Mesenchymal stem cells attenuate acute liver injury by altering ratio between interleukin 17 producing and regulatory natural killer T cells

Autor: Vladislav Volarevic, Miodrag L. Lukic, Neda Milosavljevic, Marina Gazdic, Bojana Simovic Markovic, Valentin Djonov, Jasmin Nurkovic, Aleksandar Arsenijevic, Zana Dolicanin
Rok vydání: 2017
Předmět:
0301 basic medicine
Male
Neutrophils
medicine.medical_treatment
Inflammation
Galactosylceramides
Liver transplantation
CD8-Positive T-Lymphocytes
Mesenchymal Stem Cell Transplantation
T-Lymphocytes
Regulatory
03 medical and health sciences
Mice
0302 clinical medicine
medicine
Animals
Humans
Indoleamine-Pyrrole 2
3
-Dioxygenase
610 Medicine & health
Carbon Tetrachloride
Cells
Cultured
Hepatitis
Transplantation
Hepatology
business.industry
Mesenchymal stem cell
Interleukin-17
Tryptophan
Interleukin
Forkhead Transcription Factors
Mesenchymal Stem Cells
Liver Failure
Acute
medicine.disease
Natural killer T cell
Coculture Techniques
Mice
Inbred C57BL
Interleukin 10
Disease Models
Animal
030104 developmental biology
030220 oncology & carcinogenesis
Immunology
Cancer research
Natural Killer T-Cells
Th17 Cells
Surgery
Interleukin 17
medicine.symptom
business
Zdroj: Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 23(8)
ISSN: 1527-6473
Popis: Mesenchymal stem cells (MSCs) are, due to immunomodulatory characteristics, considered as novel agents in the treatment of immune-mediated acute liver failure. Although it is known that MSCs can regulate activation of T lymphocytes, their capacity to modulate function of neutrophils and natural killer T (NKT) cells, major interleukin (IL) 17-producing cells in acute liver injury, is still unknown. By using 2 well-established murine models of neutrophil and NKT cell-mediated acute liver failure (induced by carbon tetrachloride and α-galactoceramide), we investigated molecular and cellular mechanisms involved in MSC-mediated modulation of IL17 signaling during acute liver injury. Single intravenous injection of MSCs attenuate acute hepatitis and hepatotoxicity of NKT cells in a paracrine, indoleamine 2,3-dioxygenase (IDO)-dependent manner. Decreased levels of inflammatory IL17 and increased levels of immunosuppressive IL10 in serum, reduced number of interleukin 17-producing natural killer T (NKT17) cells, and increased presence of forkhead box P3 + IL10-producing natural killer T regulatory cells (NKTregs) were noticed in the injured livers of MSC-treated mice. MSCs did not significantly alter the total number of IL17-producing neutrophils, CD4+, and CD8 + T lymphocytes in the injured livers. Injection of mesenchymal stem cell-conditioned medium (MSC-CM) resulted with an increased NKTreg/NKT17 ratio in the liver and attenuated hepatitis in vivo and significantly reduced hepatotoxicity of NKT cells in vitro. This phenomenon was completely abrogated in the presence of IDO inhibitor, 1-methyltryptophan. In conclusion, the capacity of MSCs to alter NKT17/NKTreg ratio and suppress hepatotoxicity of NKT cells in an IDO-dependent manner may be used as a new therapeutic approach in IL17-driven liver inflammation. Liver Transplantation 23 1040-1050 2017 AASLD.
Databáze: OpenAIRE
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