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

Jacob J. Orme, Yong Du, Kamala Vanarsa, Jessica Mayeux, Li Li, Azza Mutwally, Cristina Arriens, Soyoun Min, Jack Hutcheson, Laurie S. Davis, Benjamin F. Chong, Anne B. Satterthwaite, Tianfu Wu, Chandra Mohan

Research output: Contribution to journalArticle

25 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)58-68
Number of pages11
JournalClinical Immunology
Volume169
DOIs
StatePublished - Aug 1 2016

Keywords

  • Axl
  • Lupus
  • Macrophages
  • SLE

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Medicine(all)

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    Orme, J. J., Du, Y., Vanarsa, K., Mayeux, J., Li, L., Mutwally, A., Arriens, C., Min, S., Hutcheson, J., Davis, L. S., Chong, B. F., Satterthwaite, A. B., Wu, T., & Mohan, C. (2016). Heightened cleavage of Axl receptor tyrosine kinase by ADAM metalloproteases may contribute to disease pathogenesis in SLE. Clinical Immunology, 169, 58-68. https://doi.org/10.1016/j.clim.2016.05.011