title: The tryptophan metabolism enzyme L-kynureninase is a novel inflammatory factor in psoriasis and other inflammatory diseases.
abstract: Many human diseases arise from or have pathogenic contributions from a dysregulated immune response. One pathway with immunomodulatory ability is the tryptophan metabolism pathway, which promotes immune suppression through the enzyme indoleamine 2,3-dioxygenase (IDO) and subsequent production of kynurenine. However, in patients with chronic inflammatory skin disease, such as psoriasis and atopic dermatitis (AD), another tryptophan metabolism enzyme downstream of IDO, L-kynureninase (KYNU), is heavily upregulated. The role of KYNU has not been explored in patients with these skin diseases or in general human immunology.
  
  
  
  We sought to explore the expression and potential immunologic function of the tryptophan metabolism enzyme KYNU in inflammatory skin disease and its potential contribution to general human immunology.
  
  
  
  Psoriatic skin biopsy specimens, as well as normal human skin, blood, and primary cells, were used to investigate the immunologic role of KYNU and tryptophan metabolites.
  
  
  
  Here we show that KYNU(+) cells, predominantly of myeloid origin, infiltrate psoriatic lesional skin. KYNU expression positively correlates with disease severity and inflammation and is reduced on successful treatment of psoriasis or AD. Tryptophan metabolites downstream of KYNU upregulate several cytokines, chemokines, and cell adhesions. By mining data on several human diseases, we found that in patients with cancer, IDO is preferentially upregulated compared with KYNU, whereas in patients with inflammatory diseases, such as AD, KYNU is preferentially upregulated compared with IDO.
  
  
  
  Our results suggest that tryptophan metabolism might dichotomously modulate immune responses, with KYNU as a switch between immunosuppressive versus inflammatory outcomes. Although tryptophan metabolism is increased in many human diseases, how tryptophan metabolism is proceeding might qualitatively affect the immune response in patients with that disease.
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY. Electronic address: jharden@rockefeller.edu.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Harden
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Lewis
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Lish
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Center for Clinical and Translational Science, Rockefeller University, New York, NY; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Mayte
authors.initials: M
authors.lastname: Suárez-Fariñas
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gareau
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
authors.forename: Tim
authors.initials: T
authors.lastname: Lentini
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Johnson-Huang
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
authors.forename: James G
authors.initials: JG
authors.lastname: Krueger
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Division of Dermatology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Lowes
mesh_terms: D001706:Biopsy; D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D011565:Psoriasis / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014364:Tryptophan / Q000378:metabolism
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018836:Inflammation Mediators; D014364:Tryptophan; D006867:Hydrolases; C021480:kynureninase
keywords: L-kynureninase; Psoriasis vulgaris; inflammation; tryptophan metabolism