title: Retinoids induce integrin-independent lymphocyte adhesion through RAR-α nuclear receptor activity.
abstract: Oxidative metabolites of vitamin A, in particular all-trans-retinoic acid (atRA), have emerged as key factors in immunity by specifying the localization of immune cells to the gut. Although it is appreciated that isomers of retinoic acid activate the retinoic acid receptor (RAR) and retinoid X receptor (RXR) family of nuclear receptors to elicit cellular changes, the molecular details of retinoic acid action remain poorly defined in immune processes. Here we employ a battery of agonists and antagonists to delineate the specific nuclear receptors utilized by retinoids to evoke lymphocyte cell adhesion to ADAM (adisintegrin and metalloprotease) protein family members. We report that RAR agonism is sufficient to promote immune cell adhesion in both immortal and primary immune cells. Interestingly, adhesion occurs independent of integrin function, and mutant studies demonstrate that atRA-induced adhesion to ADAM members required a distinct binding interface(s) as compared to integrin recognition. Anti-inflammatory corticosteroids as well as 1,25-(OH)2D3, a vitamin D metabolite that prompts immune cell trafficking to the skin, potently inhibited the observed adhesion. Finally, our data establish that induced adhesion was specifically attributable to the RAR-α receptor isotype. The current study provides novel molecular resolution as to which nuclear receptors transduce retinoid exposure into immune cell adhesion.
authors.affiliation: Department of Biochemistry and Molecular Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834, United States.
authors.forename: Jarrett T
authors.initials: JT
authors.lastname: Whelan
authors.affiliation: Department of Biochemistry and Molecular Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834, United States.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834, United States.
authors.forename: Jianming
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834, United States.
authors.forename: Meagan E
authors.initials: ME
authors.lastname: Metts
authors.affiliation: Department of Biochemistry and Molecular Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834, United States.
authors.forename: Taj A
authors.initials: TA
authors.lastname: Nasser
authors.affiliation: Department of Biochemistry and Molecular Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834, United States.
authors.forename: Liam J
authors.initials: LJ
authors.lastname: McGoldrick
authors.affiliation: Department of Biochemistry and Molecular Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834, United States; East Carolina Diabetes and Obesity Institute, The Brody School of Medicine at East Carolina University, Greenville, NC 27834, United States. Electronic address: bridgesl@ecu.edu.
authors.forename: Lance C
authors.initials: LC
authors.lastname: Bridges
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha / Q000819:agonists* / Q000378:metabolism*; D012176:Retinoids / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D016023:Integrins; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids
keywords: Adhesion; Disintegrin; Retinoid