Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance

Lei Zhang, Matthew DeBerge, Jiaojin Wang, Anil Dangi, Xiaomin Zhang, Samantha Schroth, Zheng Jenny Zhang, Edward Benjamin Thorp*, Xunrong Luo

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Recipient infusion of donor apoptotic cells is an emerging strategy for inducing robust transplantation tolerance. Daily clearance of billions of self-apoptotic cells relies on homeostatic engagement of phagocytic receptors, in particular, receptors of the tyrosine kinase family TAM (Tyro3, Axl, and MerTK), to maintain self-tolerance. However, an outstanding question is if allogeneic apoptotic cells trigger the same receptor system for inducing allogeneic tolerance. Here, we employed allogeneic apoptotic splenocytes and discovered that the efferocytic receptor MerTK on recipient phagocytes is a critical mediator for transplantation tolerance induced by this strategy. Our findings indicate that the tolerogenic properties of allogeneic apoptotic splenocytes require MerTK transmission of intracellular signaling to suppress the production of inflammatory cytokine interferon α (IFN-α). We further demonstrate that MerTK is crucial for subsequent expansion of myeloid-derived suppressor cells and for promoting their immunomodulatory function, including maintaining graft-infiltrating CD4 + CD25 + Foxp3 + regulatory T cells. Consequently, recipient MerTK deficiency resulted in failure of tolerance by donor apoptotic cells, and this failure could be effectively rescued by IFN-α receptor blockade. These findings underscore the importance of the efferocytic receptor MerTK in mediating transplantation tolerance by donor apoptotic cells and implicate MerTK agonism as a promising target for promoting transplantation tolerance.

Original languageEnglish (US)
Pages (from-to)674-685
Number of pages12
JournalAmerican Journal of Transplantation
Volume19
Issue number3
DOIs
StatePublished - Mar 1 2019

Fingerprint

Receptor Protein-Tyrosine Kinases
Transplantation Tolerance
Transplants
Interferon Receptors
Self Tolerance
Regulatory T-Lymphocytes
Phagocytes
Interferons
Cytokines

Keywords

  • basic (laboratory) research/science
  • cell death: apoptosis
  • cytokines/cytokine receptors
  • immune regulation
  • immunobiology
  • immunosuppression/immune modulation
  • macrophage/monocyte biology: activation
  • organ transplantation in general
  • tolerance: mechanisms
  • translational research/science

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

Cite this

Zhang, Lei ; DeBerge, Matthew ; Wang, Jiaojin ; Dangi, Anil ; Zhang, Xiaomin ; Schroth, Samantha ; Zhang, Zheng Jenny ; Thorp, Edward Benjamin ; Luo, Xunrong. / Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance. In: American Journal of Transplantation. 2019 ; Vol. 19, No. 3. pp. 674-685.
@article{cb6ef09caea540cfaecae239d277c912,
title = "Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance",
abstract = "Recipient infusion of donor apoptotic cells is an emerging strategy for inducing robust transplantation tolerance. Daily clearance of billions of self-apoptotic cells relies on homeostatic engagement of phagocytic receptors, in particular, receptors of the tyrosine kinase family TAM (Tyro3, Axl, and MerTK), to maintain self-tolerance. However, an outstanding question is if allogeneic apoptotic cells trigger the same receptor system for inducing allogeneic tolerance. Here, we employed allogeneic apoptotic splenocytes and discovered that the efferocytic receptor MerTK on recipient phagocytes is a critical mediator for transplantation tolerance induced by this strategy. Our findings indicate that the tolerogenic properties of allogeneic apoptotic splenocytes require MerTK transmission of intracellular signaling to suppress the production of inflammatory cytokine interferon α (IFN-α). We further demonstrate that MerTK is crucial for subsequent expansion of myeloid-derived suppressor cells and for promoting their immunomodulatory function, including maintaining graft-infiltrating CD4 + CD25 + Foxp3 + regulatory T cells. Consequently, recipient MerTK deficiency resulted in failure of tolerance by donor apoptotic cells, and this failure could be effectively rescued by IFN-α receptor blockade. These findings underscore the importance of the efferocytic receptor MerTK in mediating transplantation tolerance by donor apoptotic cells and implicate MerTK agonism as a promising target for promoting transplantation tolerance.",
keywords = "basic (laboratory) research/science, cell death: apoptosis, cytokines/cytokine receptors, immune regulation, immunobiology, immunosuppression/immune modulation, macrophage/monocyte biology: activation, organ transplantation in general, tolerance: mechanisms, translational research/science",
author = "Lei Zhang and Matthew DeBerge and Jiaojin Wang and Anil Dangi and Xiaomin Zhang and Samantha Schroth and Zhang, {Zheng Jenny} and Thorp, {Edward Benjamin} and Xunrong Luo",
year = "2019",
month = "3",
day = "1",
doi = "10.1111/ajt.15087",
language = "English (US)",
volume = "19",
pages = "674--685",
journal = "American Journal of Transplantation",
issn = "1600-6135",
publisher = "Wiley-Blackwell",
number = "3",

}

Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance. / Zhang, Lei; DeBerge, Matthew; Wang, Jiaojin; Dangi, Anil; Zhang, Xiaomin; Schroth, Samantha; Zhang, Zheng Jenny; Thorp, Edward Benjamin; Luo, Xunrong.

In: American Journal of Transplantation, Vol. 19, No. 3, 01.03.2019, p. 674-685.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance

AU - Zhang, Lei

AU - DeBerge, Matthew

AU - Wang, Jiaojin

AU - Dangi, Anil

AU - Zhang, Xiaomin

AU - Schroth, Samantha

AU - Zhang, Zheng Jenny

AU - Thorp, Edward Benjamin

AU - Luo, Xunrong

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Recipient infusion of donor apoptotic cells is an emerging strategy for inducing robust transplantation tolerance. Daily clearance of billions of self-apoptotic cells relies on homeostatic engagement of phagocytic receptors, in particular, receptors of the tyrosine kinase family TAM (Tyro3, Axl, and MerTK), to maintain self-tolerance. However, an outstanding question is if allogeneic apoptotic cells trigger the same receptor system for inducing allogeneic tolerance. Here, we employed allogeneic apoptotic splenocytes and discovered that the efferocytic receptor MerTK on recipient phagocytes is a critical mediator for transplantation tolerance induced by this strategy. Our findings indicate that the tolerogenic properties of allogeneic apoptotic splenocytes require MerTK transmission of intracellular signaling to suppress the production of inflammatory cytokine interferon α (IFN-α). We further demonstrate that MerTK is crucial for subsequent expansion of myeloid-derived suppressor cells and for promoting their immunomodulatory function, including maintaining graft-infiltrating CD4 + CD25 + Foxp3 + regulatory T cells. Consequently, recipient MerTK deficiency resulted in failure of tolerance by donor apoptotic cells, and this failure could be effectively rescued by IFN-α receptor blockade. These findings underscore the importance of the efferocytic receptor MerTK in mediating transplantation tolerance by donor apoptotic cells and implicate MerTK agonism as a promising target for promoting transplantation tolerance.

AB - Recipient infusion of donor apoptotic cells is an emerging strategy for inducing robust transplantation tolerance. Daily clearance of billions of self-apoptotic cells relies on homeostatic engagement of phagocytic receptors, in particular, receptors of the tyrosine kinase family TAM (Tyro3, Axl, and MerTK), to maintain self-tolerance. However, an outstanding question is if allogeneic apoptotic cells trigger the same receptor system for inducing allogeneic tolerance. Here, we employed allogeneic apoptotic splenocytes and discovered that the efferocytic receptor MerTK on recipient phagocytes is a critical mediator for transplantation tolerance induced by this strategy. Our findings indicate that the tolerogenic properties of allogeneic apoptotic splenocytes require MerTK transmission of intracellular signaling to suppress the production of inflammatory cytokine interferon α (IFN-α). We further demonstrate that MerTK is crucial for subsequent expansion of myeloid-derived suppressor cells and for promoting their immunomodulatory function, including maintaining graft-infiltrating CD4 + CD25 + Foxp3 + regulatory T cells. Consequently, recipient MerTK deficiency resulted in failure of tolerance by donor apoptotic cells, and this failure could be effectively rescued by IFN-α receptor blockade. These findings underscore the importance of the efferocytic receptor MerTK in mediating transplantation tolerance by donor apoptotic cells and implicate MerTK agonism as a promising target for promoting transplantation tolerance.

KW - basic (laboratory) research/science

KW - cell death: apoptosis

KW - cytokines/cytokine receptors

KW - immune regulation

KW - immunobiology

KW - immunosuppression/immune modulation

KW - macrophage/monocyte biology: activation

KW - organ transplantation in general

KW - tolerance: mechanisms

KW - translational research/science

UR - http://www.scopus.com/inward/record.url?scp=85053722989&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053722989&partnerID=8YFLogxK

U2 - 10.1111/ajt.15087

DO - 10.1111/ajt.15087

M3 - Article

C2 - 30133807

AN - SCOPUS:85053722989

VL - 19

SP - 674

EP - 685

JO - American Journal of Transplantation

JF - American Journal of Transplantation

SN - 1600-6135

IS - 3

ER -