The innate immune cells in cirrhosis.
Cirrhosis is a multi-systemic disease where inflammatory responses originating from advanced liver disease and its sequelae affect distant compartments. Patients with cirrhosis are susceptible to develop bacterial infections, which may precipitate acute decompensation (AD) and acute-on-chronic liver failure (ACLF), associated with a high short-term mortality. Innate immune cells are essential as first line of defence against pathogens due to their various rapid antibacterial activities such as the production of reactive oxygen species (ROS) via NADPH oxidases (NOX), degranulation, phagocytosis, and formation of extracellular chromatin traps. This review focuses on the continuous and distinct perturbations arising in innate immune cells during cirrhosis development including their impact on disease progression as well as potential future therapeutic targets. Activation of liver macrophages (Kupffer cells) and resident mastocytes generate proinflammatory and vaso-permeating mediators that induce accumulation of neutrophils, lymphocytes, eosinophils and monocytes into the liver, and promote tissue damage particularly through exacerbated ROS production. During cirrhosis progression, damage- and pathogen-associated molecular patterns activate immune cells and promote development of systemic inflammatory responses which may involve different tissues and compartments, and elicit progression to AD and ACLF. The antibacterial function of circulating neutrophils and monocytes is gradually and severely impaired as cirrhosis worsens involving contributions to disease progression. The mechanisms underlying impaired antimicrobial responses are complex and incompletely understood. They include a deficient expression of the antibacterial machinery key-protein effector NOX2, signalling defects (Mitogen-activated protein (MAP)-Kinases, protein kinase B (AKT), mammalian target of rapamycin [mTOR]), phospholipase C). They also include an expansion of monocytic myeloid-derived suppressor cells and distinct monocytic subsets expressing the TYRO3/AXL/MERTK (TAM) receptors AXL or MERTK during disease progression especially during acute decompensation and ACLF stages. Impaired antimicrobial responses can be reversed with potent toll-like receptor (TLR)3/7/8 agonists, or inhibitors of glutamine synthase and TAM receptors. TLR7/8 activation boosts bacterial elimination and increases survival in a rat model of cirrhosis. This raises perspectives for their use in immunocompromised patients and supports the notion that innate immune dysfunction promotes disease progression.