Compartmentalization and its implication for peripheral immunologically‐competent cells to the liver in patients with HBV‐related acute‐on‐chronic liver failure

Zou, Zhengsheng; Xu, Da; Li, Baosen; Xin, Shaojie; Zhang, Zheng; Huang, Lei; Fu, Junliang; Yang, Yongping; Jin, Lei; Zhao, Jiyun; Shi, Ming; Zhou, Guangde; Sun, Yanling; Wang, Fusheng

doi:10.1111/j.1872-034x.2009.00571.x

Cited by 40 publications

(35 citation statements)

References 22 publications

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“…Previous data from our laboratory have indicated that both mDCs and pDCs infiltrate extensively the liver of ACLF patients and have expressed mature phenotypes. 8,14 Therefore, this DC migration from the blood to the liver may lead to the decreased DC numbers found in the blood, while infiltrated DCs in liver may be involved in the pathogenesis of ACLF. This study found that the decreased numbers of mDC at baseline was associated with a high mortality of ACLF patients and further indicated that the mDC numbers of the host may determine the outcome of ACLF patients.…”

Section: Discussionmentioning

confidence: 99%

“…Many different cell types, including T lymphocytes, monocytes and DCs, are primed in ACLF, and these are believed to play a pivotal role in the pathogenesis of this disease. [6][7][8][9][10][11] Corticosteroids have been used for the treatment of severe acute hepatic failure by either oral or intravenous administration. Mechanically, corticosteroids can suppress the effects of activated macrophages, DC subsets and other inflammatory cells, [10][11] which indicates that there is a reciprocal effect on the efficacy of therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have demonstrated the functional impairment of mDCs and pDCs in patients with chronic HBV infection. [17][18][19] Notably, these dendritic cells accumulate mostly in the liver of ACLF patients; 7,8,14 however, any correlation between the DCs and corticosteroid efficacy is unknown.…”

Section: 2mentioning

confidence: 99%

“…7,8,14 Two distinct circulating dendritic cell (DC) subsets, myeloid and plasmacytoid DCs (mDCs and pDCs), have been identified in humans based on phenotypic and functional characterizations. 15,16 In general, human mDCs are well equipped to induce type 1 T helper cell polarization via the production of interleukin-12 (IL-12) or tumor-necrosis factor-a, which plays a crucial role in the development of liver damage.…”

Section: 2mentioning

confidence: 99%

“…[6][7][8][9][10][11] These changes include exacerbated innate immunologic responses, such as the activation of monocytes/macrophages and lymphocytes and cytokine release from these inflammatory cells. Clinical findings and experimental rodent models suggest that corticosteroids can suppress the effects of these activated inflammatory cells.…”

Section: 2mentioning

confidence: 99%

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Improved survival ratios correlate with myeloid dendritic cell restoration in acute-on-chronic liver failure patients receiving methylprednisolone therapy

Zhao

Zhang

et al. 2012

Cell Mol Immunol

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Acute-on-chronic liver failure (ACLF) is a severe life-threatening complication. Liver transplantation is the only available therapeutic option; however, several limitations have restricted its use in patients. The use of corticosteroids as an optional therapy for ACLF has received a great deal of interest. The rationale behind its use is the possible role of the immune system in initiating and perpetuating hepatic damage. In order to assess the relationship between myeloid dendritic cells (mDCs) and the efficacy of methylprednisolone (MP) treatment for hepatitis B virus (HBV)-associated ACLF patients, we recruited 30 HBV-associated ACLF patients who had received MP treatment at 10-day intervals; 26 patients received conservative medical (CM) management as a control. The functionality of DC subsets was lower in these ACLF patients compared with healthy subjects. In addition, compared with survivors, dead/transplanted patients had lower functional mDC in both groups. Furthermore, a decreased numbers of mDC at baseline was associated with high mortality of ACLF patients. Importantly, MP treatment resulted in a significant decrease in 28-day mortality, and all MP patients exhibited an initial rapid decrease in circulating mDC numbers within 10 days of MP treatment. Subsequently, MP survivors displayed a continuous increase in mDC numbers accompanied by a decrease in total bilirubin levels by more than 30%. However, MP dead/ transplanted patients lacked these sequential responses compared with survivors. This evidence suggests strongly that the higher mDC numbers at baseline and the recovery of mDC number at the end of treatment may represent a prognostic marker for favorable response to corticosteroid treatment in ACLF patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: 2mentioning

confidence: 99%

Section: 2mentioning

confidence: 99%

Section: 2mentioning

confidence: 99%

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Improved survival ratios correlate with myeloid dendritic cell restoration in acute-on-chronic liver failure patients receiving methylprednisolone therapy

Zhao

Zhang

et al. 2012

Cell Mol Immunol

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

et al. 2014

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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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Dysregulation of FTX/miR‐545 signaling pathway downregulates Tim‐3 and is responsible for the abnormal activation of macrophage in cirrhosis

Liu

Zhu

et al. 2018

J of Cellular Biochemistry

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Background Accumulating evidence has suggested the involvement of miR‐545 and long noncoding RNA (lncRNA) FTX in a wide range of diseases. Therefore, this study aimed to investigate the molecular mechanism underlying the function of miR‐545 and lncRNA FTX in hepatitis B virus (HBV)‐related cirrhosis. Method The level of Tim‐3, TLR‐4, and endotoxin was detected in CD14+, CD14 +CD16 +, and CD14 +CD16 − monocytes isolated from both patients with cirrhosis and healthy controls. ELISA assays were performed to detect the effect of Lipopolysaccharide (LPS) or FTX on the expression of tumor necrosis factor alpha (TNF‐a), interleukin‐6 (IL‐6), IL‐1β, and Nuclear factor kB (NF‐kB). In‐silico analysis, luciferase assay, real‐time polymerase chain reaction (PCR), and Western blot analysis were utilized to determine the regulatory relationship between miR‐545 and Tim‐3. Results The levels of Tim‐3, Tim‐3 MIF and endotoxin were reduced in the CD14+ monocytes isolated from patients with cirrhosis. In addition, the level of Tim‐3 was also decreased in the CD14 +CD16 − monocytes isolated from patients with cirrhosis, whereas the level of Tim‐3 in CD14 +CD16 + monocytes showed no evident difference between healthy controls and patients with cirrhosis. Furthermore, TLR‐4 was highly expressed in CD14 +CD16 + monocytes isolated from patients with cirrhosis, whereas Tim‐3 was negatively regulated by endotoxin and the correlation coefficient was ‐0.5287. After the LPS stimulation, although the level of TNF‐a, IL‐6, IL‐1β, and NF‐kB was higher in both patients with cirrhosis and healthy controls, the effect of LPS in patients with cirrhosis was much more significant. In addition, the cirrhosis group showed a lower level of FTX and Tim‐3, but a higher level of miR‐545. Moreover, miR‐545 directly bound to the 3′untranslated region (3′UTR) of Tim‐3 and inhibited the luciferase activity of cells cotransfected with miR‐545 mimics and wild‐type 3′UTR of Tim‐3. Furthermore, FTX downregulated the expression of miR‐545, TNF‐a, IL‐6, IL‐1β, and NF‐kB, but upregulated the expression of Tim‐3. Conclusion The results of this study confirmed the effect of FTX, miR‐545, and Tim‐3 on the expression of inflammatory cytokines, the lymphocyte/monocyte ratio, and the severity and prognosis of HBV‐related cirrhosis.

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Compartmentalization and its implication for peripheral immunologically‐competent cells to the liver in patients with HBV‐related acute‐on‐chronic liver failure

Abstract: The abnormal prevalence of circulating and intrahepatic ICCs possibly acts as an important factor that may drive the progression of HBV-related ACLF.

Cited by 40 publications

References 22 publications

Improved survival ratios correlate with myeloid dendritic cell restoration in acute-on-chronic liver failure patients receiving methylprednisolone therapy

Improved survival ratios correlate with myeloid dendritic cell restoration in acute-on-chronic liver failure patients receiving methylprednisolone therapy

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

Dysregulation of FTX/miR‐545 signaling pathway downregulates Tim‐3 and is responsible for the abnormal activation of macrophage in cirrhosis

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