PT  - JOURNAL ARTICLE
AU  - Kristofor Glinton
AU  - Matthew DeBerge
AU  - Emily Fisher
AU  - Samantha Schroth
AU  - Arjun Sinha
AU  - Jiao-Jing Wang
AU  - J. Andrew Wasserstrom
AU  - Mohammed Javeed Ansari
AU  - Zheng Jenny Zhang
AU  - Matthew Feinstein
AU  - Joseph R. Leventhal
AU  - Joseph M. Forbess
AU  - Jon Lomasney
AU  - Xunrong Luo
AU  - Edward B. Thorp
TI  - Bone Marrow-Derived AXL Tyrosine Kinase Promotes Mitogenic Crosstalk and Cardiac Allograft Vasculopathy
AID  - 10.1101/2021.02.04.429773
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.02.04.429773
4099  - http://biorxiv.org/content/early/2021/02/05/2021.02.04.429773.short
4100  - http://biorxiv.org/content/early/2021/02/05/2021.02.04.429773.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.