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 clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (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.
Animals ; Mice ; Chemokine CXCL9/metabolism* ; Vagus Nerve/physiology* ; Acute-On-Chronic Liver Failure/metabolism* ; Humans ; Male ; Mice, Inbred C57BL ; Proteomics ; Flow Cytometry ; Receptors, CXCR3/metabolism*

The rise in global life expectancy has led to an increase in the older population, presenting significant challenges in managing infectious diseases. Aging affects the innate and adaptive immune systems, resulting in chronic low-grade inflammation (inflammaging) and immune function decline (immunosenescence). These changes would impair defense mechanisms, increase susceptibility to infections and reduce vaccine efficacy in older adults. Cellular senescence exacerbates these issues by releasing pro-inflammatory factors, further perpetuating chronic inflammation. Moreover, comorbidities, such as cardiovascular disease and diabetes, which are common in older adults, amplify immune dysfunction, while immunosuppressive medications further complicate responses to infections. This review explores the molecular and cellular mechanisms driving inflammaging and immunosenescence, focusing on genomic instability, telomere attrition, and mitochondrial dysfunction. Additionally, we discussed how aging-associated immune alterations influence responses to bacterial, viral, and parasitic infections and evaluated emerging antiaging strategies, aimed at mitigating these effects to improve health outcomes in the aging population.
Humans ; Aging/physiology* ; Communicable Diseases/immunology* ; Immunosenescence/physiology* ; Inflammation/immunology* ; Genomic Instability

Objective To detect the protective role of high mobility group box-1 protein (HMGB1 )antibody in concanavalin A(ConA)-induced liver injury in mice.Methods The healthy male Balb/c mice were grouped into con-trol group (saline injection),model group(ConA injection)and experimental group(ConA+HMGB1 antibody injec-tion).After 6 hours of injection,mice blood was collected for detecting alanine transaminase (ALT)and HMGB1 , liver tissue was used to do HE stain,Tunel,and immunofluorescence detection.Results Pathological inflammation in experimental group was slighter than model group.The levels of ALT and HMGB1 in mice serum were (52.00± 8.34)U/L and (7.54 ±0.53)ng/mL in control group,(5 551 .50 ±1 445.74)U/L and (18.06 ±1 .65 )ng/mL in model group,(1 977.40±654.89)U/L and (10.77±0.71)ng/mL in experimental group,respectively;the expres-sion levels of HMGB1 mRNA and HMGB1 (relative value)in liver tissue were 1 .886±0.253 and 0.086±0.028 in control group,4.718±0.341 and 0.268±0.043 in model group,3.005 ±0.331 and 0.116±0.008 in experimental group,respectively;the expression levels of ALT and HMGB1 in serum,as well as HMGB1 mRNA and HMGB1 in liver tissue of experimental group were all lower than model group(all P <0.001).Apoptosis and HMGB1 migra-tion in the liver cell (normalized)were 1 ±0 and 1 ±0 in control group,4.67 ±0.33 and 4.50 ±0.22 in model group,2.67±0.21 and 2.33 ±0.21 in experimental group,respectively;apoptosis and HMGB1 migration in liver tissue of experimental group were both lower than model group(both P <0.001).Conclusion HMGB1 antibody can improve the pathological injury of liver tissue,and protect mice liver against the injury induced by ConA.