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Interplay Between Inflammatory-immune and Interleukin-17 Signalings Plays a Cardinal Role on Liver Ischemia-reperfusion Injury—Synergic Effect of IL-17Ab, Tacrolimus and ADMSCs on Rescuing the Liver Damage

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Abstract

Background

This study tested the hypothesis that inflammatory and interleukin (IL)-17 signalings were essential for acute liver ischemia (1 h)-reperfusion (72 h) injury (IRI) that was effectively ameliorated by adipose-derived mesenchymal stem cells (ADMSCs) and tacrolimus.

Methods

Adult-male SD rats (n = 50) were equally categorized into groups 1 (sham-operated-control), 2 (IRI), 3 [IRI + IL-17-monoclonic antibody (Ab)], 4 (IRI + tacrolimus), 5 (IRI + ADMSCs) and 6 (IRI + tacrolimus-ADMSCs) and liver was harvested at 72 h.

Results

The main findings included: (1) circulatory levels: inflammatory cells, immune cells, and proinflammatory cytokines as well as liver-damage enzyme at the time point of 72 h were highest in group 2, lowest in group 1 and significantly lower in group 6 than in groups 3 to 5 (all p < 0.0001), but they did not differ among these three latter groups; (2) histopathology: the liver injury score, fibrosis, inflammatory and immune cell infiltration in liver immunity displayed an identical pattern of inflammatory cells among the groups (all p < 0.0001); and (3) protein levels: upstream and downstream inflammatory signalings, oxidative-stress, apoptotic and mitochondrial-damaged biomarkers exhibited an identical pattern of inflammatory cells among the groups (all p < 0.0001).

Conclusion

Our results obtained from circulatory, pathology and molecular-cellular levels delineated that acute IRI was an intricate syndrome that elicited complex upstream and downstream inflammatory and immune signalings to damage liver parenchyma that greatly suppressed by combined tacrolimus and ADMSCs therapy.

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Data Availability

The data contained within the paper are available from the authors upon reasonable request.

Abbreviations

IR:

ischemia and reperfusion

IL:

interleukin

ADMSCs:

adipose-derived mesenchymal stem cells

MPO:

Myeloperoxidase

CD:

cluster of differentiation

TLR4:

Toll-like receptor 4

TNF-α:

tumor nuclear factor-α

HMGB1:

high-mobility group box 1

TLR4:

Toll-like receptor 4

TLR2:

Toll-like receptor 2

MYD88:

myeloid differentiation primary response 88

NF-κB:

nuclear factor-κB

NOX-1:

NADPH oxidase 1

NOX-2:

NADPH oxidase 2

PARP:

Poly ADP-ribose Polymerase

γ-H2AX:

γ-Histone H2AX

WBC:

white blood cell

ALT:

alanine aminotransferase

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Acknowledgements

Not applicable.

Funding

This study was supported by a project grant from Chang Gung Memorial Hospital, Chang Gung University [CMRPG8L0791]. The funding body played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Author information

Authors and Affiliations

  1. Department of Radiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan

    Sheung-Fat Ko

  2. Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan

    Yi-Chen Li, Pei-Hsun Sung, Yi-Ling Chen & Hon-Kan Yip

  3. Department of Nursing, Asia University, Taichung, 41354, Taiwan

    Pei-Lin Shao

  4. Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung, 80424, Taiwan

    John Y. Chiang

  5. Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan

    John Y. Chiang

  6. Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan

    Pei-Hsun Sung, Yi-Ling Chen & Hon-Kan Yip

  7. Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan

    Pei-Hsun Sung & Hon-Kan Yip

  8. Taoyuan, Taiwan

    Hon-Kan Yip

  9. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan

    Hon-Kan Yip

Authors
  1. Sheung-Fat Ko
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  2. Yi-Chen Li
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  3. Pei-Lin Shao
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  4. John Y. Chiang
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  5. Pei-Hsun Sung
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  6. Yi-Ling Chen
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  7. Hon-Kan Yip
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Contributions

SFK, and HKY supervised the study and wrote the manuscript. SFK and YLC applied the grant project. SFK, YLC and PLS performed the experiments. YCL, JYC, PHS and YLC collected and analyzed data. YCL reviewed and revised the manuscript. All authors contributed to the article and approved the submitted version.

Corresponding authors

Correspondence to Yi-Ling Chen or Hon-Kan Yip.

Ethics declarations

Ethics Approval and Consent to Participate

All animal procedures were approved by the Institute of Animal Care and Use Committee at Kaohsiung Chang Gung Memorial Hospital (Affidavit of Approval of Animal Use Protocol No. 2020092301) on 10/26/2020 and performed in accordance with the Guide for the Care and Use of Laboratory Animals. The approved title was “Interleukin-17 signaling pathway plays a crucial role on participating in acute liver ischemia-reperfusion injury—impact of immune-pharmaco-modulation of ADMSCs and tacrolimus.“

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Not applicable.

Competing interests

The authors declare that they have no conflict of interest.

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Yi-Ling Chen and Hon-Kan Yip contributed equally to this work.

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Ko, SF., Li, YC., Shao, PL. et al. Interplay Between Inflammatory-immune and Interleukin-17 Signalings Plays a Cardinal Role on Liver Ischemia-reperfusion Injury—Synergic Effect of IL-17Ab, Tacrolimus and ADMSCs on Rescuing the Liver Damage. Stem Cell Rev and Rep 19, 2852–2868 (2023). https://doi.org/10.1007/s12015-023-10611-4

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