Histidine alleviates Hashimoto's thyroiditis via the neutrophil extracellular traps-NF-κB signaling pathway.

Metabolite abnormalities are potentially implicated in pathogenesis of Hashimoto’s thyroiditis (HT). An in-depth study of the relationship between HT and small molecule metabolites, as well as its pathogenesis, can help enhance the diagnosis, prognosis, and treatment of HT patients. We used metabolomics to analyze changes in serum metabolite levels in 20 HT patients and 20 healthy controls (HC) and the most significant differentially expressed metabolite was analyzed. Western blot and qPCR were used to measure the expression of histidine decarboxylase (HDC) and histamine receptor 1 (H1R). Increasing concentrations of histidine were used to treat neutrophils and observe the effect on neutrophil extracellular traps (NETs) synthesis. Histidine treated neutrophils were co-culture with thyroid follicular cells to study the protective effects of histidine on HT thyroid follicular cells and related mechanisms. A total of 48 differentially expressed metabolites were found. Histidine exhibited reduced expression levels in HT patients, displaying the most significant discrepancy (p < 0.001). ROS and NETs were increased and HDC, H1R, and histamine were upregulated in neutrophils upon stimulated. These effects were corrected by addition of histidine, in a dose dependent manner. In addition, in co-culture experiments, histidine enhanced expression of SOD and suppressed production of inflammatory cytokines IL-6 and TNF-α and NF-κB pathway in thyroid follicular cells, thereby inhibiting inflammation and oxidative stress. Histidine inhibits NETs synthesis and NF-κB signaling. Thus, histidine play an anti-inflammatory and antioxidant role by decreasing thyroid follicular cell inflammation in HT.