To the best of our knowledge, this is the first study investigating serum RVE1 in HT patients. In the present study, we found that the serum RVE1 level in the HT group was significantly lower than that in the control group, which might indicate dysregulation of inflammation resolution in HT patients.
Omega-3 PUFAs can produce lipid mediators with both anti-inflammatory and pro-resolution properties, including resolvins [22]. The anti-inflammatory action indicates that proinflammatory mediators are suppressed, while pro-resolution represents the activation of the termination process of inflammation, such as the removal of apoptotic cells by macrophages [23]. Dysregulation of resolution has been shown to increase the risk of autoimmune diseases. Although anti-inflammatory drugs can improve the symptoms of autoimmune diseases, they cannot achieve the purpose of curing the disease and are even ineffective for most patients. Therefore, the combination of anti-inflammation and pro-resolution may become a superior treatment method. Moreover, pro-resolution pathways themselves will not increase the body's susceptibility to infection [24]. Omega-3 PUFAs have shown therapeutic potential in some autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and type 1 diabetes mellitus (T1DM) [25]. After treatment with omega-3 PUFAs in patients with inflammatory arthritis, the RVE1 in the knee effusion and plasma was significantly higher than that in the healthy control group, suggesting that RVE1 may be the mediator of omega-3 PUFAs [26]. In the present study, the serum levels of RVE1 in HT patients were significantly lower than those in HCs. We inferred that this might be a sign that HT is associated with inflammatory resolution dysfunction. Similarly, RVE1 was also a marker of inflammatory resolution defects in other diseases, such as cardiovascular diseases [27], periodontitis [28], and type 2 diabetes mellitus [29].
In this study, we also analyzed the correlation between RVE1 levels and thyroid antibodies. The HT patients recruited in our study were euthyroid, so the interference of thyroid hormones can be excluded. Spearman correlation analysis showed that RVE1 levels were negatively correlated with TgAb (r=-0.426, P = 0.001). As the TgAb level increased, the RVE1 content showed a decreasing trend (P for trend = 0.001). Moreover, multivariable ordinal logistic regression analysis showed that RVE1 was negatively correlated with TgAb in both the unadjusted (OR = 0.9446, 95% CI = 0.9111–0.9782, P = 0.002) and adjusted models (OR = 0.9380, 95% CI = 0.8967–0.9811, P = 0.005). We also assessed the relationship between RVE1 and TPOAb levels, and as TPOAb increased, the RVE1 levels showed an inverted U-shaped trend (P for trend = 0.036). However, when the logistic model was adjusted for age, sex, TT3, TT4, TSH, FT3, FT4, and TgAb, RVE1 showed no significant correlation with increasing TPOAb (OR = 0.9860, 95% CI = 0.9627-1.010, P = 0.244). Although it is currently believed that TgAb is not as specific and sensitive as TPOAb, some studies have confirmed that TgAb and TPOAb may represent two different aspects of thyroid autoimmunity. TgAb represents the initial or innate immune response, and TPOAb represents the later adaptive immune response [1]. Studies have confirmed a significant positive correlation between TgAb and clinical symptoms (fragile hair, face edema, edema of the eyes and harsh voice) in untreated HT patients [29]. Therefore, we speculate that RVE1 may be a protective factor for elevated TgAb levels. However, further research is needed to verify the relationship between RVE1 and TgAb.
A recent study confirmed that topical application of RVE1 can alleviate inflammation-induced tissue damage and reduce bone loss in an animal model of periodontitis [30]. Similarly, RVE1 could reverse experimental periodontitis and malnutrition [31]. RVE1 can inhibit the activation of dental pulp fibroblasts in a ChemR23-dependent manner and inhibit inflammation in the early stages of pulpitis [32]. The pathogeneses of autoimmune thyroid disease and periodontitis are different: the former is an autoimmune-driven disease, and the latter is an infection-driven disease. However, the two have many common pathological and immunological characteristics, such as autoimmune antibodies, apoptosis, inflammation, and oxidative stress. Therefore, we infer that RVE1 may also have a protective effect on HT [33]. Further longitudinal studies are needed to verify our speculation. In some other diseases, the application of RVE1 has also been shown to promote inflammation resolution. RVE1 can reduce airway responsiveness and inflammation in asthmatic mice [34]. Moreover, RVE1 can reduce neutrophil infiltration, reduce proinflammatory cytokine expression, and reduce inflammatory pain [35]. Oral or topical application of RVE1 can prevent vascular inflammation and arteriosclerosis and reduce systemic CRP levels [36]. RVE1 can reduce lipopolysaccharide (LPS)-induced proinflammatory factors (IL-8, MCP-1) in isolated human pancreatic islets and exhibit antiapoptotic effects in a proinflammatory environment [37].
This study has many limitations. First, our study was a cross-sectional study, and whether RVE1 undergoes dynamic alterations related to changes in thyroid function and thyroid autoimmunity could not be determined. Second, our sample size was small; thus, a longitudinal study with a larger sample size is needed to explore the role of RVE1 in HT.
In conclusion, we found that the serum content of RVE1 in HT patients was significantly lower than that in HCs, and RVE1 may be a protective factor for elevated TgAb levels. A follow-up longitudinal study with a larger sample size is needed to verify the role of RVE1 in the development of HT.