title: Dysfunction in macrophage toll-like receptor signaling caused by an inborn error of cationic amino acid transport.
abstract: Amino acids, especially arginine, are vital for the well-being and activity of immune cells, and disruption of amino acid balance may weaken immunity and predispose to infectious and autoimmune diseases. We present here a model of an inborn aminoaciduria, lysinuric protein intolerance (LPI), in which a single mutation in y(+)LAT1 cationic amino acid transporter gene SLC7A7 leads to a multisystem disease characterized by immunological complications, life-threatening pulmonary alveolar proteinosis and nephropathy. Macrophages are suggested to play a central role in LPI in the development of these severe secondary symptoms. We thus studied the effect of the Finnish y(+)LAT1 mutation on monocyte-derived macrophages where toll-like receptors (TLRs) act as the key molecules in innate immune response against external pathogens. The function of LPI patient and control macrophage TLR signaling was examined by stimulating the TLR2/1, TLR4 and TLR9 pathways with their associated pathogen-associated molecular patterns. Downregulation in expression of TLR9, IRF7, IRF3 and IFNB1 and in secretion of IFN-α was detected, suggesting an impaired response to TLR9 stimulation. In addition, secretion of TNF-α, IL-12 and IL-1RA by TLR2/1 stimulation and IL-12 and IL-1RA by TLR4 stimulation was increased in the LPI patients. LPI macrophages secreted significantly less nitric oxide than control macrophages, whereas plasma concentrations of inflammatory chemokines CXCL8, CXCL9 and CXCL10 were elevated in the LPI patients. In conclusion, our results strengthen the relevance of macrophages in the pathogenesis of LPI and, furthermore, suggest that cationic amino acid transport plays an important role in the regulation of innate immune responses.
authors.affiliation: Department of Medical Biochemistry and Genetics, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland. Electronic address: johanna.kurko@utu.fi.
authors.forename: Johanna
authors.initials: J
authors.lastname: Kurko
authors.affiliation: Department of Pediatrics, Turku University Hospital and University of Turku, Kiinamyllynkatu 4-8, PL 52, 20521 Turku, Finland. Electronic address: mari.vaha-makila@utu.fi.
authors.forename: Mari
authors.initials: M
authors.lastname: Vähä-Mäkilä
authors.affiliation: Department of Medical Biochemistry and Genetics, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland. Electronic address: maaria.tringham@utu.fi.
authors.forename: Maaria
authors.initials: M
authors.lastname: Tringham
authors.affiliation: Department of Medical Biochemistry and Genetics, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland; Department of Clinical Genetics, Turku University Hospital, Kiinamyllynkatu 4-8, PL 52, 20521 Turku, Finland. Electronic address: laura.tanner@utu.fi.
authors.forename: Laura
authors.initials: L
authors.lastname: Tanner
authors.affiliation: Department of Pediatrics, Turku University Hospital and University of Turku, Kiinamyllynkatu 4-8, PL 52, 20521 Turku, Finland. Electronic address: paavanen@gmail.com.
authors.forename: Sari
authors.initials: S
authors.lastname: Paavanen-Huhtala
authors.affiliation: Department of Pediatrics, Turku University Hospital and University of Turku, Kiinamyllynkatu 4-8, PL 52, 20521 Turku, Finland; Department of Public Health, University of Turku, Lemminkäisenkatu 1, 20014 Turku, Finland. Electronic address: maiju.m.saarinen@utu.fi.
authors.forename: Maiju
authors.initials: M
authors.lastname: Saarinen
authors.affiliation: Department of Pediatrics, Turku University Hospital and University of Turku, Kiinamyllynkatu 4-8, PL 52, 20521 Turku, Finland. Electronic address: kirsti.nanto-salonen@tyks.fi.
authors.forename: Kirsti
authors.initials: K
authors.lastname: Näntö-Salonen
authors.affiliation: Department of Pediatrics, Turku University Hospital and University of Turku, Kiinamyllynkatu 4-8, PL 52, 20521 Turku, Finland. Electronic address: olli.simell@utu.fi.
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
authors.affiliation: Department of Pediatrics, Turku University Hospital and University of Turku, Kiinamyllynkatu 4-8, PL 52, 20521 Turku, Finland. Electronic address: harri.niinikoski@tyks.fi.
authors.forename: Harri
authors.initials: H
authors.lastname: Niinikoski
authors.affiliation: Department of Pediatrics, Turku University Hospital and University of Turku, Kiinamyllynkatu 4-8, PL 52, 20521 Turku, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland. Electronic address: juha.mykkanen@utu.fi.
authors.forename: Juha
authors.initials: J
authors.lastname: Mykkänen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D026923:Amino Acid Transport Systems, Basic / Q000378:metabolism*; D018925:Chemokines / Q000097:blood / Q000378:metabolism; D002648:Child; D003470:Culture Media / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051193:Toll-Like Receptors / Q000378:metabolism*; D055815:Young Adult
chemical_list: D026923:Amino Acid Transport Systems, Basic; D018925:Chemokines; D003470:Culture Media; D051193:Toll-Like Receptors; D009569:Nitric Oxide
keywords: Cationic amino acid transport; Cytokine; Gene expression; Lysinuric protein intolerance; Macrophage; TLR