Bone marrow-derived AXL tyrosine kinase promotes mitogenic crosstalk and cardiac allograft vasculopathy

Kristofor Glinton, Matthew DeBerge, Emily Fisher, Samantha Schroth, Arjun Sinha, Jiao Jing Wang, J. Andrew Wasserstrom, Mohammed Javeed Ansari, Zheng Jenny Zhang, Matthew Feinstein, Joseph R. Leventhal, Joseph M. Forbess, Jon Lomasney, Xunrong Luo, Edward B. Thorp

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)435-446
Number of pages12
JournalJournal of Heart and Lung Transplantation
Volume40
Issue number6
DOIs
StatePublished - Jun 2021
Externally publishedYes

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

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