Correction of lung inflammation in a F508del CFTR murine cystic fibrosis model by the sphingosine-1-phosphate lyase inhibitor LX2931.
Progressive lung disease with early onset is the main cause of mortality and morbidity in cystic fibrosis patients. Here we report a reduction of sphingosine-1-phosphate (S1P) in the lung of unchallenged Cftrtm1EURF508del CFTR mutant mice. This correlates with enhanced infiltration by inducible nitric oxide synthase (iNOS)-expressing granulocytes, B cells, and T cells. Furthermore, the ratio of macrophage-derived dendritic cells (MoDC) to conventional dendritic cells (cDC) is higher in mutant mouse lung, consistent with unprovoked inflammation. Oral application of a S1P lyase inhibitor (LX2931) increases S1P levels in mutant mouse tissues. This normalizes the lung MoDC/cDC ratio and reduces B and T cell counts. Lung granulocytes are enhanced, but iNOS expression is reduced in this population. Although lung LyC6+ monocytes are enhanced by LX2931, they apparently do not differentiate to MoDC and macrophages. After challenge with bacterial toxins (LPS-fMLP) we observe enhanced levels of proinflammatory cytokines TNF-α, KC, IFNγ, and IL-12 and the inducible mucin MUC5AC in mutant mouse lung, evidence of deficient resolution of inflammation. LX2931 does not prevent transient inflammation or goblet cell hyperplasia after challenge, but it reduces MUC5AC and proinflammatory cytokine levels toward normal values. We conclude that lung pathology in homozygous mice expressing murine F508del CFTR, which represents the most frequent mutation in CF patients, is characterized by abnormal behavior of infiltrating myeloid cells and delayed resolution of induced inflammation. This phenotype can be partially corrected by a S1P lyase inhibitor, providing a rationale for therapeutic targeting of the S1P signaling pathway in CF patients.
Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
Mieke
M
Veltman
Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
Marta
M
Stolarczyk
Departments of Medicine and Human Genetics, McGill University, Montreal, Canada.
Danuta
D
Radzioch
Departments of Medicine and Human Genetics, McGill University, Montreal, Canada.
Gabriella
G
Wojewodka
Faculty of Medicine. Universidad Central de Venezuela, Institute of Immunology, Caracas, Venezuela.
Juan B
JB
De Sanctis
Immunology, Erasmus MC, Rotterdam, The Netherlands.
Willem A
WA
Dik
Department of Radiology, Division of Image Processing, Leiden University Medical Center, Leiden, The Netherlands.
Oleh
O
Dzyubachyk
Lexicon Pharmaceuticals, Inc., The Woodlands, Texas.
Tamas
T
Oravecz
Department of Pediatrics, Division of Respiratory Medicine, Erasmus MC, Rotterdam, The Netherlands; and.|Laboratory of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands.
Ismé
I
de Kleer
Cell Biology, Erasmus MC, Rotterdam, The Netherlands; b.scholte@erasmusmc.nl.
Bob J
BJ
Scholte
D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003550:Cystic Fibrosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D008810:Mice, Inbred C57BL; D055271:Mucin 5AC / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology / Q000627:therapeutic use*; D011014:Pneumonia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D012469:Salivary Glands / Q000187:drug effects / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D055114:X-Ray Microtomography
C555223:1-(4-(1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime; D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; D008246:Lysophospholipids; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D010091:Oximes; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C060506:sphingosine 1-phosphate; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase); D013110:Sphingosine
cystic fibrosis; dendritic cells; granulocytes; macrophages; mouse model