title: 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.
authors.affiliation: The Department of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Orme
authors.affiliation: The Department of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; The Department of Biomedical Engineering, University of Houston, Houston, TX 77204-5060, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Du
authors.affiliation: The Department of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; The Department of Biomedical Engineering, University of Houston, Houston, TX 77204-5060, United States.
authors.forename: Kamala
authors.initials: K
authors.lastname: Vanarsa
authors.affiliation: The Department of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Mayeux
authors.affiliation: The Department of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: The Department of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Azza
authors.initials: A
authors.lastname: Mutwally
authors.affiliation: The Department of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Cristina
authors.initials: C
authors.lastname: Arriens
authors.affiliation: The Department of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Soyoun
authors.initials: S
authors.lastname: Min
authors.affiliation: The Department of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Jack
authors.initials: J
authors.lastname: Hutcheson
authors.affiliation: The Department of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Laurie S
authors.initials: LS
authors.lastname: Davis
authors.affiliation: The Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Chong
authors.affiliation: The Department of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Satterthwaite
authors.affiliation: The Department of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; The Department of Biomedical Engineering, University of Houston, Houston, TX 77204-5060, United States.
authors.forename: Tianfu
authors.initials: T
authors.lastname: Wu
authors.affiliation: The Department of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; The Department of Biomedical Engineering, University of Houston, Houston, TX 77204-5060, United States. Electronic address: cmohan@Central.UH.EDU.
authors.forename: Chandra
authors.initials: C
authors.lastname: Mohan
mesh_terms: D000072197:ADAM10 Protein / Q000276:immunology* / Q000378:metabolism; D000072198:ADAM17 Protein / Q000276:immunology* / Q000378:metabolism; D000328:Adult; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
keywords: Axl; Lupus; Macrophages; SLE