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MERTK Mediates Transplantation Tolerance via Inhibition of TBK1 Phosphorylation and IFN-a Production.

L. Zhang,1 M. DeBerge,2 X. Zhang,3 J. Wang,3 Z. Zhang,3 E. Thorp,2 X. Luo.1,2,3

1Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL
2Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL
3Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL

Meeting: 2017 American Transplant Congress

Abstract number: C299

Keywords: Apoptosis

Session Information

Session Name: Poster Session C: Tolerance/Immune Regulation

Session Type: Poster Session

Date: Monday, May 1, 2017

Session Time: 6:00pm-7:00pm

 Presentation Time: 6:00pm-7:00pm

Location: Hall D1

Introduction: The TAM (Tyro3, Axl and MERTK) receptor tyrosine kinases (RTKs) mediate homeostatic phagocytosis of apoptotic cells, and transmit regulatory signals that modulate immune response. Currently, their role in transplant tolerance is unknown.

Methods: In this study, we address the role of MERTK in transplant tolerance in a BALB/c to C57BL6/J heart transplant model in which tolerance is induced by recipient treatment with donor splenocytes (SP) treated with 1-ehtyl-3-(3-dimethylaminopropyl) carbodiimide (ECDI).

Results: MERTK-/- recipients exhibited markedly impaired transplant tolerance induction by ECDI-SP treatment. We observed that MERTK-/- macrophages exhibited markedly elevated IFN-a production upon co-culturing with allogeneic ECDI-SPs. This elevation was associated with a heightened expression level of the transcription factor TBK1 and its phosphorylated form by Western blot, but independent of the expression level of Myd88. This finding suggests that MERTK interferes with TRIF-mediated TLR signaling and subsequent induction of IFN-a production. Consistent with the role of IFN-a in mediating the observed transplant tolerance resistance in MERTK-/- recipients, treatment of MERTK-/- with IFN-a receptor blockade resulted in restoration of tolerance efficacy by ECDI-SP. This treatment also restored the number of graft infiltrating CD4+Foxp3+ Tregs, together with an inhibition of graft infiltrating inflammatory monocytes. On the contrary, treatment of MERTK WT recipients with recombinant IFN-a resulted in a similar tolerance impairment observed in MERTK-/- recipients treated with ECDI-SPs. These results underscored the critical role of recipient MERTK signaling in suppression of IFN-a production and subsequent induction of graft protective environment in the allograft.

Conclusion: The receptor tyrosine kinase MERTK plays a critical role in mediating transplantation tolerance by ECDI-SPs, likely via inhibition of specific TLR mediated induction of IFN-a production. Enhancement of MERTK signaling may represent a novel therapeutic target for tolerance induction for transplantation.

CITATION INFORMATION: Zhang L, DeBerge M, Zhang X, Wang J, Zhang Z, Thorp E, Luo X. MERTK Mediates Transplantation Tolerance via Inhibition of TBK1 Phosphorylation and IFN-a Production. Am J Transplant. 2017;17 (suppl 3).

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To cite this abstract in AMA style:

Zhang L, DeBerge M, Zhang X, Wang J, Zhang Z, Thorp E, Luo X. MERTK Mediates Transplantation Tolerance via Inhibition of TBK1 Phosphorylation and IFN-a Production. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/mertk-mediates-transplantation-tolerance-via-inhibition-of-tbk1-phosphorylation-and-ifn-a-production/. Accessed June 16, 2025.

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