1. Academic Validation
  2. Interleukin-22 regulating Kupffer cell polarization through STAT3/Erk/Akt crosstalk pathways to extenuate liver fibrosis

Interleukin-22 regulating Kupffer cell polarization through STAT3/Erk/Akt crosstalk pathways to extenuate liver fibrosis

  • Life Sci. 2021 Jan 1;264:118677. doi: 10.1016/j.lfs.2020.118677.
Si-Biao Su 1 Shan-Yu Qin 1 Xiao-Long Xian 2 Fei-Fei Huang 2 Qiu-Lan Huang 2 Han-Jing ZhangDi 2 Hai-Xing Jiang 3
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Province, China.
  • 2 Graduate School of Guangxi Medical University, Nanning 530021, Guangxi Province, China.
  • 3 Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Province, China. Electronic address: jianghaixing2001@163.com.
Abstract

Aims: Interleukin (IL)-22 activates multiple signaling pathways to exert anti-inflammatory effects, but few studies have examined whether and how IL-22 may shift macrophage polarization between M1 (pro-inflammatory) and M2 (anti-inflammatory) states and thereby influence the progression of hepatic fibrosis.

Main methods: Utilized CCl4 to induce liver fibrosis in mice, detected the role of IL-22 in inhibiting liver fibrosis by regulating Kupffer cells (KCs) polarization in vivo and in vitro. U937 cells were used to confirm the mechanism of IL-22 regulating macrophage polarization via the STAT3/ERK/Akt pathways. Human liver specimens were collected to verify the correlation between the levels of IL-22 and KCs during liver fibrogenesis.

Key findings: During CCl4-induced liver fibrosis progression in mice, adding exogenous IL-22 significantly inhibited pro-fibrogenic and macrophage phenotype-altering factors secreted by M1-KCs, and it increased the number of M2-KCs. In co-cultures of hepatic stellate cells and KCs from mice treated with IL-22, a high M2/M1-KCs ratio inhibited collagen production and stellate cell activation. These results suggest that IL-22 can increase the ratio of M2-KCs to M1-KCs and thereby attenuate the progression of liver fibrosis. Mechanistic studies in vitro showed that IL-22 promoted polarization of lipopolysaccharide-treated U937 macrophages from M1 to M2. The cytokine exerted these effects by activating the STAT3 pathway while suppressing ERK1/2 and Akt pathways. Furthermore, immunofluorescent staining in human liver specimens confirmed that IL-22 levels positively correlated with the number of M2-KCs during liver fibrogenesis.

Significance: IL-22 regulates the STAT3/ERK/Akt to increase the M2/M1-KCs ratio and thereby slow liver fibrogenesis.

Keywords

Hepatic stellate cell; Interleukin-22; Kupffer cell; Liver fibrosis; Polarization.

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