Plasma Metabolomics In Chronic Urticaria

Background: Chronic urticaria(CU)is a chronic inflammatory and immune skin disorder,characterized by recurrent wheal and/or angioedema.The lifetime prevalence of chronic urticaria is about 4.4%,and about 11.4% of patients with CU suffer from a total disease duration more than 5 years,imposing a large burden on patients’ life quality as well as on social economy.It is well established that CU is a mast cell-driven immunoinflammatory disease that possibly related to autoimmunity,coagulation cascade,genetic susceptibility,infection,food and drug intolerance.Inflammatory mediators,such as histamine,released from the degranulation of mast cells lead to the recurrence of wheal and angioedema.There is no objective testing criteria or specific biomarkers for CU,therefore disease diagnosis is mainly based on clinical manifestations and medical history.The second generation H1-antihistamines are the first line treatments,however,about 40-55% of CU patients are resistant to antihistamine therapies after application of standard and doubled doses of antihistamines.In recent years,increasing evidence indicates that CU may be a metabolic-related skin disease,but current studies on the metabolome of CU are quite limited and more is needed to further investigate the pathogenesis of CU.Objectives:(1)To investigate the characteristics of plasma metabolome of CU and its subtypes;(2)To investigate the correlation between plasma differential metabolites and the clinical manifestations of CU;(3)To investigate the effects of differential metabolites of CU on passive skin anaphylaxis model in mice;(4)To investigate the effects of differential metabolites on mast cell degranulation.Methods: A total of 80 patients with CU and 82 healthy controls were included in this study.Plasma metabolome in patients with CU and healthy controls was detected by UPLC-MS/MS to identify the differential metabolites in CU and its subtypes.To observe the effects of differential metabolites of CU and its subtypes on passive skin allergic reactions in mice.Real-time quantitative PCR was used to detect the differential expression of inflammatory molecules and cytokines in mice skin lesions.Mast cell degranulation assay was used to assess the effect of differential metabolites on mast cell function.Results:(1)There were significant differences between the plasma metabolome of CU compared with healthy controls,as well as between each subtype of chronic urticaria;(2)The plasma levels of maleic acid and pyruvic acid were significantly decreased and the plasma levels of aspartate was significantly increased in CU patients;(3)The changes in plasma differential metabolites of chronic urticaria were correlated with clinical manifestations of CU: aspartic acid and pyruvic acid were negatively correlated with UAS7 scores,aspartic acid and pyruvic acid were positively correlated with UCT scores,and aspartic acid was negatively correlated with DLQI scores;(4)In vivo and in vitro experiments showed that pyruvic acid alleviated passive skin anaphylaxis model in mice and reduced the degranulation of mast cells.Conclusion: There are differences between the plasma metabolome of CU patients and the healthy population,and plasma levels of differential metabolites is correlated with the score of clinical manifestations.The plasma differential metabolite,pyruvic acid,could decrease the level of mast cell degranulation.