Trained Immunity in Liver Cirrhosis: From Molecular Mechanisms to Prognosis Implications A Preliminary Observation

ABSTRACT

Introduction: Trained Immunity (TI) represents a novel concept of the immunological reaction involving the innate immune cells, triggered by a second antigenic contact, gaining a long-term reversible pro-inflammatory phenotype. In liver cirrhosis, immune dysfunction impacts the onset of chronic local and systemic inflammation, the disease worsening, and the development of its complications. Aims & Methods: The aim was to highlight TI response impairment along with the progression of chronic liver disease and to estimate its implications on the cirrhosis outcome. Healthy subjects, patients with chronic hepatitis (CH) (alcoholic and nonalcoholic fatty liver disease ones), and liver cirrhosis (LC) were enrolled. For each patient, medical history and a peripheral venous blood sample were collected (20 ml). After a per gradient isolation, monocytes were sequentially stimulated with beta-glucan for 24 h (1 mug/mL) and lipopolysaccharide (LPS) (10 ng/mL) for 24 hours in order to assess the pro-inflammatory [tumor necrosis factor (TNF)-alpha, interleukin (IL)-6] and anti-inflammatory response(IL-10)(at day 3 and 6 respectively).Evaluation of blood levels of LPS, IL-6, and TNF-alpha was also performed. Result(s) Regarding TNF-alpha and IL-6, the maintenance of TI was highlighted in healthy subjects (n.10) and CH (n.15) as well but not in LC patients (n.38) (TNF-alpha controls, LPS2800+/-628.8, beta-glucan+LPS5046+/-136.2 pg/ ml, p0.008, IL-6 controls, LPS2487+/-562.4, beta-glucan+LPS4556+/-190.2 pg/ ml, p0.008;TNF-alpha CH, LPS1839+/-70.7, beta-glucan+LPS4445+/-162.6 pg/ ml, p0.007, IL-6 CH, LPS2576+/-177.9, beta-glucan+LPS3865+/-332.3 pg/ml, p0.008 ). IL-10 levels showed a typical TI trend only in healthy subjects (LPS2797+/-518.9, beta-glucan+LPS6001+/-1523 pg/ml p 0.001). In cirrhotic group, the bivariate analysis revealed an inverse correlation between circulating LPS, IL-6 (R = -2.511;p = 0.01) and TNF-alpha (R -1.887;p = 0.02). The Kaplan-Meier Log-Rank test analysis (24 LC patients with inefficient and 14 with efficient TI response) on not SARS-CoV-2 infections development and liver-related hospitalizations (HR 4.09, 95% CI 1.57-10.61, p= 0.01;HR 4.66, 95% CI 1.5-14.47, p= 0.02 respectively) revealed lower risk for patients with efficient TI response. Conclusion(s) The worsening of chronic liver disease appears related to the progressive impairment of the TI response whose maintenance seems to be associated with a lower risk of unfavorable clinical events in cirrhotic patients. (Table Presented).