Inflammatory pathways in alcoholic steatohepatitis

Abstract

Inflammatory processes are primary contributors to the development and progression of alcoholic steatohepatitis (ASH), with severe alcoholic hepatitis characterised by non-resolving inflammation. Inflammation in the progression of ASH is a complex response to microbial dysbiosis, loss of barrier integrity in the intestine, hepatocellular stress and death, as well as inter-organ crosstalk. Herein, we review the roles of multiple cell types that are involved in inflammation in ASH, including resident macrophages and infiltrating monocytes, as well as other cell types in the innate and adaptive immune system. In response to chronic, heavy alcohol exposure, hepatocytes themselves also contribute to the inflammatory process; hepatocytes express a large number of chemokines and inflammatory mediators and can also release damage-associated molecular patterns during injury and death. These cellular responses are mediated and accompanied by changes in the expression of pro-and anti-inflammatory cytokines and chemokines, as well as by signals which orchestrate the recruitment of immune cells and activation of the inflammatory process. Additional mechanisms for cell-cell and inter-organ communication in ASH are also reviewed, including the roles of extracellular vesicles and microRNAs, as well as inter-organ crosstalk. We highlight the concept that inflammation also plays an important role in promoting liver repair and controlling bacterial infection. Understanding the complex regulatory processes that are disrupted during the progression of ASH will likely lead to better targeted strategies for therapeutic interventions.

Immune Checkpoint Axes Are Dysregulated in Patients With Alcoholic Hepatitis

“…In this study, we systematically profiled 18 sICPs in the plasma samples from a large cohort of patients with AH, HDCs, and HCs. In line with profound immune dysregulation in patients with AH, (3,19) we found that 17 out of 18 sICPs examined here were dysregulated (six up-regulated and 11 down-regulated). A previous study found that the TIM-3 ligand galectin-9 was elevated in patients with AH.…”

“…Alcoholic hepatitis (AH) is a severe inflammatory liver disease that develops in 10%‐35% of chronic heavy drinkers. Although the exact trigger for development of AH is still unclear, alcohol‐induced translocation of gut bacteria and bacterial components into the liver and blood and subsequent activation of liver‐resident macrophages (Kupffer cells) and other immune and nonimmune cells play a critical role in the initiation and progression of AH . Patients with AH have elevated levels of a wide range of proinflammatory factors, such as interleukin‐8 (IL‐8) and tumor necrosis factor alpha (TNF‐α), and their immune cells are highly dysregulated, which is characterized by immune hyperactivation, exhaustion, and dysfunction …”

“…Although the exact trigger for development of AH is still unclear, alcohol-induced translocation of gut bacteria and bacterial components into the liver and blood and subsequent activation of liver-resident macrophages (Kupffer cells) and other immune and nonimmune cells play a critical role in the initiation and progression of AH. (1)(2)(3) Patients with AH have elevated levels of a wide range…”

“…of proinflammatory factors, such as interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α), and their immune cells are highly dysregulated, which is characterized by immune hyperactivation, exhaustion, and dysfunction. (1,(3)(4)(5)(6) Immune homeostasis, which is critical for maintaining immune self-tolerance and preventing overexuberant immune responses, is regulated by multiple factors, including balanced signals from a network of immune costimulatory and coinhibitory receptors/ ligands, collectively known as immune checkpoints (ICPs). More than 20 ICP pathways consisting of ICP receptors and their ligands have been identified, such as the costimulatory cluster of differentiation (CD)28/ CD80/CD86 pathway and the inhibitory pathways of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)/CD80/CD86 and programmed death 1 (PD-1)/PD ligand 1 (PD-L1)/PD-L2.…”

Paneth Cell Dysfunction Mediates Alcohol‐related Steatohepatitis Through Promoting Bacterial Translocation in Mice: Role of Zinc Deficiency

“…Wei Zhong, 1,2 Xiaoyuan Wei, 3 Liuyi Hao, 1 Tai-Du Lin, 1,4 Ruichao Yue, 1 Xinguo Sun, 1 Wei Guo, 1 Haibo Dong, 1 Tianjiao Li, 2 Ali R. Ahmadi, 5 Zhaoli Sun, 5 Qibin Zhang, 1,4 Jiangchao Zhao, 3…”