Inflammasome activation in decompensated liver cirrhosis

Abstract

Inflammation participates in the pathogenesis of many liver diseases, including liver cirrhosis. Certain inflammatory citokines, such as interleukin (IL)-1β and IL-18, are produced after the activation of a multiprotein complex known as the inflammasome. Activation of the inflammasome has been documented in several liver diseases, but its role in the development and progression of liver cirrhosis or the complications associated with this disease is still largely unknown. We have recently studied the impact of the inflammasome in the sterile inflammatory response that takes place in the ascitic fluid of patients with decompensated cirrhosis, providing evidence that activation of the absent in melanoma 2 (AIM2) inflammasome is an important response in these patients. Ascitic fluid-derived macrophages were able to mount a very robust AIM2-mediated response even in the absence of a priming signal, which is usually required for the full activation of all the inflammasomes. In addition, high level of inflammasome activation in these patients was associated with a higher degree of liver disease and an increased incidence of spontaneous bacterial peritonitis. These results may help explain the exacerbated inflammatory response that usually occurs in patients with decompensated cirrhosis in the absence of detectable infections. Thus, inflammasomes should be considered as possible therapeutic targets in sterile inflammatory complications in patients with cirrhosis.

Keywords: Absent in melanoma 2; Ascites; Cirrhosis; Inflammasome; Interleukin-1β.

Figure 1

Basic representation of inflammasome activation. Inflammasomes are formed after NLR or PYHIN family members recognize signals associated with tissue damage or infection. Receptors that have a CARD domain can recruit pro-caspase-1 directly (e.g., NLRC4), whereas those that contain a PYD domain (e.g., NLRP3 and AIM2) recruit pro-caspase-1 through the accessory protein ASC (which contains a PYD and a CARD). NLRP1 contains a CARD and can bypass the requirement for ASC, but also contains a PYD and its interaction with ASC enhances the activity of the NLRP1 inflammasome. CARD: Caspase-1 recruitment domain; PYD: Pyrin domain; ASC: Apoptosis-associated speck-like protein containing a CARD; LRR: Leucine rich repeat; HIN-200: Hematopoietic interferon-inducible nuclear antigen with 200 amino-acid repeat; PAMPs: Pathogen-associated molecular patterns; DAMPs: Damage-associated molecular patterns; AIM2: Absent in melanoma 2; dsDNA: Double-stranded DNA; IL: Interleukin; S. aureus: Staphylococcus aureus; L. monocytogenes: Listeria monocytogenes; C. albicans: Candida albicans; TLR: Toll-like receptor.

Figure 2

Theoretical mechanism of inflammasome activation in ascitic fluid. Advanced cirrhosis is typically associated with overgrowth of intestinal bacteria and increased intestinal permeability, which results in the translocation of bacterial products (e.g., DNA or LPS) to the ascitic fluid. The presence of these PAMPs activates PRRs in innate immune cells of the ascitic fluid, inducing the synthesis of IL-1β and IL-18 precursors and inflammasome components (signal I). At the same time, continuous liver damage (e.g., by virus or alcohol) would result in hepatocyte death and release of DAMPs (e.g., host dsDNA). These DAMPs (and probably new translocation events of PAMPs from the intestinal lumen) would activate inflammasome-forming receptors such as AIM2 (providing signal II), which in turn results in the activation of caspase-1 and the maturation and release of IL-1β and IL-18 into the ascitic fluid. IL: Interleukin; PAMPs: Pathogen-associated molecular patterns; DAMPs: Damage-associated molecular patterns; AIM2: Absent in melanoma 2; dsDNA: Double-stranded DNA; PRRs: Pattern recognition receptors; LPS: Lipopolysaccharide.