Functions of 1,25-dihydroxy vitamin D3, vitamin D3 receptor and interleukin-22 involved in pathogenesis of gout arthritis through altering metabolic pattern and inflammatory responses

Abstract

Background. Gouty arthritis (GA) is a common type of inflammatory arthritis. Recent studies demonstrated that 1,25-dihydroxy vitamin D3 (1,25(OH) 2 VD3) and vitamin D3 receptor (VD-R) play a protective role in acute inflammation, but interleukin-22(IL- 22) promotes inflammation, especially for arthritis. However, our understanding of the responses of 1,25(OH) 2VD3 and IL-22 to gout was still unclear. Presently, in-depth metabolomics, bioinformatics and clinical characteristics analyses were performed to elucidate the pathogenesis and valuable clinical indicators of gouty arthritis. Methods. Peripheral venous blood was taken for investigation. The levels of IL-22 and 1,25(OH)2VD3 were determined in patient's plasma via ELISA, and the mRNA levels of IL-22 and VD-R were measured via qRT-PCR. The interaction network of VD-R and IL22 were constructed by the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and the biological function of the related proteins were analyzed by Clusterprofiler Metabolomics were performed to decipher the metabolic variations of GA. Results. The levels of VD-R and 1,25(OH) 2 VD3 were identified to be low. What, s more, GA patients were reported to have high expression of IL-22. And IL-22 levels positively correlated with C-reactiveprotein (CRP) serum levels in the bivariate correlation analysis, whereas the level of 1,25(OH) 2VD3 negatively correlated with that of CRP. GO and KEGG analyses revealed that IL-22 and 1,25(OH) 2 VD3 were involved in stress immunity and inflammatory responses. These pathways are known to play a role in GA pathogenesis. Meanwhile, the metabolic profiles of GA serum showed that the increase in various amino acids and uric acid are involved in GA pathogenesis. Importantly, VD-R and IL22 closely correlated with the level of key metabolites uric acid, whose increase promoted the occurrence of GA. Conclusion. GA patients have low levels of VD-R and 1,25(OH) 2 VD3, and high levels of IL-22 together with various amino acids and uric acid. The levels of IL-22 and 1,25(OH) 2VD3 were positively and negatively correlated with C-reactive protein (CRP) serum levels, respectively. Both IL-22 and 1,25(OH) 2 VD3 functioned in GA- related immune and inflammatory responses, and closely correlated with the level of GA-related uric acid. Overall, IL-22, VD-R and 1,25(OH) 2 VD3 play functionally important roles in inflammatory responses and are relevant to gout pathogenesis.