Blockage of sphingosine‐1‐phosphate receptor 2 attenuates allergic asthma in mice

Abstract

Background and Purpose: Sphingosine-1-phosphate 2 (S1P 2 ) receptors have been implicated in degranulation of mast cells. However, functions of S1P 2 receptors have not been investigated in an in vivo model of allergic asthma.Experimental Approach: Using an ovalbumin (OVA)-induced asthma model, the function of S1P 2 receptors was evaluated in S1P 2 -deficient mice or in mice treated with JTE-013, a selective S1P 2 antagonist. Bone marrow-derived dendritic cells (BMDCs) were used to investigate the roles of S1P 2 receptors in dendritic cell maturation and migration.Key Results: Eosinophil accumulation and elevated Th2 cytokine levels in bronchoalveolar lavage fluid and inflamed lung tissues were strongly inhibited by administration of JTE-013 before OVA sensitization, before OVA challenge, and before both events. In S1P 2 -deficient mice, allergic responses were significantly lower than in wild-type mice. LPS-and OVA-induced maturation of BMDCs was significantly blunted in dendritic cells from S1P 2 -deficient mice and by treatment with JTE-013.Migrations of immature and mature BMDCs were also dependent on S1P 2 receptors.It was found that OVA-challenged mice into which in vitro OVA primed BMDCs from S1P 2 -deficient mice were adoptively transferred, had less severe asthma responses than OVA-challenged mice into which OVA-primed BMDCs from wild-type mice were adoptively transferred.Conclusions and Implications: Pro-allergic functions of S1P 2 receptors were elucidated in a murine asthma model. S1P 2 receptors were involved not only in maturation and migration of dendritic cells in the sensitization phase but also in mast cell degranulation in the challenge phase. These results suggest S1P 2 receptor as a therapeutic target for allergic asthma.

Topical Application of S1P2 Antagonist JTE-013 Attenuates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis in Mice

“…Furthermore, topical application could avoid the possible side effects of systemic JTE-013 administration. In addition, this study supports the previous finding of pro-allergic functions of S1P 2 ( Park and Im, 2019a ) and also pro-inflammatory functions of S1P 2 ( Park and Im, 2019b ). Therefore, this finding proves a new direction for S1P 2 receptor therapeutics.…”

“…The in vivo anti-atopic effects of topical JTE-013 treatment may be caused by the inhibition of S1P 2 in mast cells and dendritic cells ( Oskeritzian et al ., 2010 ; Japtok et al ., 2012 ; Olivera et al ., 2013 ; Bock et al ., 2016 ; Park and Im, 2019a ), because S1P 2 has been proven to function as an activator of mast cell degranulation and dendritic cell maturation and migration ( Prieschl et al ., 1999 ; Oskeritzian et al ., 2010 ; Park and Im, 2019a ). However, the inhibition of S1P 2 in other cell types such as keratinocytes also could contribute to the effect of JTE-013 ( Kim et al ., 2004 ; Jeong et al ., 2015 ).…”

“…Synthesized cDNA products, primers for each gene, and Promega Go-Taq DNA polymerase (Madison, WI, USA) were used for PCR. Specific primers and PCR conditions were previously described ( Park and Im, 2019a ). Aliquots (5 μL) were electrophoresed in 1.2% agarose gels and stained with StaySafeTM Nucleic Acid Gel Stain (Real Biotech Corporation, Taipei, Taiwan).…”

“…Previously, S1P was found to act as a pro-allergic factor via S1P 2 in murine ovalbumin-induced allergic asthma model ( Park and Im, 2019a ). In addition, S1P modulates antigen capture by murine and human Langerhans cells via S1P 2 in the skin ( Japtok et al ., 2012 ; Bock et al ., 2016 ).…”

Streptococcus pneumoniae aminopeptidase N regulates dendritic cells that attenuates type‐2 airway inflammation in murine allergic asthma

“…Study by Schulke et al showed that the fusion protein of flagellin A and OVA suppressed the Th2 response and prevented murine intestinal allergy when administrated during or before sensitization (Schulke et al, 2011). Park et al also investigated the effect of a sphingosine-1-phosphate 2 antagonist on allergic asthma in mice when treated during or before sensitization (Park & Im, 2019). In this context, we mainly studied the effect of S. pneumoniae aminopeptidase N (PepN) on allergic asthma when administrated during OVA sensitization and its mechanism and we also performed a model of prophylactic administration of PepN to further confirmed the protective effect of PepN on allergic asthma.…”