Cigarette smoke attenuates mesenchymal stem cell-based suppression of immune cell-driven acute liver failure

Dragica Pavlovic; Dragana Miloradovic; Milica Dimitrijevic Stojanovic; Carl Randall Harrell; Riccardo Polosa; Sonja Rust; Giovanni Li Volti; Massimo Caruso; Vladimir Jakovljevic; Valentin Djonov; Vladislav Volarevic

doi:10.1016/j.toxlet.2023.08.006

Cigarette smoke attenuates mesenchymal stem cell-based suppression of immune cell-driven acute liver failure

Toxicol Lett. 2023 Aug 15:385:12-20. doi: 10.1016/j.toxlet.2023.08.006. Epub 2023 Aug 10.

Affiliations

¹ Department of Genetics, Center for harm reduction of biological and chemical hazards, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia.
² Department of Pathology, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia.
³ Regenerative Processing Plant, LLC, 34176 US Highway 19 N Palm Harbor, Palm Harbor, FL 34684, USA.
⁴ Center of Excellence for the Acceleration of Harm Reduction (CoEHAR), University of Catania, Via S. Sofia, 89, 95123 Catania, Italy; Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia, 89, 95123 Catania, Italy.
⁵ ECLAT Srl, University of Catania, Via S. Sofia, 89, 95123 Catania, Italy.
⁶ Center of Excellence for the Acceleration of Harm Reduction (CoEHAR), University of Catania, Via S. Sofia, 89, 95123 Catania, Italy; Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia, 89, 95123 Catania, Italy.
⁷ Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia.
⁸ Institute of Anatomy, University of Bern, Baltzerstrasse 2, 3012 Bern, Switzerland.
⁹ Department of Genetics, Center for harm reduction of biological and chemical hazards, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia; Departments of Genetics and Department of Microbiology and Immunology, Center for harm reduction of biological and chemical hazards, Faculty of Medical Sciences University of Kragujevac, Serbia. Electronic address: drvolarevic@yahoo.com.

PMID: 37572970
DOI: 10.1016/j.toxlet.2023.08.006

Abstract

Detrimental effects of smoking on mesenchymal stem cell (MSC)-dependent immunosuppression and hepatoprotection are unknown. Herewith, by using α-galactosylceramide (α-GalCer)-induced liver injury, a well-established murine model of fulminant hepatitis, we examined molecular mechanisms which were responsible for negative effects of cigarette smoke on MSC-dependent immunomodulation. MSC which were grown in cigarette smoke-exposed medium (MSC^WS-CM) obtained pro-inflammatory phenotype, were not able to optimally produce hepatoprotective and immunosuppressive cytokines (TGF-β, HGF, IL-10, NO, KYN), and secreted significantly higher amounts of inflammatory cytokines (IFN-γ, TNF-α, IL-17, IL-6) than MSC that were cultured in standard medium never exposed to cigarette smoke (MSC^CM). In contrast to MSC^CM, which efficiently attenuated α-GalCer-induced hepatitis, MSC^WS-CM were not able to prevent hepatocyte injury and liver inflammation. MSC^WS-CM had reduced capacity for the suppression of liver-infiltrated inflammatory macrophages, dendritic cells (DCs) and lymphocytes. Although significantly lower number of IL-12-producing macrophages and DCs, TNF-α, IFN-γ or IL-17-producing CD4 + and CD8 +T lymphocytes, NK and NKT cells were noticed in the livers of α-GalCer+MSC^CM-treated mice compared to α-GalCer+saline-treated animals, this phenomenon was not observed in α-GalCer-injured mice that received MSC^WS-CM. MSC^WS-CM could not induce expansion of anti-inflammatory IL-10-producing FoxP3 +CD4 + and CD8 + T regulatory cells and were not able to create immunosuppressive microenvironment in the liver as MSC^CM. Similarly as it was observed in mice, MSC^WS-CM were not able to optimally inhibit production of inflammatory and hepatototoxic cytokines in activated human Th1/Th17 and NKT1/NKT17 cells, confirming the hypothesis that cigarette smoke significantly attenuates therapeutic potential of MSC in cell-based immunotherapy of inflammatory liver diseases.

Keywords: Acute hepatitis; Cigarette smoke; Hepatoprotection; Immunosuppression; Mesenchymal stem cells; Therapy.

MeSH terms

Animals
Cigarette Smoking*
Cytokines
Hepatitis*
Humans
Interleukin-10
Interleukin-17
Liver Failure, Acute* / chemically induced
Mesenchymal Stem Cells*
Mice
Smoking
Tumor Necrosis Factor-alpha

Substances

alpha-galactosylceramide
Interleukin-10
Interleukin-17
Tumor Necrosis Factor-alpha
Cytokines