Neuroimmune modulation in liver pathophysiology.

The liver, the largest organ in the human body, plays a multifaceted role in digestion, coagulation, synthesis, metabolism, detoxification, and immune defense. Changes in liver function often coincide with disruptions in both the central and peripheral nervous systems. The intricate interplay between the nervous and immune systems is vital for maintaining tissue balance and combating diseases. Signaling molecules and pathways, including cytokines, inflammatory mediators, neuropeptides, neurotransmitters, chemoreceptors, and neural pathways, facilitate this complex communication. They establish feedback loops among diverse immune cell populations and the central, peripheral, sympathetic, parasympathetic, and enteric nervous systems within the liver. In this concise review, we provide an overview of the structural and compositional aspects of the hepatic neural and immune systems. We further explore the molecular mechanisms and pathways that govern neuroimmune communication, highlighting their significance in liver pathology. Finally, we summarize the current clinical implications of therapeutic approaches targeting neuroimmune interactions and present prospects for future research in this area.

Vagus nerve modulates acute-on-chronic liver failure progression via CXCL9.

BACKGROUND: Hepatic inflammatory cell accumulation and the subsequent systematic inflammation drive acute-on-chronic liver failure (ACLF) development. Previous studies showed that the vagus nerve exerts anti-inflammatory activity in many inflammatory diseases. Here, we aimed to identify the key molecule mediating the inflammatory process in ACLF and reveal the neuroimmune communication arising from the vagus nerve and immunological disorders of ACLF. METHODS: Proteomic analysis was performed and validated in ACLF model mice or patients, and intervention animal experiments were conducted using neutralizing antibodies. PNU-282987 (acetylcholine receptor agonist) and vagotomy were applied for perturbing vagus nerve activity. Single-cell RNA sequencing (scRNA-seq), flow cytometry, immunohistochemical and immunofluorescence staining, and CRISPR/Cas9 technology were used for in vivo or in vitro mechanistic studies. RESULTS: The unbiased proteomics identified C-X-C motif chemokine ligand 9 (CXCL9) as the greatest differential protein in the livers of mice with ACLF and its relation to the systematic inflammation and mortality were confirmed in patients with ACLF. Interventions on CXCL9 and its receptor C-X-C chemokine receptor 3 (CXCR3) improved liver injury and decreased mortality of ACLF mice, which were related to the suppressing of hepatic immune cells' accumulation and activation. Vagus nerve stimulation attenuated while vagotomy aggravated the expression of CXCL9 and the severity of ACLF. Blocking CXCL9 and CXCR3 ameliorated liver inflammation and increased ACLF-associated mortality in ACLF mice with vagotomy. scRNA-seq revealed that hepatic macrophages served as the major source of CXCL9 in ACLF and were validated by immunofluorescence staining and flow cytometry analysis. Notably, the expression of CXCL9 in macrophages was modulated by vagus nerve-mediated cholinergic signaling. CONCLUSIONS: Our novel findings highlighted that the neuroimmune communication of the vagus nerve-macrophage-CXCL9 axis contributed to ACLF development. These results provided evidence for neuromodulation as a promising approach for preventing and treating ACLF.

sTREM-1 as promising prognostic biomarker for acute-on-chronic liver failure and mortality in patients with acute decompensation of cirrhosis.

BACKGROUND: Acute decompensation (AD) of cirrhosis is associated with high short-term mortality, mainly due to the development of acute-on-chronic liver failure (ACLF). Thus, there is a need for biomarkers for early and accurate identification of AD patients with high risk of development of ACLF and mortality. Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is released from activated innate immune cells and correlated with various inflammatory processes. AIM: To explore the prognostic value of sTREM-1 in patients with AD of cirrhosis. METHODS: A multicenter prospective cohort of 442 patients with cirrhosis hospitalized for AD was divided into a study cohort (n = 309) and validation cohort (n = 133). Demographic and clinical data were collected, and serum sTREM-1 was measured at admission. All enrolled patients were followed-up for at least 1 year. RESULTS: In patients with AD and cirrhosis, serum sTREM-1 was an independent prognosis predictor for 1-year survival and correlated with liver, coagulation, cerebral and kidney failure. A new prognostic model of AD (P-AD) incorporating sTREM-1, blood urea nitrogen (BUN), total bilirubin (TBil), international normalized ratio (INR) and hepatic encephalopathy grades was established and performed better than the model for end-stage liver disease (MELD), MELD-sodium (MELD-Na), chronic liver failure-consortium (CLIF-C) ACLF and CLIF-C AD scores. Additionally, sTREM-1 was increased in ACLF and predicted the development of ACLF during first 28-d follow-up. The ACLF risk score incorporating serum sTREM-1, BUN, INR, TBil and aspartate aminotransferase levels was established and significantly superior to MELD, MELD-Na, CLIF-C ACLF, CLIF-C AD and P-AD in predicting risk of ACLF development. CONCLUSION: Serum sTREM-1 is a promising prognostic biomarker for ACLF development and mortality in patients with AD of cirrhosis.

The clinical courses of HBV-related acute-on-chronic liver failure and a multi-state model to predict disease evolution.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a highly dynamic syndrome. The objective of this study was to delineate the clinical course of patients with HBV-ACLF and to develop a model to estimate the temporal evolution of disease severity. METHODS: We enrolled eligible patients from 2 large, multicenter prospective cohorts. The ACLF grade, organ failures, and outcomes were assessed at multiple time points (days 1/4/7/14/21/28). Probabilities for ACLF transitions between these disease states and to death within 28 days were calculated using a multi-state model that used baseline information and updated ACLF status. The model was validated in independent patients. RESULTS: Among all the 445 patients with HBV-ACLF, 76 represented disease progression, 195 had a stable or fluctuating course, 8 with improvement, and the remaining 166 with resolution within 28-day follow-up. New coagulation (63.64%) or renal failure (45.45%) was frequently observed during early progression. Patients with disease progression had a higher incidence of new episodes of ascites [10 (13.16%) vs. 22 (5.96%), p = 0.027] and HE [13(17.11%) vs. 21 (5.69%), p = 0.001], and a significant increase in white blood cell count. The multi-state model represented dynamic areas under the receiver operating characteristic curves ranging from 0.71 to 0.84 for predicting all ACLF states and death at 4, 7, 14, 21, and 28 days post-enrollment and from 0.73 to 0.94 for predicting death alone, performing better than traditional prognostic scores. CONCLUSIONS: HBV-ACLF is a highly dynamic syndrome with reversibility. The multi-state model is a tool to estimate the temporal evolution of disease severity, which may inform clinical decisions on treatment.

HMGB1 in the interplay between autophagy and apoptosis in cancer.

Lysosome-mediated autophagy and caspase-dependent apoptosis are dynamic processes that maintain cellular homeostasis, ensuring cell health and functionality. The intricate interplay and reciprocal regulation between autophagy and apoptosis are implicated in various human diseases, including cancer. High-mobility group box 1 (HMGB1), a nonhistone chromosomal protein, plays a pivotal role in coordinating autophagy and apoptosis levels during tumor initiation, progression, and therapy. The regulation of autophagy machinery and the apoptosis pathway by HMGB1 is influenced by various factors, including the protein's subcellular localization, oxidative state, and interactions with binding partners. In this narrative review, we provide a comprehensive overview of the structure and function of HMGB1, with a specific focus on the interplay between autophagic degradation and apoptotic death in tumorigenesis and cancer therapy. Gaining a comprehensive understanding of the significance of HMGB1 as a biomarker and its potential as a therapeutic target in tumor diseases is crucial for advancing our knowledge of cell survival and cell death.