5-hydroxyeicosatetraenoic acid and 12-hydroxyeicosapentaenoic acid regulate basophil and mast cell activation and basophil recruitment in chronic spontaneous urticaria

BACKGROUND: The underlying pathomechanisms of wheal reaction enlargement in chronic spontaneous urticaria (CSU) remain largely unclear. We hypothesized that the activation of mast cells (MCs) and recruitment of basophils to locally inflamed skin would be enhanced by lipid mediators (LMs) following initial skin MC activation. This study aimed to identify the LMs responsible for enhancing the aggregation of IgE-mediated MC activation and basophil chemotaxis. METHODS: We enrolled 77 CSU patients and 36 non-atopic control (NC) subjects. Lipid profiling of plasma from these subjects was performed using liquid chromatography-tandem mass spectrometry/mass spectrometry. We compared LMs before and after omalizumab treatment between responders and non-responders. RESULTS: The concentration of 5-lipoxygenase-mediated LMs was significantly higher in the plasma obtained from patients than in the plasma obtained from NC subjects. The stepwise model demonstrated that 5-hydroxyeicosatetraenoic acid (HETE) (odds ratio, 3.34; 95 % confidence interval, 1.91-5.86; p = 0.0001) was the strongest independent marker of CSU. Here, 5-HETE significantly upregulated IgE-dependent basophil and MC activation. 12-hydroxyeicosapentaenoic acid (HEPE) demonstrated statistically significant correlations between changes in basophil counts and changes in the LM levels before and after omalizumab administration (p = 0.0146). Additionally, 12-HEPE significantly inhibits TNF-α/IFN-β-induced CCL2 mRNA expression in human keratinocytes. Furthermore, 12-HEPE showed a significant increase in concentration after omalizumab treatment in responders (p = 0.0095), but not in non-responders. CONCLUSIONS: In conclusion, 5-HETE and 12-HEPE may regulate IgE-mediated activation of MCs and basophils and recruitment of basophils in the CSU, respectively, suggesting that these LMs may be involved in the enlargement of wheal reactions.