Retinoic acids up‐regulate functional eosinophil‐driving receptor CCR3

Abstract

Eotaxins and their receptor CCR3 have a definitive role for tissue accumulation of eosinophils both under homeostatic and pathologic conditions. However, physiological stimuli that can up-regulate CCR3 in blood-derived human eosinophils have not been recognized. As a prior gene microarray study revealed up-regulation of CCR3 in eosinophils stimulated with retinoic acids (RAs), the expression of functional CCR3 was examined. We found that 9-cis RA and all-trans RA (ATRA) significantly induced surface CCR3 expression regardless of the presence of IL-3 or IL-5. Pharmacological manipulations with receptor-specific agonists and antagonists indicated that retinoic acid receptor-α activation is critical for CCR3 up-regulation. RA-induced CCR3 was associated with its functional capacity, in terms of the calcium mobilization and chemotactic response to eotaxin-1 (CCL11). Our study suggests an important role of vitamin A derivatives in the tissue accumulation of eosinophils.

Eosinophil ETosis and DNA Traps: a New Look at Eosinophilic Inflammation

“…Since the majority of eosinophils normally reside within mucosal tissues interfacing with the environment [42, 43], it is conceivable that crosslinking of IgA receptors induces EETosis and contributes to mucosal immunity. High concentration of monosodium urate induces rapid eosinophil death [44] and DNA traps [45], suggesting that endogenous danger signals also elicit EETosis.…”

Mare's and cow's milk: promote similar metabolic effects and expression of innate markers in Caco-2 cells?

“…Molecular complexes between β-lg and retinoids provoke inflammation and hypersensitivity due to interactions with the transient receptor potential channel vanilloid subtype 1 (TRPV1) (Yin et al, 2013). Moreover, these protein domains up-regulate the eosinophil-driving receptor CCR3 (Ueki et al, 2013). These characteristics indicate that the digestion of β-lg is a key process in food tolerance and allergenicity.…”

Eliciting Eosinophil CCR3 Expression by Synthetic Retinoids

“…In a series in our previous study, we found that naturally occurring retinoids, retinoic acids ( RAs ), elicit CCR 3 expression on human blood eosinophils. 2 Peripheral blood eosinophils constitutively express nuclear receptors for retinoids, RA receptor ( RAR) -α, -β, and -γ, and retinoid X receptor (RXR)-α and -β. 3 Using a gene microarray, we have screened up-regulation of CCR3 transcription in RAstimulated eosinophils.…”

“…Furthermore, RA-induced CCR3 leads to enhanced functional capacities in terms of calcium signaling and chemotactic responses. 2 Surprisingly, RAs are the first recognized physiological CCR3 upregulator in mature human eosinophils despite the recent progress in eosinophil biology.…”

“…The effects of synthetic retinoids were studied at the concentration of 10 −7 M, which is applied to the optimal concentration for 9-cisRA. 2 Among the six synthetic retinoids we tested, Am80 (also called tamibarotene), IT-compounds (a kind gift from Dr. K. Shudo, Itsuu Laboratory, Tokyo, Japan), 5 and Ch55 up-regulated CCR3 expression ( Table 1 ) . The flow cytometric histograms indicated that the whole population of eosinophils responded to increased CCR3 expression induced by synthetic retinoids (Am80: Fig.1).…”