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

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.