Воспаление как движущая сила нейродегенерации. Основы персонифицированной диагностики и лечения (обзор литературы)

ЦНС интегрирует эфферентные сигналы соматической и вегетативной частей. При этом ЦНС получает информацию с периферии о воспалении и инфекции. Цитокины, хемокины и ассоциированные с повреждением растворимые медиаторы системного воспаления могут попасть в ЦНС через кровеносную и/или лимфатическую системы, проникнуть непосредственно через околожелудочковые структуры, посредством повышения проницаемости гематоэнцефалического барьера и нарушить здоровое функционирование нейронов и глии, приводя к нарушению гомеостаза мозга. Это может привести к дебюту нейродегенеративного заболевания или ухудшить его клинические симптомы. В данной публикации мы приводим современные международные научные данные, свидетельствующие о связи между нейродегенеративным процессом и иммунными нарушениями. Кроме указания на иммуноопосредованные пути нейродегенерации, приводятся новые потенциально значимые иммуномодулирующие мишени для разработки возможной эффективной терапии данной группы заболеваний.

1. Microglia are polarized to M1 type in highanxiety inbred mice in response to lipopolysaccharide challenge / Z. Li [et al.] // Brain Behav. Immun. - 2014. - Vol.38. - P. 237-248. https://doi.org/10.1016/j.bbi.2014.02.008

2. Long-term cognitive impairment and functional disability among survivors of severe sepsis / T.J. Iwashyna [et al.] // JAMA. - 2010. - Vol. 304. - P. 1787-1794. https://doi.org/10.1001/jama.2010.1553

3. Systemic inflammation and disease progression in Alzheimer disease / C. Holmes [et al.] // Neurology 2009. - Vol. 73. - P. 768-774. https://doi.org/10.1212/WNL.0b013e3181b6bb95

4. Inflammatory processes induce beta-amyloid precursor protein changes in mouse brain / B. Brugg [et al.] // Proc. Natl. Acad. Sci. U.S.A. 1995. - Vol. 92. - P. 3032-3035. https://doi.org/10.1073/pnas.92.7.3032

5. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurode-generative disease / C. Cunningham [et al.] // Biol. Psychiatry 2009. - Vol. 65. - P. 304-312. https://doi.org/10.1016/j.biopsych.2008.07.024

6. Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson’s disease / M.C. Pott Godoy [et al.] // Brain 2008. - Vol.131(Pt 7). - P. 1880-1894. https://doi.org/10.1093/brain/awn101

7. A resilient, low-frequency, small-world human brain functional network with highly connected association cortical hubs / S. Achard [et al.] // J. Neurosci. 2006. - Vol. 26. - P. 63-72. https://doi.org/10.1523/JNEUROSCI.3874-05.2006

8. Bullmore, E. Complex brain networks: graph theoretical analysis of structural and functional systems / E. Bullmore, O. Sporns // Nat. Rev. Neurosci. - 2009. - Vol. 10. - P. 186-198. https://doi.org/10.1038/nrn2575

9. Mapping the human connectome / A.W. Toga [et al.] // Neurosurgery. - 2012. - Vol. 71. - P. 1-5. https://doi.org/10.1227/NEU.0b013e318258e9ff

10. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity / U. Fünfschilling [et al.] // Nature. - 2012. - Vol. 485. - P. 517-521. https://doi.org/10.1038/nature11007

11. Oligodendroglia metabolically support axons and contribute to neurodegeneration / Y. Lee [et al.] // Nature. - 2012. - Vol. 487. - P. 443-448. https://doi.org/10.1038/nature11314

12. Brain lesions in septic shock: a magnetic resonance imaging study / T. Sharshar [et al.] // Intensive Care Med. - 2007. - Vol. 33. - P. 798-806. https://doi.org/10.1007/s00134-007-0598-y

13. The relationship between delirium duration, white matter integrity, and cognitive impairment in intensive care unit survivors as determined by diffusion tensor imaging: the VISIONS prospective cohort magnetic resonance imaging study / A. Morandi [et al.] // Crit. Care Med. - 2012. - Vol. 40 - P. https://doi.org/-2189.doi:10.1097/CCM.0b013e318250acdc

14. Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors / A. Semmler [et al.] // J. Neurol. Neurosurg. Psychiatr. - 2013. - Vol. 84. - P. 62-69. https://doi.org/10.1136/jnnp-2012-302883

15. Sepsis induces brain mitochondrial dysfunction / J.C. d’Avila [et al.] // Crit. Care Med. - 2008. - Vol. 36. - P. 1925-1932. https://doi.org/10.1097/CCM.0b013e3181760c4b

16. Alterations in inflammatory mediators, oxidative stress parameters and energetic metabolism in the brain of sepsis survivor rats / C.M. Comim [et al.] // Neurochem. Res. - 2011. - Vol. 36. - P. 304-311. https://doi.org/10.1007/s11064-010-0320-2

17. Singer, M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure / M. Singer // Virulence. - 2014. - Vol. 5. - P. 66-72. https://doi.org/10.4161/viru.26907

18. Understanding brain dysfunction in sepsis / R. Sonneville [et al.] // Ann. Intensive Care. - 2013. - Vol. 3. - P. 15. https://doi.org/10.1186/2110-5820-3-15

19. Ben Salem, C. The pathogenesis of the antiphospholipid syndrome / C. Ben Salem / N. Engl. J. Med. - 2013. - Vol. 368. - P. 2334. https://doi.org/10.1056/NEJMc1304515

20. Million, M. The pathogenesis of the antiphospholipid syndrome / M. Million, D. Raoult // N. Engl. J. Med. - 2013. - Vol. 368. - P. 2335. https://doi.org/10.1056/NEJMc1300484

21. Cognitive deficits in patients with antiphospholipid syndrome: association with clinical, laboratory, and brain magnetic resonance imaging findings / M.G. Tektonidou [et al.] // Arch. Intern. Med. - 2006. - Vol. 166. - P. 2278-2284. https://doi.org/10.1001/archinte.166.20.2278

22. Cerebral changes in SLE with or without antiphospholipid syndrome. A case-control MRI study / S.I. Valdés-Ferrer [et al.] // J. Neuroimaging. - 2008. - Vol. 18. - P. 62-65. https://doi.org/10.1111/j.1552-6569.2007.00183.x

23. Medzhitov, R. Disease tolerance as a defense strategy / R. Medzhitov, D.S. Schneider, M.P. Soares // Science. - 2012. - Vol. 335. - P. 936-941. https://doi.org/10.1126/science.1214935

24. The resolution of neuroinflammation in neurodegeneration: leukocyte recruitment via the choroid plexus. / M. Schwartz, K. Baruch // EMBO J. - 2014. - Vol. 33. - P. 7-22. https://doi.org/10.1002/embj.201386609

25. Immunogenic and tolerogenic cell death / D.R. Green [et al.] // Nat. Rev. Immunol. - 2009. - Vol. 9. - P. 353-363. https://doi.org/10.1038/nri2545

26. Zitvogel, L. Decoding cell death signals in inflammation and immunity / L. Zitvogel, O. Kepp, G. Kroemer // Cell. - 2010. - Vol. 140. - P. 798-804. https://doi.org/10.1016/j.cell.2010.02.015

27. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases / F. Martinon, J. Tschopp // Cell. - 2004. - Vol. 117. P. 561-574. https://doi.org/10.1016/j.cell.2004.05.004

28. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice / M.T. Heneka [et al.] // Nature. - 2013. - Vol. 493. - P. 674-678. https://doi.org/10.1038/nature11729

29. Caspase signalling controls microglia activation and neurotoxicity / M.A. Burguillos [et al.] // Nature. - 2011. - Vol. 472. - P. 319-324. https://doi.org/10.1038/nature09788

30. Yee, C. The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C. elegans / C. Yee, W. Yang, S. Hekimi // Cell. - 2014. - Vol. 157. - P. 897-909. https://doi.org/10.1016/j.cell.2014.02.055

31. IL-18 associates to microvesicles shed from human macrophages by a LPS/TLR-4 independent mechanism in response to P2X receptor stimulation / S. Gulinelli [et al.] // Eur. J. Immunol. - 2012. - Vol. 42. - P. 3334-3345. https://doi.org/10.1002/eji.201142268

32. Myeloid microvesicles are a marker and therapeutic target for neuroinflammation / C. Verderio [et al.] // Ann. Neurol. - 2012. - Vol. 72. - P. 610-624. https://doi.org/10.1002/ana.23627

33. Microglia convert aggregated amyloid-[beta] into neurotoxic forms through the shedding of microvesicles / P. Joshi [et al.] // Cell Death Differ. - 2014. - Vol. 21. - P. 582-593. https://doi.org/10.1038/cdd.2013.180

34. Rego, A.C. Mitochondrial dysfunction and reactive oxygen species in excitotoxicity and apoptosis: implications for the pathogenesis of neurodegenerative diseases / A.C. Rego, C.R. Oliveira // Neurochem. Res. - 2003. - Vol. 28. - P. 1563-1574. https://doi.org/10.1023/A:1025682611389

35. Green, D.R. The pathophysiology of mitochondrial cell death / D.R. Green, G. Kroemer // Science. - 2004. - Vol. 305. - P. 626-629. https://doi.org/10.1126/science.1099320

36. Greenlund, L. J. Superoxide dismutase delays neuronal apoptosis: a role for reactive oxygen species in programmed neuronal death / L.J. Greenlund, T.L. Deckwerth, E.M.Jr. Johnson // Neuron 1995. - Vol. 14. - P. 303-315. https://doi.org/10.1016/0896-6273(95)90287-2

37. Microglia-derived proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1beta induce Purkinje neuronal apoptosis via their receptors in hypoxic neonatal rat brain / C. Kaur [et al.] // Brain Struct. Funct. - 2014. - Vol. 219. - P. 151-170. https://doi.org/10.1007/s00429-012-0491-5

38. Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL. / O. Aktas [et al.] // Neuron. - 2005. - Vol. 46. - P. 421- 432. https://doi.org/10.1016/j.neuron.2005.03.018

39. Depressive-like behavior induced by tumor necrosis factor-α in mice / M.P. Kaster [et al.] // Neuropharmacology. - 2012. - Vol. 62. - P. 419-426. https://doi.org/10.1016/j.neuropharm.2011.08.018

40. From inflammation to sickness and depression: when the immune system subjugates the brain / R. Dantzer [et al.] // Nat. Rev. Neurosci. - 2008. - Vol. 9. - P. 46-56. https://doi.org/10.1038/nrn2297

41. Block, M.L. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms / M.L. Block, L. Zecca, J.S. Hong // Nat. Rev. Neurosci. - 2007. - Vol. 8. - P. 57-69. https://doi.org/10.1038/nrn2038

42. Deletion of the prostaglandin E2 EP2 receptor reduces oxidative damage and amyloid burden in a model of Alzheimer’s disease / X. Liang [et al.] // J. Neurosci. 2005. - Vol. 25. - P. 10180-10187. https://doi.org/10.1523/JNEUROSCI.3591-05.2005

43. Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models / J.U. Johansson [et al.] // J. Clin. Invest. - 2015. - Vol. 125. - P. 350-364. https://doi.org/10.1172/JCI77487

44. Schmitt, C. Brain leukocyte infiltration initiated by peripheral inflammation or experimental autoimmune encephalomyelitis occurs through pathways connected to the CSF-filled compartments of the forebrain and midbrain / C. Schmitt, N. Strazielle, J.F. Ghersi- Egea // J. Neuroinflammation. - 2012. - Vol. 9. - P. 187. https://doi.org/10.1186/1742-2094-9-187

45. Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases / H. Neumann [et al.] // Trends Neurosci. - 2002. - Vol. 25. - P. 313-319. https://doi.org/10.1016/S0166-2236(02)02154-9

46. Direct impact of T cells on neurons revealed by two-photon microscopy in living brain tissue. / R. Nitsch [et al.] // J. Neurosci. - 2004. - Vol. 24. - P. 2458-2464. https://doi.org/10.1523/JNEUROSCI.4703-03.2004

47. Brain-reactive antibodies and disease / B. Diamond [et al.] // Annu. Rev. Immunol. - 2013. - Vol. 31. - P. 345-385. https://doi.org/10.1146/annurev-immunol-020711-075041

48. Neuromyelitis optica unique area postrema lesions: nausea, vomiting, and pathogenic implications / B.F. Popescu [et al.] // Neurology. - 2011. - Vol. 76. - P. 1229-1237. https://doi.org/10.1212/WNL.0b013e318214332c

49. Evidence for stroke-induced neurogenesis in the human brain / K. Jin [et al.] // Proc. Natl. Acad. Sci. U.S.A. - 2006. - Vol. 103. - P. 13198-13202. https://doi.org/10.1073/pnas.0601164103

50. Lazarov, O. Neurogenesis and Alzheimer’s disease: at the crossroads / O. Lazarov, R.A. Marr // Exp. Neurol. - 2010. - Vol. 223. - P. 267-281. https://doi.org/10.1016/j.expneurol.2009.08.009

51. Sahay, A. Adult hippocampal neurogenesis in depression / A. Sahay, R. Hen // Nat. Neurosci. - 2007. - Vol. 10. - P. 1110-1115. https://doi.org/10.1038/nn1969

52. Donepezil, an acetylcholinesterase inhibitor, enhances adult hippocampal neurogenesis / S. Kotani [et al.] // Chem. Biol. Interact. - 2008. - Vol. 175. - P. 227-230. https://doi.org/10.1016/j.cbi.2008.04.004

53. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants / L. Santarelli [et al.] // Science. - 2003. - Vol. 301. - P. 805-809. https://doi.org/10.1126/science.1083328

54. Monje, M.L. Inflammatory blockade restores adult hippocampal neurogenesis / M.L. Monje, H. Toda, T.D. Palmer // Science. - 2003. - Vol. 302. - P. 1760-1765. https://doi.org/10.1126/science.1088417