Abstract
Cardiac Allograft Vasculopathy (CAV) is a leading contributor to late transplant rejection. Although implicated, the mechanisms by which bone marrow-derived cells promote CAV remain unclear. Emerging evidence implicates the cell surface receptor tyrosine kinase AXL to be elevated in rejecting human allografts. AXL protein is found on multiple cell types, including bone marrow-derived myeloid cells. The causal role of AXL from this compartment and during transplant is largely unknown. This is important because AXL is a key regulator of myeloid inflammation. Utilizing experimental chimeras deficient in the bone marrow-derived Axl gene, we report that Axl antagonizes cardiac allograft survival and promotes CAV. Flow cytometric and histologic analyses of Axl-deficient transplant recipients revealed reductions in both allograft immune cell accumulation and vascular intimal thickness. Co-culture experiments designed to identify cell-intrinsic functions of Axl uncovered complementary cell-proliferative pathways by which Axl promotes CAV-associated inflammation. Specifically, Axl-deficient myeloid cells were less efficient at increasing the replication of both antigen-specific T cells and vascular smooth muscle cells (VSMCs), the latter a key hallmark of CAV. For the latter, we discovered that Axl-was required to amass the VSMC mitogen Platelet-Derived Growth Factor. Taken together, our studies reveal a new role for myeloid Axl in the progression of CAV and mitogenic crosstalk. Inhibition of AXL-protein, in combination with current standards of care, is a candidate strategy to prolong cardiac allograft survival.
Original language | English (US) |
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Pages (from-to) | 435-446 |
Number of pages | 12 |
Journal | Journal of Heart and Lung Transplantation |
Volume | 40 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2021 |
Funding
We appreciate the assistance of Lisa Wilsbacher, M.D. Ph.D. FAHA, Anna Huskin, RN, BSN, CCRC, Program Development Manager in the Clinical Trials Unit of the Bluhm Cardiovascular Institute and Patrick McCarthy, MD, the Executive Director of the Bluhm Cardiovascular Institute. Publication of this research was supported by the Sidney and Bess Eisenberg Memorial Fund. This work was supported by the National Institutes R01HL139812, R01HL122309, and an AHA postdoctoral fellowship to 18POST33960228 KG. We appreciate the assistance of Lisa Wilsbacher, M.D. Ph.D., FAHA, Anna Huskin, RN, BSN, CCRC, Program Development Manager in the Clinical Trials Unit of the Bluhm Cardiovascular Institute and Patrick McCarthy, MD, the Executive Director of the Bluhm Cardiovascular Institute. Publication of this research was supported by the Sidney and Bess Eisenberg Memorial Fund . This work was supported by the National Institutes R01HL139812 , R01HL122309 , and an AHA postdoctoral fellowship to 18POST33960228 KG .
Keywords
- Axl tyrosine kinase
- cardiac allograft vasculopathy
- inflammation
- myeloid
- vascular smooth muscle cell
ASJC Scopus subject areas
- Surgery
- Pulmonary and Respiratory Medicine
- Cardiology and Cardiovascular Medicine
- Transplantation