Identification of cinnabarinic acid as a novel endogenous aryl hydrocarbon receptor ligand that drives IL-22 production.
The aryl hydrocarbon receptor (AHR) binds to environmental toxicants including synthetic halogenated aromatic hydrocarbons and is involved in a diverse array of biological processes. Recently, the AHR was shown to control host immunity by affecting the balance between inflammatory T cells that produce IL-17 (Th17) and IL-22 versus regulatory T cells (Treg) involved in tolerance. While environmental AHR ligands can mediate this effect, endogenous ligands are likely to be more relevant in host immune responses. We investigated downstream metabolites of tryptophan as potential AHR ligands because (1) tryptophan metabolites have been implicated in regulating the balance between Th17 and Treg cells and (2) many of the AHR ligands identified thus far are derivatives of tryptophan. We characterized the ability of tryptophan metabolites to bind and activate the AHR and to increase IL-22 production in human T cells. We report that the tryptophan metabolite, cinnabarinic acid (CA), is an AHR ligand that stimulates the differentiation of human and mouse T cells producing IL-22. We compare the IL-22-stimulating activity of CA to that of other tryptophan metabolites and define stimulation conditions that lead to CA production from immune cells. Our findings link tryptophan metabolism to AHR activation and define a novel endogenous AHR agonist with potentially broad biological functions.
Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Margaret M
MM
Lowe
Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Jeff E
JE
Mold
Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America ; Division of Gastroenterology, Department of Pediatrics, University of California San Francisco, San Francisco, California, United States of America.
Bittoo
B
Kanwar
Drug Studies Unit, Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.
Yong
Y
Huang
Drug Studies Unit, Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.
Alexander
A
Louie
Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, United States of America.
Michael P
MP
Pollastri
Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, United States of America.
Cuihua
C
Wang
Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, United States of America.
Gautam
G
Patel
Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts, United States of America.
Diana G
DG
Franks
Department of Environmental Health, School of Public Health, Boston University, Boston, Massachusetts, United States of America.
Jennifer
J
Schlezinger
Department of Environmental Health, School of Public Health, Boston University, Boston, Massachusetts, United States of America.
David H
DH
Sherr
Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, New York, United States of America.
Allen E
AE
Silverstone
Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts, United States of America.
Mark E
ME
Hahn
Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Joseph M
JM
McCune
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010078:Oxazines / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D058504:Th17 Cells; D014364:Tryptophan / Q000378:metabolism; D000097043:Interleukin-22
D019363:Cytochrome P-450 CYP1A1; D007378:Interleukins; D008024:Ligands; D010078:Oxazines; D018336:Receptors, Aryl Hydrocarbon; D014364:Tryptophan; D000097043:Interleukin-22; C000483:cinnabarinic acid