Human urinary exosomes as innate immune effectors.
Exosomes are small extracellular vesicles, approximately 50 nm in diameter, derived from the endocytic pathway and released by a variety of cell types. Recent data indicate a spectrum of exosomal functions, including RNA transfer, antigen presentation, modulation of apoptosis, and shedding of obsolete protein. Exosomes derived from all nephron segments are also present in human urine, where their function is unknown. Although one report suggested in vitro uptake of exosomes by renal cortical collecting duct cells, most studies of human urinary exosomes have focused on biomarker discovery rather than exosome function. Here, we report results from in-depth proteomic analyses and EM showing that normal human urinary exosomes are significantly enriched for innate immune proteins that include antimicrobial proteins and peptides and bacterial and viral receptors. Urinary exosomes, but not the prevalent soluble urinary protein uromodulin (Tamm-Horsfall protein), potently inhibited growth of pathogenic and commensal Escherichia coli and induced bacterial lysis. Bacterial killing depended on exosome structural integrity and occurred optimally at the acidic pH typical of urine from omnivorous humans. Thus, exosomes are innate immune effectors that contribute to host defense within the urinary tract.
Department of Medicine, Cambridge Centre for Proteome Research and Cambridge Systems Biology Centre, Department of Biochemistry.
Thomas F
TF
Hiemstra
Cambridge Centre for Proteome Research and Cambridge Systems Biology Centre, Department of Biochemistry.
Philip D
PD
Charles
Department of Medical Genetics, and.
Tannia
T
Gracia
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
Svenja S
SS
Hester
Cambridge Centre for Proteome Research and Cambridge Systems Biology Centre, Department of Biochemistry.
Laurent
L
Gatto
Department of Medicine.
Rafia
R
Al-Lamki
Department of Medicine.
R Andres
RA
Floto
Department of Medical Genetics, and.
Ya
Y
Su
Multi-Imaging Centre, Department of Anatomy, University of Cambridge, Cambridge, United Kingdom; and.
Jeremy N
JN
Skepper
Cambridge Centre for Proteome Research and Cambridge Systems Biology Centre, Department of Biochemistry, ksl23@cam.ac.uk fek1000@cam.ac.uk.
Kathryn S
KS
Lilley
Department of Medical Genetics, and ksl23@cam.ac.uk fek1000@cam.ac.uk.
Fiona E
FE
Karet Frankl
D000328:Adult; D015415:Biomarkers / Q000652:urine; D055354:Exosomes / Q000276:immunology* / Q000648:ultrastructure; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D016253:Microscopy, Immunoelectron; D020543:Proteome / Q000276:immunology; D014551:Urinary Tract / Q000276:immunology* / Q000382:microbiology; D056689:Uropathogenic Escherichia coli / Q000254:growth & development / Q000276:immunology; D055815:Young Adult
D015415:Biomarkers; D020543:Proteome