SIRT3 Activator Honokiol Inhibits Th17 Cell Differentiation and Alleviates Colitis

Astract Background Honokiol (HKL), a natural extract of the bark of the magnolia tree and an activator of the mitochondrial protein sirtuin-3 (SIRT3), has been proposed to possess anti-inflammatory effects. This study investigated the inhibitory effects of HKL on T helper (Th) 17 cell differentiation in colitis. Methods Serum and biopsies from 20 participants with ulcerative colitis (UC) and 18 healthy volunteers were collected for the test of serum cytokines, flow cytometry analysis (FACS), and relative messenger RNA (mRNA) levels of T cell subsets, as well as the expression of SIRT3 and phosphorylated signal transducer and activator of transcription/retinoic acid-related orphan nuclear receptor gamma t (p-STAT3/ROR gamma t) signal pathway in colon tissues. In vitro, naive clusters of differentiation (CD) 4 + T cells isolated from the mouse spleen differentiated to subsets including Th1, Th2, Th17, and regulatory T (Treg) cells. Peripheral blood monocytes (PBMCs) from healthy volunteers were induced to the polarization of Th17 cells. After HKL treatment, changes in T cell subsets, related cytokines, and transcription factors were measured. The dextran sulfate sodium (DSS)-induced colitis and interleukin (IL)-10-deficient mice were intraperitoneally injected with HKL. These experiments were conducted to study the effect of HKL on the development, cytokines, and expression of signaling pathway proteins in colitis. Results Patients with UC had higher serum IL-17 and a higher proportion of Th17 differentiation in blood compared with healthy participants; while IL-10 level and the proportion of Treg cells were lower. Higher relative mRNA levels of ROR gamma t and a lower SIRT3 expression in colon tissues were observed. In vitro, HKL had little effect on the differentiation of naive CD4(+) T cells to Th1, Th2, or Treg cells, but it downregulated IL-17 levels and the Th17 cell ratio in CD4(+) T cells from the mouse spleen and human PBMCs under Th17 polarization. Even with a STAT3 activator, HKL still significantly inhibited IL-17 levels. In DSS-induced colitis mice and IL-10 deficient mice treated with HKL, the length of the colon, weight loss, disease activity index, and histopathological scores were improved, IL-17 and IL-21 levels, and the proportion of Th17 cells were decreased. Sirtuin-3 expression was increased, whereas STAT3 phosphorylation and ROR gamma t expression were inhibited in the colon tissue of mice after HKL treatment. Conclusions Our study demonstrated that HKL could partially protect against colitis by regulating Th17 differentiation through activating SIRT3, leading to inhibition of the STAT3/ROR gamma t signaling pathway. These results provide new insights into the protective effects of HKL against colitis and may facilitate the research of new drugs for inflammatory bowel disease. An imbalance in Th17/Treg cells is one of the leading causes of inflammatory bowel disease. In this introductory study, honokiol (HKL), an activator of mitochondrial protein SIRT3, has been shown to inhibit Th17 cell differentiation and alleviate colitis through the activation of SIRT3 and inhibition of the STAT3/ROR gamma t signaling pathway. Honokiol has been poorly studied in IBD; therefore, this study provides new directions for treating IBD.

Automated summary

This study found that Honokiol (HKL), an active compound in magnolia bark, can inhibit the differentiation of Th17 cells in ulcerative colitis by activating SIRT3. The results of the experiments showed that HKL can regulate Th17 cell differentiation by activating SIRT3 and inhibiting the STAT3/ROR gamma t signaling pathway, thus partially alleviating the symptoms of colitis.