Itaconate attenuates autoimmune hepatitis via PI3K/AKT/mTOR pathway-mediated inhibition of dendritic cell maturation and autophagy

Qiyu Zhang; Yang Luo; Qiuxia Zheng; Haixia Zhao; Xiaofeng Wei; Xun Li

doi:10.1016/j.heliyon.2023.e17551

Itaconate attenuates autoimmune hepatitis via PI3K/AKT/mTOR pathway-mediated inhibition of dendritic cell maturation and autophagy

Heliyon. 2023 Jun 22;9(7):e17551. doi: 10.1016/j.heliyon.2023.e17551. eCollection 2023 Jul.

Authors

Qiyu Zhang^{1

2

3}, Yang Luo^{4

5}, Qiuxia Zheng¹, Haixia Zhao¹, Xiaofeng Wei^{1

4}, Xun Li^{1

2

4

3

5}

Affiliations

¹ The First School of Clinical Medicine, Lanzhou University, 730000 Lanzhou, China.
² Department of General Surgery, The First Hospital of Lanzhou University, 730000 Lanzhou, China.
³ Hepatopancreatobiliary Surgery Institute of Gansu Province, The First Hospital of Lanzhou University, 730000 Lanzhou, China.
⁴ Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, 730000 Lanzhou, China.
⁵ Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, 730000 Lanzhou, China.

Abstract

Autoimmune hepatitis (AIH) results from an autoimmune-mediated chronic inflammatory response against liver cells. Defective self-tolerance and dysfunctional dendritic cells (DCs) play a regulatory role in AIH. Itaconate has recently attracted attention in the field of immunometabolism because of its crucial role as an anti-inflammatory metabolite that negatively regulates the inflammatory response. However, the underlying mechanism of itaconate mediation of DCs in AIH remains unclear. In this study, we found that itaconate acts as an anti-inflammatory factor in the liver. Endogenous itaconate levels were significantly increased in mice with S100-induced AIH model and correlated with upregulation of the immune-responsive gene 1 expression. However, the anti-inflammatory response from endogenously itaconate may not represent the effects exogenously-produced itaconate. We investigated the anti-inflammatory response from exogenous itaconate in S100-induced AIH, and our results showed that itaconate treatment attenuated liver histopathological damage, hepatocyte apoptosis, aminotransferase elevation, and IL-6 production in the S100-induced AIH model. In addition, Itaconate decreased glycolysis to suppress the maturation of DCs in the liver and spleen of AIH models, thereby directly regulating differentiation of Th17 and Tregs in vivo. The percentage of Th17 cells among the CD4⁺ population were decreased and Tregs were increased (P < 0.05). Furthermore, Itaconate-induced bone marrow-derived monocytes suppressed CD4⁺cells proliferation. In vitro and in vivo, we found that itaconate suppressed autophagy via activating the PI3K/AKT/mTOR signalling pathway in bone marrow-derived DCs and liver tissues. We further investigated the function of Itaconate on DC-specific mTOR-deficient mice. mTOR-deficient DCs augmented inflammatory reactions in mTOR^DC-/- AIH mice and induced autophagy. MHY1485 (an agonist of mTOR) and itaconate significantly alleviated the inflammatory reaction and autophagy signalling. In conclusion, itaconate ameliorate liver inflammation in S100-induced AIH mice by regulating the PI3K/AKT/mTOR pathway to decrease DCs autophagy and maturation. These results provide insight useful for treating AIH.

Keywords: Autoimmune hepatitis; Autophagy; Dendritic cell; Itaconate; PI3K/AKT/mTOR.