Pathological functions of interleukin-22 in chronic liver inflammation and fibrosis with hepatitis B virus infection by promoting T helper 17 cell recruitment

Abstract

It is well established that interleukin (IL)-22 has hepatoprotective and anti-fibrotic functions in acute liver injury models; however, its function in patients with liver fibrosis and liver cirrhosis (LC) remains obscure. In the current study, we demonstrated that expression of numerous IL-22 pathway-associated genes was significantly upregulated in hepatitis B virus (HBV)-infected liver tissues compared with normal controls through microarray analysis. In agreement with these findings, liver-infiltrating IL-22+ cells were largely increased in HBV-infected patients with LC compared with those without LC or healthy subjects, and were positively associated with liver fibrosis staging scores. Immunohistochemistry and flow cytometric analyses revealed that IL-22 was produced by multiple intrahepatic immune cells, and preferentially by Th17 cells in LC patients. In a HBV transgenic mouse model of T cell-mediated chronic liver inflammation/fibrosis, blockade of IL-22 attenuated hepatic expression of CXCL10 and CCL20, and subsequently reduced Th17 recruitment and liver inflammation/fibrosis progression. In vitro treatment with IL-22 stimulated hepatic stellate cells (HSCs) to secret several chemokines and subsequently promoted Th17 cell chemotaxis. Blocking CXCR3 or CCL20 reduced Th17 cell chemotaxis by IL-22-treated HSCs. Conclusions Our findings suggest that IL-22 plays a pathological role in exacerbating chronic liver inflammation and fibrosis by recruiting hepatic Th17 cells in HBV infected patients and HBV transgenic mice.

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“…As with others, 3 we observed a strong positive association between SF and alcohol consumption. Adjusting for alcohol provides greater power to detect associations with modifier alleles, but it is not apparent whether Bardou-Jacquet et al made such an adjustment.…”

Plasmacytoid dendritic cells promote HIV-1–induced group 3 innate lymphoid cell depletion

“…The humanized mouse model will also serve as a valuable model to develop therapeutics that target pDC/IFN-I and restore functions of human ILC3s in HIV-1-infected patients. jci.org Volume 125 Number 9 September 2015 tions according to our protocols (44 (57). Briefly, the tissues were incubated overnight with primary Abs (anti-human CD3, anti-human IL-17, and anti-human IL-22, all diluted 1:10) followed by secondary Abs (rabbit anti-mouse FITC-conjugated IgG Ab, rhodamine-conjugated goat anti-mouse IgG Ab, and DAPI for nucleic acid staining) for 45 minutes at room temperature.…”

“…IL-17 and IL-22 are important for protection against mucosal bacterial infections and for maintenance of the mucosal barrier by promotion of intestinal epithelial integrity (24,39,40). Multiple immune cells, including Th17 cells (44), NKp44 + NK22 cells (7,22,25), and CD3 -CD8 hi subsets (21), could produce these 2 cytokines. The loss of these cells in chronic HIV-1/SIV infection has been correlated with breakdown of intestinal mucosal integrity, resulting in microbial translocation, chronic immune activation, and disease progression (21,22,24,25,(45)(46)(47).…”

Expression of the novel adipokine C1qTNF-related protein 4 (CTRP4) suppresses colitis and colitis-associated colorectal cancer in mice

“…27,45 However, in LECs, IL-22 is detrimental and can mediate chronic hepatitis and fibrosis, as indicated by the observation that the blockade of IL-22 attenuated the hepatic expression of chemokine (C-X-C motif) ligand 10 and chemokine (C-C motif) ligand 20 (CCL20) and subsequently reduced Th17 recruitment as well as liver inflammation and fibrosis progression. 46 In summary, our results suggest that CTRP4 plays an important role in colitis and inflammation-associated colon tumorigenesis. CTRP4 may be involved in the regulation of the inflammatory network.…”