THP1-BASED CYBRID CELLS WITH VARIOUS MTDNA MUTATIONS DIFFER BY THE ABILITY TO FORM INFLAMMATORY RESPONSE
- Authors: Zhuravlev A.D.1,2, Verkhova S.S.1,2, Kubekina M.V.3
-
Affiliations:
- Institute of General Pathology and Pathophysiology
- Avtsyn Research Institute of Human Morphology of FSBSI "Petrovsky National Research Centre of Surgery"
- Institute of Gene Biology, Russian Academy of Sciences,
- Section: Joint Immunology Forum 2024
- URL: https://rusimmun.ru/jour/article/view/16781
- DOI: https://doi.org/10.46235/1028-7221-16781-TCC
- ID: 16781
Cite item
Full Text
Abstract
Most age-related human diseases are accompanied by chronic inflammation. Modern research is aimed at studying the principles of the formation of the immune response. The reasons why the local inflammatory reaction cannot be resolved and becomes a sluggish chronic form are still unknown. Immune cells secrete cytokines in response to pathogens. To avoid cell death as a result of high concentrations of cytokines and resulting tissue damage, there is a mechanism of innate immune tolerance. Innate immune tolerance involves a decrease in the secretion of proinflammatory cytokines in response to repeated exposure to a pathogen. It is known that mitochondria play an important role in the formation of the immune response. Consequently, impaired mitochondrial function can lead to impaired immune response. To control the quality of mitochondria in the cell, there is a mechanism - mitophagy. Previously, we have created cybrid lines based on the monocytic cell line THP-1. Cybrids were obtained by fusion of THP-1 cells (mitochondria were removed) with platelets from patients. Each of the cybrid lines had the THP-1 nuclear genome and an individual patient's mitochondrial genome. In our study, we decided to study the ability of cells carrying different mitochondrial genomes to generate a pro-inflammatory response, as well as to form tolerance in the future. For this purpose, we chose a model of ecdotoxin tolerance. Thus, we stimulated the cybrid lines twice with lipopolysaccharide and then assessed the secretion of the cytokines TNF-α, IL-1β, IL-6, IL-8, and CCL2 using ELISA. The cybrids demonstrated two levels of pro-inflammatory response: high and low. Moreover, cybrids with a high pro-inflammatory response either did or did not develop tolerance upon repeated stimulation. In our study, cells that differed from each other only in mitochondrial genome demonstrated three types of reactions upon the induction of immune tolerance to LPS. Future studies will improve our understanding of the mechanisms of mitochondrial involvement in pathological processes. It is likely that studies of deficient mitophagy and the role of certain mtDNA mutations in its development will yield promising results.
About the authors
Alexandr Dmitrievich Dmitrievich Zhuravlev
Institute of General Pathology and Pathophysiology; Avtsyn Research Institute of Human Morphology of FSBSI "Petrovsky National Research Centre of Surgery"
Email: Zhuravel17@yandex.ru
ORCID iD: 0000-0002-0451-2594
SPIN-code: 7309-2433
Scopus Author ID: 57391753500
Postgraduate Student, Junior Researcher Fellow, Laboratory of Angiopathology
Russian Federation, 125315, Russia, Moscow, st. Baltiyskaya, 8; 117418, Russia, Moscow, st. Tsyurupy, 3Svetlana Sergeevna Verkhova
Institute of General Pathology and Pathophysiology; Avtsyn Research Institute of Human Morphology of FSBSI "Petrovsky National Research Centre of Surgery"
Email: verxova.svetlana@gmail.com
Postgraduate Student, Senior Laboratory Assistant. Laboratory of Cellular and Molecular Pathology of the Cardiovascular System
Russian Federation, 125315, Russia, Moscow, st. Baltiyskaya, 8; 117418, Russia, Moscow, st. Tsyurupy, 3Marina Vladislavovna Kubekina
Institute of Gene Biology, Russian Academy of Sciences,
Author for correspondence.
Email: marykumy@gmail.com
ORCID iD: 0000-0002-8834-1111
SPIN-code: 2156-2430
Scopus Author ID: 56957229000
PhD, Research Fellow , Core Facility Center and Center for Precision Genome Editing and Genetic Technologies for Biomedicine
Russian Federation, 119334, Russia, Moscow, st. Vavilova, 34/5References
- Dela Cruz C.S., Kang M.J. Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases. Mitochondrion, 2018, Vol. 41, pp. 37-44. doi: 10.1016/j.mito.2017.12.001
- Dominguez-Andres J., Netea M.G. Long-term reprogramming of the innate immune system. J Leukoc Biol, 2019, Vol. 105, no. 2, pp. 329-338. doi: 10.1002/JLB.MR0318-104R
- Fang E.F., Hou Y., Palikaras K., Adriaanse B.A., Kerr J.S., Yang B., Lautrup S., Hasan-Olive M.M., Caponio D., Dan X., Rocktäschel P., Croteau D.L., Akbari M., Greig N.H., Fladby T., Nilsen H., Cader M.Z., Mattson M.P., Tavernarakis N., Bohr V.A. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci, 2019, Vol. 22 no. 3, pp. 401-412. doi: 10.1038/s41593-018-0332-9
- Karan K.R., Trumpff C., Cross M., Engelstad K.M., Marsland A.L., McGuire P.J., Hirano M., Picard M. Leukocyte cytokine responses in adult patients with mitochondrial DNA defects. J Mol Med (Berl), 2022, Vol. 100, no. 6, pp. 963-971. doi: 10.1007/s00109-022-02206-2
- Marian A.J. Mitochondrial genetics and human systemic hypertension. Circ Res, 2011, Vol. 108, no. 7, pp. 784-6. doi: 10.1161/CIRCRESAHA.111.242768
- Sazonova M.A., Sinyov V.V., Ryzhkova A.I., Sazonova M.D., Khasanova Z.B., Shkurat T.P., Karagodin V.P., Orekhov A.N., Sobenin I.A. Creation of Cybrid Cultures Containing mtDNA Mutations m.12315G>A and m.1555G>A, Associated with Atherosclerosis. Biomolecules, 2019, Vol. 9, no. 9, pp. 499. doi: 10.3390/biom9090499
- Seeley J.J., Ghosh S. Molecular mechanisms of innate memory and tolerance to LPS. J Leukoc Biol, 2017, Vol. 101, no. 1, pp. 107-119. doi: 10.1189/jlb.3MR0316-118RR
- Sliter D.A., Martinez J., Hao L., Chen X., Sun N., Fischer T.D., Burman J.L., Li Y., Zhang Z., Narendra D.P., Cai H., Borsche M., Klein C., Youle R.J.. Parkin and PINK1 mitigate STING-induced inflammation. Nature, 2018,Vol. 561, no. 7722, pp. 258-262. doi: 10.1038/s41586-018-0448-9
- Vaamonde-García C., López-Armada M.J. Role of mitochondrial dysfunction on rheumatic diseases. Biochem Pharmacol, 2019, Vol. 165, pp. 181-195. doi: 10.1016/j.bcp.2019.03.008
- Vacchelli E., Galluzzi L., Eggermont A., Galon J., Tartour E., Zitvogel L., Kroemer G. Trial Watch: Immunostimulatory cytokines. Oncoimmunology, 2012, Vol. 1, no. 4, pp. 493-506. doi: 10.4161/onci.20459
- Xu Y., Shen J., Ran Z. Emerging views of mitophagy in immunity and autoimmune diseases. Autophagy, 2020, Vol. 16, no. 1, pp. 3-17. doi: 10.1080/15548627.2019.1603547