Table 2.
Genetic and functional studies of inflammatory components associated with ALD
| ALD Association*1 | Knockout/antagonist phenotype | References | |
|---|---|---|---|
| Pathogen/Danger Sensors | |||
| TLR4 | Increased expression on the neutrophils and in the liver in patients with alcoholic cirrhosis | TLR4KO (whole body or bone-marrow derived cells): reduced inflammation and injury in mice; | (44, 131, 140) |
| TLR2 | Increased liver expression in alcohol-fed mice and in neutrophils of alcoholic cirrhotic patients | TLR2KO: No appreciable effect on inflammation and liver injury in alcohol-fed mice | (35, 41) |
| Cytokines/chemokines | |||
| TNFα | Elevated in circulation and liver in alcoholics with ALD; elevated in alcohol-fed rodents | TNF-αKO and antagonists: reduced liver fat and injury in rodents; TNF-α antagonists: increased infections in AH patients | (10, 42) |
| TNFR1 | Receptor for TNFα | TNFR1KO: reduced liver fat, inflammation, and hepatocyte necrosis | (141) |
| IL-6 | Elevated in circulation and liver in alcoholics with or without liver disease; | IL-6KO: increased liver fat and injury; increased mitochondrial DNA damage; | (26, 144) |
| IL10 | Reduced in chronic alcohol fed mice; Moderately to highly elevated in alcoholics with liver diseases | IL-10KO: [alcohol only] reduced liver fat but increased inflammation w/o increased injury; [alcohol+LPS]: increased liver | (36, 81, 117) |
| IL-8, IL-17 | Elevated in alcoholics with liver disease | N/D | (62, 115) |
| HIF-1α | Induced in alcohol-fed animal model in response to hypoxia | Hepatocyte-specific HIF-1αKO: reduced liver fat, inflammation, and hepatocyte necrosis | (90) |
| Inflammatory Signaling pathways | |||
| IRF3 | (One of two major signal transducers for TLR4) | Global IRF3KO: reduced liver fat, inflammation and injury | (98, 145) |
| IRF3 deficiency in parenchymal cells: aggravated liver fat, inflammation and injury | (98, 145) | ||
| IRF3 deficiency in myeloid cells: reduced inflammation, but no change in liver injury | (98, 145) | ||
| STAT3 | (downstream target for IL-6, 10, and 22) Activation at early phase in animal; low activation in AH patients | STAT3 deficiency in hepatocyte: increased steatosis & lipogenic gene expression | (40) |
| STAT3 deficiency in macrophage/neutrophil or endothelial cells: increased inflammation and liver injury | (40, 82) | ||
| Immune cells | |||
| Kupffer cells (macrophage) | (acute alcohol) Increased tolerance to LPS; (Chronic alcohol) Increased sensitization to LPS. | Depletion: reduced liver injury | (1) |
| Neutrophils | Increased liver infiltration in AH with high resting respiratory burst | Anti-PMN antibody attenuated alcohol- induced liver injury in rat | (6, 84) |
| monocytes | Increased spontaneous and LPS induced cytokine production | Knockout of monocyte chemoattractant protein-1 (MCP-1) attenuates alcohol- induced liver injury, steatosis and oxidative stress in mice | (73, 79) |
| Plasma components | |||
| complement | Increases C1q, C3b liver deposition in alcohol fed mice; Low in alcoholics with cirrhosis | C1q KO: blocked an early inflammation and attenuated liver injury | (16) |
| C5KO: reduced liver inflammation and injury with no effect on liver fat accumulation | (101) | ||
| C3, C3R, or C5RKO: reduced an early phase of inflammation and injury | (111) | ||