Heightened cleavage of Axl receptor tyrosine kinase by ADAM metalloproteases may contribute to disease pathogenesis in SLE

Abstract

Systemic lupus erythematosus (SLE) is characterized by antibody-mediated chronic inflammation in the kidney, lung, skin, and other organs to cause inflammation and damage. Several inflammatory pathways are dysregulated in SLE, and understanding these pathways may improve diagnosis and treatment. In one such pathway, Axl tyrosine kinase receptor responds to Gas6 ligand to block inflammation in leukocytes. A soluble form of the Axl receptor ectodomain (sAxl) is elevated in serum from patients with SLE and lupus-prone mice. We hypothesized that sAxl in SLE serum originates from the surface of leukocytes and that the loss of leukocyte Axl contributes to the disease. We determined that macrophages and B cells are a source of sAxl in SLE and in lupus-prone mice. Shedding of the Axl ectodomain from the leukocytes of lupus-prone mice is mediated by the matrix metalloproteases ADAM10 and TACE (ADAM17). Loss of Axl from lupus-prone macrophages renders them unresponsive to Gas6-induced anti-inflammatory signaling in vitro. This phenotype is rescued by combined ADAM10/TACE inhibition. Mice with Axl-deficient macrophages develop worse disease than controls when challenged with anti-glomerular basement membrane (anti-GBM) sera in an induced model of nephritis. ADAM10 and TACE also mediate human SLE PBMC Axl cleavage. Collectively, these studies indicate that increased metalloprotease-mediated cleavage of leukocyte Axl may contribute to end organ disease in lupus. They further suggest dual ADAM10/TACE inhibition as a potential therapeutic modality in SLE.

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

“…These soluble forms of the receptors can be detected in the blood and tissue, and may compete with membrane-form receptors for the binding of protein S and GAS6. Disruption of AXL/MERTK ligand binding or AXL/ MERTK deficiency inhibits clearance of apoptotic cells (25,26) and enhances production of inflammatory cytokines (27), leading to disease pathogenesis (28,29).…”

“…Cleavage of MERTK and AXL by the metalloproteinases ADAM17 and ADAM10 leads to soluble forms of the receptors and incompetent receptor functioning at the cell surface (29,(83)(84)(85). Indeed, sAXL and sMERTK have been shown to inhibit macrophage efferocytosis (23).…”

The effects of vitamin K1 and vitamin K2 on the proliferation, cytokine production and regulatory T‐cell frequency in peripheral blood mononuclear cells of paediatric atopic dermatitis patients

“…Gas6 is a plasma vitamin K‐dependent protein that plays an important immunoregulatory role in various cells by interacting with the three receptors of TAM (Tyro3, Axl and Mertk) . However, lymphocytes do not express TAM receptors; thus, the GAS6 receptors do not seem to be related to the main mechanism underlying the effects of VK 2 .…”

Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer

“…For instance, the closely related AXL expressed on cancer cells is cleaved by ADAM10 and ADAM17; AXL surface levels, phosphorylation, and co-immunoprecipitation with other ADAM-substrates including HER2 and MET increase with protease inhibition; and direct sheddase inhibition affects cell signaling and mitosis in an AXL-dependent manner (11). Likewise, evidence for ADAM-mediated AXL shedding has been found in macrophages and B-cells of lupus-prone mice (24). The hepatocyte growth factor receptor (HGF-R / MET) also exhibits decreased biological activity after ectodomain shedding.…”