TEffects of stress on hippocampal MMP2 and MMP9 activity following Brucella melitensis exposure in rats

Document Type : Original Research

Author
Damghan University
Abstract
Introduction: Matrix Metalloproteinases (MMPs) are inflammatory mediators involved in bacterial infection and other pathological conditions. Inflammation can damage all parts of the brain, particularly sensitive areas such as the hippocampus. Chronic stress can make the brain more susceptible to infection and inflammation. This study aimed to investigate the effects of stress on the activity of MMP2 and MMP9 in the hippocampus of male Wistar rats following the administration of Brucella Melitensis (BM) vaccine.

Methods: The non-stressed group received a Brucella Melitensis vaccine strain via intracebroventicular (i.c.v) and intraperitoneal (i.p) routes. The animals were subjected to heterogeneous sequential stress for nine days and/or received the same volume of Brucella Melitensis vaccine (BMV). The activity of MMP-2 and MMP-9 was measured by Gelatin Zymography.

Results: The results showed that stress increased the activity of MMP9 in both the control group and the BMV, i.p., injected animals. However, stress did not affect the activity of MMP2 in either the control or the BM, i.p., inoculated conditions. Stress also increased the activity of MMP9 following i.c.v. injection of BM, without a concomitant change in the activity of MMP2 in the hippocampus.

Conclusion: The study suggests that vaccination in stressed conditions could activate MMPs, which are essential players in inflammatory processes, in brain of immunized animals. Since the Brucella melitensis vaccine is used for the prophylaxis of brucellosis in small ruminants, these findings have important implications for understanding the effects of stress on the immune response to vaccination and inflammation in the brain.

Keywords

Subjects


References:
1. Reuben PM, Cheung HS. Regulation of matrix metalloproteinase (MMP) gene expression by protein kinases. Front Biosci. 2006;11:1199-215.
2. Cui N, Hu M, Khalil RA. Biochemical and Biological Attributes of Matrix Metalloproteinases. Prog Mol Biol Transl Sci. 2017;147:1-73.
3. Fingleton B. Matrix metalloproteinases as regulators of inflammatory processes. Biochim Biophys Acta Mol Cell Res. 2017;1864(11 Pt A):2036-42.
4. Hijova E. Matrix metalloproteinases: their biological functions and clinical implications. Bratisl Lek Listy. 2005;106(3):127-32.
5. Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. 2007;8(3):221-33.
6. Mysliwiec AG, Ornstein DL. Matrix metalloproteinases in colorectal cancer. Clin Colorectal Cancer. 2002;1(4):208-19.
7. Bassiouni W, Ali MAM, Schulz R. Multifunctional intracellular matrix metalloproteinases: implications in disease. FEBS J. 2021;288(24):7162-82.
8. Apte SS, Parks WC. Metalloproteinases: A parade of functions in matrix biology and an outlook for the future. Matrix Biol. 2015;44-46:1-6.
9. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92(8):827-39.
10. Lam C, Jamerson M, Cabral G, Carlesso AM, Marciano-Cabral F. Expression of matrix metalloproteinases in Naegleria fowleri and their role in invasion of the central nervous system. Microbiology. 2017;163(10):1436-44.
11. Park SH, Kim JH, Lee DH, Kang JW, Song HH, Oh SR, et al. Luteolin 8-C-beta-fucopyranoside inhibits invasion and suppresses TPA-induced MMP-9 and IL-8 via ERK/AP-1 and ERK/NF-kappaB signaling in MCF-7 breast cancer cells. Biochimie. 2013;95(11):2082-90.
12. Piek A, de Boer RA, Sillje HH. The fibrosis-cell death axis in heart failure. Heart Fail Rev. 2016;21(2):199-211.
13. Herrera I, Cisneros J, Maldonado M, Ramirez R, Ortiz-Quintero B, Anso E, et al. Matrix metalloproteinase (MMP)-1 induces lung alveolar epithelial cell migration and proliferation, protects from apoptosis, and represses mitochondrial oxygen consumption. J Biol Chem. 2013;288(36):25964-75.
14. Du SQ, Wang XR, Xiao LY, Tu JF, Zhu W, He T, et al. Molecular Mechanisms of Vascular Dementia: What Can Be Learned from Animal Models of Chronic Cerebral Hypoperfusion? Mol Neurobiol. 2017;54(5):3670-82.
15. Brkic M, Balusu S, Libert C, Vandenbroucke RE. Friends or Foes: Matrix Metalloproteinases and Their Multifaceted Roles in Neurodegenerative Diseases. Mediators Inflamm. 2015;2015:620581.
16. Bijata M, Baczynska E, Muller FE, Bijata K, Masternak J, Krzystyniak A, et al. Activation of the 5-HT7 receptor and MMP-9 signaling module in the hippocampal CA1 region is necessary for the development of depressive-like behavior. Cell Rep. 2022;38(11):110532.
17. Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS injury and disease. Br J Pharmacol. 2006;147 Suppl 1:S232-40.
18. Perry VH, Teeling J. Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol. 2013;35(5):601-12.
19. Kumar RG, Boles JA, Wagner AK. Chronic Inflammation After Severe Traumatic Brain Injury: Characterization and Associations With Outcome at 6 and 12 Months Postinjury. J Head Trauma Rehabil. 2015;30(6):369-81.
20. Vezzani A, Aronica E, Mazarati A, Pittman QJ. Epilepsy and brain inflammation. Exp Neurol. 2013;244:11-21.
21. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132(Pt 5):1175-89.
22. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16(1):22-34.
23. Klein RS, Garber C, Howard N. Infectious immunity in the central nervous system and brain function. Nat Immunol. 2017;18(2):132-41.
24. Hanke ML, Kielian T. Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci (Lond). 2011;121(9):367-87.
25. Baker RG, Hayden MS, Ghosh S. NF-kappaB, inflammation, and metabolic disease. Cell Metab. 2011;13(1):11-22.
26. McCoy MK, Tansey MG. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation. 2008;5:45.
27. Garcia-Bueno B, Caso JR, Leza JC. Stress as a neuroinflammatory condition in brain: damaging and protective mechanisms. Neurosci Biobehav Rev. 2008;32(6):1136-51.
28. Xanthos DN, Sandkuhler J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci. 2014;15(1):43-53.
29. Johnston JN, Greenwald MS, Henter ID, Kraus C, Mkrtchian A, Clark NG, et al. Inflammation, stress and depression: An exploration of ketamine's therapeutic profile. Drug Discov Today. 2023;28(4):103518.
30. Tait AS, Butts CL, Sternberg EM. The role of glucocorticoids and progestins in inflammatory, autoimmune, and infectious disease. J Leukoc Biol. 2008;84(4):924-31.
31. Burnley B, H PJ. Corticotropin-releasing hormone improves survival in pneumococcal pneumonia by reducing pulmonary inflammation. Physiol Rep. 2017;5(1).
32. Boitard C, Cavaroc A, Sauvant J, Aubert A, Castanon N, Laye S, et al. Impairment of hippocampal-dependent memory induced by juvenile high-fat diet intake is associated with enhanced hippocampal inflammation in rats. Brain Behav Immun. 2014;40:9-17.
33. Chesnokova V, Pechnick RN, Wawrowsky K. Chronic peripheral inflammation, hippocampal neurogenesis, and behavior. Brain Behav Immun. 2016;58:1-8.
34. Prieto GA, Cotman CW. Cytokines and cytokine networks target neurons to modulate long-term potentiation. Cytokine Growth Factor Rev. 2017;34:27-33.
35. Dubey D, McRae PA, Rankin-Gee EK, Baranov E, Wandrey L, Rogers S, et al. Increased metalloproteinase activity in the hippocampus following status epilepticus. Epilepsy Res. 2017;132:50-8.
36. Bronisz E, Kurkowska-Jastrzebska I. Matrix Metalloproteinase 9 in Epilepsy: The Role of Neuroinflammation in Seizure Development. Mediators Inflamm. 2016;2016:7369020.
37. Car H, Michaluk P. Baclofen influences acquisition and MMP-2, MMP-9 levels in the hippocampus of rats after hypoxia. Pharmacol Rep. 2012;64(3):536-45.
38. Espinosa-Oliva AM, de Pablos RM, Villaran RF, Arguelles S, Venero JL, Machado A, et al. Stress is critical for LPS-induced activation of microglia and damage in the rat hippocampus. Neurobiol Aging. 2011;32(1):85-102.
39. Szklarczyk A, Lapinska J, Rylski M, McKay RD, Kaczmarek L. Matrix metalloproteinase-9 undergoes expression and activation during dendritic remodeling in adult hippocampus. J Neurosci. 2002;22(3):920-30.
40. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265-75.
41. Zhang JW, Gottschall PE. Zymographic measurement of gelatinase activity in brain tissue after detergent extraction and affinity-support purification. J Neurosci Methods. 1997;76(1):15-20.
42. Pearson-Leary J, Eacret D, Chen R, Takano H, Nicholas B, Bhatnagar S. Inflammation and vascular remodeling in the ventral hippocampus contributes to vulnerability to stress. Transl Psychiatry. 2017;7(6):e1160.
43. White AG, Elias E, Orozco A, Robinson SA, Manners MT. Chronic Stress-Induced Neuroinflammation: Relevance of Rodent Models to Human Disease. Int J Mol Sci. 2024;25(10).
44. Dal-Pizzol F, Rojas HA, dos Santos EM, Vuolo F, Constantino L, Feier G, et al. Matrix metalloproteinase-2 and metalloproteinase-9 activities are associated with blood-brain barrier dysfunction in an animal model of severe sepsis. Mol Neurobiol. 2013;48(1):62-70.
45. Pilat D, Paumier JM, Garcia-Gonzalez L, Louis L, Stephan D, Manrique C, et al. MT5-MMP promotes neuroinflammation, neuronal excitability and Abeta production in primary neuron/astrocyte cultures from the 5xFAD mouse model of Alzheimer's disease. J Neuroinflammation. 2022;19(1):65.
46. Solarz A, Majcher-Maslanka I, Kryst J, Chocyk A. Early-life stress affects peripheral, blood-brain barrier, and brain responses to immune challenge in juvenile and adult rats. Brain Behav Immun. 2023;108:1-15.
47. Rosenberg GA. Extracellular matrix inflammation in vascular cognitive impairment and dementia. Clin Sci (Lond). 2017;131(6):425-37.
48. Woo CH, Lim JH, Kim JH. Lipopolysaccharide induces matrix metalloproteinase-9 expression via a mitochondrial reactive oxygen species-p38 kinase-activator protein-1 pathway in Raw 264.7 cells. J Immunol. 2004;173(11):6973-80.
49. Cardoso FL, Kittel A, Veszelka S, Palmela I, Toth A, Brites D, et al. Exposure to lipopolysaccharide and/or unconjugated bilirubin impair the integrity and function of brain microvascular endothelial cells. PLoS One. 2012;7(5):e35919.