Bone marrow-derived AXL tyrosine kinase promotes mitogenic crosstalk and cardiac allograft vasculopathy
| Autor: | Joseph R. Leventhal, Samantha Schroth, Jiao Jing Wang, Joseph M. Forbess, J. Andrew Wasserstrom, Mohammed Javeed I. Ansari, Zheng Jenny Zhang, Matthew DeBerge, Arjun Sinha, Kristofor Glinton, Matthew J. Feinstein, Edward B. Thorp, Jon W. Lomasney, Xunrong Luo, Emily Fisher |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Graft Rejection Male Myeloid medicine.medical_treatment Muscle Smooth Vascular Mice 0302 clinical medicine Myocytes Cardiac Cells Cultured Mice Inbred BALB C Graft Survival Flow Cytometry Transplant rejection medicine.anatomical_structure Echocardiography 030220 oncology & carcinogenesis cardiovascular system medicine.symptom Cardiology and Cardiovascular Medicine Tyrosine kinase Pulmonary and Respiratory Medicine Adult Cell type Myocytes Smooth Muscle Inflammation Bone Marrow Cells Article 03 medical and health sciences Cell surface receptor Proto-Oncogene Proteins medicine Animals Humans Transplantation Homologous Cell Proliferation Transplantation business.industry Growth factor Receptor Protein-Tyrosine Kinases medicine.disease Axl Receptor Tyrosine Kinase Disease Models Animal 030104 developmental biology Gene Expression Regulation Cancer research Heart Transplantation RNA Surgery Bone marrow business |
| Zdroj: | J Heart Lung Transplant |
| ISSN: | 1557-3117 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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