Retinoids induce integrin-independent lymphocyte adhesion through RAR-α nuclear receptor activity

• Published in: Biochemical and biophysical research communications 2014-11, Vol.454 (4), p.537-542
• Main Authors: Whelan, Jarrett T., Wang, Lei, Chen, Jianming, Metts, Meagan E., Nasser, Taj A., McGoldrick, Liam J., Bridges, Lance C.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ADHESION; Cell Adhesion - drug effects; COMPARATIVE EVALUATIONS; CYCLOHEXIMIDE; DEXAMETHASONE; Disintegrin; Dose-Response Relationship, Drug; Humans; IMMUNITY; INFLAMMATION; Integrins - metabolism; ISOMERS; LYMPHOCYTES; Lymphocytes - cytology; Lymphocytes - drug effects; Lymphocytes - metabolism; METABOLITES; MOLECULES; MUTANTS; OXIDATION; RECEPTORS; RETINOIC ACID; Retinoic Acid Receptor alpha - agonists; Retinoic Acid Receptor alpha - metabolism; Retinoid; Retinoids - pharmacology; SKIN; Structure-Activity Relationship; TRANSCRIPTION; VITAMIN A; VITAMIN D
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2014.10.120

[Display omitted] •Transcription and translation are required for retinoid-induced lymphocyte adhesion.•RAR activation is sufficient to induced lymphocyte cell adhesion.•Vitamin D derivatives inhibit RAR-prompted lymphocyte adhesion.•Adhesion occurs through a novel binding site within ADAM disintegrin domains.•RARα is a key nuclear receptor for retinoid-dependent lymphocyte cell adhesion. 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.