title: Inhibition of PI3Kδ reduces kidney infiltration by macrophages and ameliorates systemic lupus in the mouse.
abstract: Systemic lupus erythematosus (SLE) is a human chronic inflammatory disease generated and maintained throughout life by autoreactive T and B cells. Class I phosphoinositide 3-kinases (PI3K) are heterodimers composed of a regulatory and a catalytic subunit that catalyze phosphoinositide-3,4,5-P3 formation and regulate cell survival, migration, and division. Activity of the PI3Kδ isoform is enhanced in human SLE patient PBLs. In this study, we analyzed the effect of inhibiting PI3Kδ in MRL/lpr mice, a model of human SLE. We found that PI3Kδ inhibition ameliorated lupus progression. Treatment of these mice with a PI3Kδ inhibitor reduced the excessive numbers of CD4(+) effector/memory cells and B cells. In addition, this treatment reduced serum TNF-α levels and the number of macrophages infiltrating the kidney. Expression of inactive PI3Kδ, but not deletion of the other hematopoietic isoform PI3Kγ, reduced the ability of macrophages to cross the basement membrane, a process required to infiltrate the kidney, explaining MRL/lpr mice improvement by pharmacologic inhibition of PI3Kδ. The observations that p110δ inhibitor prolonged mouse life span, reduced disease symptoms, and showed no obvious secondary effects indicates that PI3Kδ is a promising target for SLE.
authors.affiliation: Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Cantoblanco, Madrid 28049, Spain;
authors.forename: Abel
authors.initials: A
authors.lastname: Suárez-Fueyo
authors.affiliation: Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Cantoblanco, Madrid 28049, Spain;
authors.forename: José M
authors.initials: JM
authors.lastname: Rojas
authors.affiliation: Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Cantoblanco, Madrid 28049, Spain;
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Cariaga
authors.affiliation: Departamento de Biologia Molecular e Celular, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Cantoblanco, Madrid 28049, Spain; and.
authors.forename: Esther
authors.initials: E
authors.lastname: García
authors.affiliation: Department of Biology, Gilead Sciences, Seattle, WA 98102.
authors.forename: Bart H
authors.initials: BH
authors.lastname: Steiner
authors.affiliation: Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Cantoblanco, Madrid 28049, Spain;
authors.forename: Domingo F
authors.initials: DF
authors.lastname: Barber
authors.affiliation: Department of Biology, Gilead Sciences, Seattle, WA 98102.
authors.forename: Kamal D
authors.initials: KD
authors.lastname: Puri
authors.affiliation: Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Cantoblanco, Madrid 28049, Spain; acarrera@cnb.csic.es.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Carrera
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D007074:Immunoglobulin G / Q000097:blood; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008181:Lupus Nephritis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D018655:Lymphocyte Count; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018613:Microscopy, Confocal; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D016019:Survival Analysis; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D000241:Adenosine; D000974:Antibodies, Antinuclear; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D016207:Cytokines; D007074:Immunoglobulin G; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D052999:Quinazolinones; D011810:Quinoxalines; D045162:Thiazolidinediones; C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; C000591923:GS-9829; C421683:Pik3cd protein, mouse; C546764:Pik3cg protein, mouse