Granulocyte Colony-Stimulating Factor Accelerates the Recovery of Hepatitis B Virus-Related Acute-on-Chronic Liver Failure by Promoting M2-Like Transition of Monocytes

Abstract

Background and AimAcute-on-chronic liver failure (ACLF) has a high mortality rate. The role of granulocyte colony-stimulating factor (G-CSF) in ACLF remains controversial. Monocytes/macrophages are core immune cells, which are involved in the initiation and progression of liver failure; however, the effect of G-CSF on monocytes/macrophages is unclear. The study aimed to verify the clinical efficacy of G-CSF and explore the effect of it on monocytes in hepatitis B virus (HBV)-related ACLF (HBV-ACLF) paitents.MethodsWe performed a large randomized controlled clinical trial for the treatment of HBV-ACLF using G-CSF. A total of 111 patients with HBV-ACLF were prospectively randomized into the G-CSF group (5 μg/kg G-CSF every day for 6 days, then every other day until day 18) or the control group (standard therapy). All participants were followed up for at least 180 days. The relationship between monocyte count and mortality risk was analyzed. The effect of G-CSF on the phenotype and function of monocytes from patients with HBV-ACLF was evaluated using flow cytometry in vivo and in vitro experiments.ResultsThe survival probability of the G-CSF group at 180 days was higher than that of the control group (72.2% vs. 53.8%, P = 0.0142). In the G-CSF-treated group, the monocyte counts on days 0 and 7 were independently associated with an evaluated mortality risk in the fully adjusted model (Model 3) [at day 0: hazard ratio (HR) 95% confidence interval (CI): 15.48 (3.60, 66.66), P = 0.0002; at day 7: HR (95% CI): 1.10 (0.50, 2.43), P=0.8080]. Further analysis showed that after treatment with G-CSF in HBV-ACLF patients, the expression of M1-like markers (HLA-DR and CD86) in monocytes decreased (HLA-DR: P = 0.0148; CD86: P = 0.0764). The expression of MerTK (M2-like marker) increased (P = 0.0002). The secretion of TNF-α, IL-6, and IL-10 from monocytes decreased without lipopolysaccharide (LPS) stimulation (TNF-α: P < 0.0001; IL-6: P= 0.0025; IL-10: P = 0.0004) or with LPS stimulation (TNF-α: P = 0.0439; P = 0.0611; IL-10: P = 0.0099). Similar effects were observed in vitro experiments.ConclusionG-CSF therapy confers a survival benefit to patients with HBV-ACLF. G-CSF can promote the anti-inflammatory/pro-restorative phenotype (M2-like) transition of monocytes, which may contribute to the recovery of ACLF.Clinical Trial Registration NumberClinicalTrials.gov, identifier (NCT02331745).

Treatment cessation in HBeAg-negative chronic hepatitis B: clinical response is associated with increase in specific proinflammatory cytokines

“…G-CSF is a hematopoietic growth factor and stimulates neutrophil development and differentiation 37 . G-CSF therapy has been used in HBV associated acute on chronic liver failure, and some Asian studies have found improved liver function and survival rates in patients receiving this treatment 38 , 39 . However, a European multicentre study on acute on chronic liver failure of different etiologies failed to demonstrate any positive effect of G-CSF therapy 40 .…”

Plasma interleukin-7 correlation with human immunodeficiency virus RNA and CD4+ T cell counts, and interleukin-5 with circulating hepatitis B virus DNA may have implications in viral control

“…Granulocyte-colony stimulating factor are primarily produced by monocytes, fibroblasts and endothelial cells of the stroma of the bone marrow ( 62 ). G-CSF can encourage monocytes to convert to an anti-inflammatory/pro-restorative phenotype (M2-like) ( 63 ), and could aid in prompt clearance of HBV ( 64 ) be inferred that G-CSF may aid in viral clearance during chronic infections. Myeloid lineage cells need GM-CSF in order to proliferate, differentiate, and survive ( 65 ).…”

An Update on the Current Management of Hepatitis B Virus in Special Populations

“…The 90-day cumulative liver transplantation free survival rate in Tα1 was 75% compared to 53.4% in the standard medical therapy group (P = 0.03), and the incidence of complications such as bacterial infection and hepatic encephalopathy was lower in the Tα1 group (32.1%) compared to the standard treatment group (58.6%) (P = 0.029) 17 . Granulocyte Colony Stimulating Factor (G-CSF) was compared to standard therapy in in a randomized control trial of 114 HBV-ACLF patients, and the G-CSF group was shown at 180 days to have greater survival (72.2 vs. 53.8%, P 0.014) 18 . However, aside from immediately starting antiviral therapy for ACLF-HBV, these newer modalities are still under investigation and cannot be recommended.…”