinger E, Riedel M, Obermeier M, Gruber R, Schwarz M, Müller N (2012) Intracellular monocytic cytokine levels in schizophrenia show an alteration of IL-6. Eur Arch Psychiatry Clin Neurosci 262:393–401. doi:10.1007/s00406-012-0290-2

    Article  PubMed  Google Scholar 

  21. Gibney SM, Drexhage HA (2013) Evidence for a dysregulated immune system in the etiology of psychiatric disorders. J Neuroimmune Pharmacol 8:900–920. doi:10.1007/s11481-013-9462-8

    Article  PubMed  Google Scholar 

  22. Müller N, Riedel M, Ackenheil M, Schwarz MJ (2000) Cellular and humoral immune system in schizophrenia: a conceptual re-evaluation. World J Biol Psychiatry 1(4):173–179

    Article  PubMed  Google Scholar 

  23. Schrader M, Godinho LF, Costello JL, Islinger M (2015) The different facets of organelle interplay-an overview of organelle interactions. Front Cell Dev Biol 3:56. doi:10.3389/fcell.2015.00056

    Article  PubMed Central  PubMed  Google Scholar 

  24. Netea MG, Simon A, van de Veerdonk F, Kullberg B-J, Van der Meer JWM, Joosten LAB (2010) IL-1β processing in host defense: beyond the inflammasomes. PLoS Pathog 6:e1000661. doi:10.1371/journal.ppat.1000661 (PMCID: PMC2829053).

    Article  PubMed Central  PubMed  Google Scholar 

  25. Yolken RH, Torrey EF (2008) Are some cases of psychosis caused by microbial agents? A review of the evidence. Mol Psychiatry 13:470–479. doi:10.1038/mp.2008.5

    Article  CAS  PubMed  Google Scholar 

  26. Torrey EF, Bartko JJ, Yolken RH (2012) Toxoplasma gondii and other risk factors for schizophrenia: an update. Schizophr Bull 38:642–647. doi:10.1093/schbul/sbs043

    Article  PubMed Central  PubMed  Google Scholar 

  27. Severance EG, Gressitt KL, Stallings CR, Origoni AE, Khushalani S, Leweke FM et al (2013) Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia. Schizophr Res 148:130–137. doi:10.1016/j.schres.2013.05.018

    Article  PubMed Central  PubMed  Google Scholar 

  28. Leonard BE, Schwarz M, Myint AM (2012) The metabolic syndrome in schizophrenia: is inflammation a contributing cause? J Psychopharmacol 26:33–41. doi:10.1177/0269881111431622

    Article  PubMed  Google Scholar 

  29. Steiner J, Bernstein HG, Schiltz K, Müller UJ, Westphal S, Drexhage HA et al (2014) Immune system and glucose metabolism interaction in schizophrenia: a chicken-egg dilemma. Prog Neuropsychopharmacol Biol Psychiatry 48:287–294. doi:10.1016/j.pnpbp.2012.09.016

    Article  CAS  PubMed  Google Scholar 

  30. Drexhage RC, Hoogenboezem TA, Cohen D, Versnel MA, Nolen WA, van Beveren NJ et al (2011) An activated set point of T-cell and monocyte inflammatory networks in recent-onset schizophrenia patients involves both pro- and anti-inflammatory forces. Int J Neuropsychopharmacol 14:746–755. doi:10.1017/S1461145710001653

    Article  CAS  PubMed  Google Scholar 

  31. Weigelt K, Carvalho LA, Drexhage RC, Wijkhuijs A, de Wit H, van Beveren NJ et al (2011) TREM-1 and DAP12 expression in monocytes of patients with severe psychiatric disorders. EGR3, ATF3 and PU.1 as important transcription factors. Brain Behav Immun 25:1162–1169. doi:10.1016/j.bbi.2011.03.006

    Article  CAS  PubMed  Google Scholar 

  32. Raimundo N, Fernández-Mosquera L, Yambire KF, Diogo CV (2016) Mechanisms of communication between mitochondria and lysosomes. Int J Biochem Cell Biol 79:345–349. doi:10.1016/j.biocel.2016.08.020

    Article  CAS  PubMed  Google Scholar 

  33. Baixauli F, Acín-Pérez R, Villarroya-Beltrí C, Mazzeo C, Nuñez-Andrade N, Gabandé-Rodriguez E et al (2015) Mitochondrial respiration controls lysosomal function during inflammatory T Cell responses. Cell Metab 22(3):485–498. doi:10.1016/j.cmet.2015.07.020

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Schmitz G, Leuthäuser-Jaschinski K, Orsó E (2009) Are circulating monocytes as microglia orthologues appropriate biomarker targets for neuronal diseases? Cent Nerv Syst Agents Med Chem 9:307–330

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported from the Federal Budget. The authors would like to thank technician O.V. Litvinova for her expert technical assistance.

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Correspondence to Natalya A. Uranova.

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Uranova, N.A., Bonartsev, P.D., Androsova, L.V. et al. Impaired monocyte activation in schizophrenia: ultrastructural abnormalities and increased IL-1β production. Eur Arch Psychiatry Clin Neurosci 267, 417–426 (2017). https://doi.org/10.1007/s00406-017-0782-1

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  • DOI: https://doi.org/10.1007/s00406-017-0782-1

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