Propranolol Suppresses the T-Helper Cell Depletion-Related Immune Dysfunction in Cirrhotic Mice.

Hung-Cheng Tsai,Tzu-Hao Li,Tzung-Yan Lee,Chien-Fu Hsu,Han-Chieh Lin,Ying-Ying Yang,Chia-Chang Huang,Shiang-Fen Huang,Ming-Chih Hou,Yi-Hsiang Huang,Ming-Wei Lin,Chih-Wei Liu

doi:10.3390/cells9030604

Abstract

Bacterial translocation (BT) and splenomegaly contribute to cirrhosis-associated immune dysfunction (CAID) including T cell depletion, infection, and chronic inflammation. β-blockers have been reported to decrease BT and improve splenomegaly. This study explores the modulation of β1 and β2 adrenergic receptors (ADRB1/ADRB2) by propranolol treatment on the peripheral and splenic immune dysfunction of cirrhotic mice. In vivo experiments were performed in bile duct ligation (BDL)- and thioacetamide (TAA)-cirrhotic mice receiving two weeks of propranolol treatment. Acute effects of propranolol were evaluated in T-helper (Th) cells isolated from spleen of cirrhotic mice. Over-expression of β1 and β2 adrenergic receptors (ADRB1/ADRB2) in spleen and T lymphocytes was associated with high peripheral/splenic lipopolysaccharide binding protein levels. Moreover, a decrease in Th cells percentage, increase in Treg subset, and cytokines were accompanied by increased apoptosis, proliferation, and reduced white pulp hyperplasia in cirrhotic mice, which were counteracted by propranolol treatment. The Th-cell depletion, systemic inflammation, BT, and infection were improved by chronic propranolol treatment. Acute propranolol treatment inhibited apoptosis, Treg-conditioned differentiation, and promoted Th2-conditioned differentiation through ADRB-cyclic adenosine monophosphate (cAMP) signals in cirrhotic mice. In conclusion, suppression of ADRB1 and ADRB2 expressions in spleen and splenic T lymphocytes by acute and chronic propranolol treatment ameliorate systemic and splenic immune dysfunction in cirrhosis.

Highlights

In cirrhosis, T cell depletion plays a key role in the pathogenesis of cirrhosis-associated immune dysfunction [1,2]
In comparison with sham mice, cirrhotic (BDL-V and TAA-V) mice were characterized by grossly observing cirrhotic livers, ascites, splenomegaly, higher plasma norepinephrine levels, and high incidence of systemic infection (Tables 2 and 3)
We mainly explore the effects of chronic propranolol treatment on the abnormal changes in the Th1, Th2, Treg cytokines in mice with cirrhosis-related immune dysfunction

Summary

Introduction

T cell depletion plays a key role in the pathogenesis of cirrhosis-associated immune dysfunction [1,2]. Bacterial translocation (BT)-related expansion of splenic lymphoid tissue and inflammation, as well as splenic sequestration results in T lymphopenia [3,4,5,6]. BT is commonly found in cirrhotic patients with portal hypertension (PH), splenomegaly, and immune dysfunction. Munoz et al [7] have reported that in cirrhosis, over-activated T lymphocytes, and inflamed mesenteric lymph nodes (MLNs) facilitate BT and that such patients develop systemic inflammatory syndrome. MLNs and the spleen are closely connected via the portal vein. Splenomegaly has been considered as an activator of T cells and tissue inflammation due to a reduction in the hepatic capacity to handle BT-related pathogens [8]

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