Table 3 Role of CXCLs-CXCR2 in human liver diseases

ALD

CXCL1,4,5,6,8, TNF-α

Neutrophil chemoattractant; increased expression were biomarkers for poor prognosis.

Antibodies neutralizing CXCLs or genetic deletion CXCR2 alleviated inflammation.

[98, 106]

NAFLD

CXCL8, IL-1, 6, 18, MCP-1, TNF-α

Immune cell recruitment, metabolic disorder, oxidative stress, and increased serum CXCL8 predicted the severity of hepatic fibrosis.

Antibody-mediated neutrophil depletion suppressed steatohepatitis and avoided tissue damage.

[61, 96, 107, 108]

Cirrhosis

Fibrosis

PDGF, TGF-β, CCL2, 5, CXCL8,16, IL-4, 6,10, 13

CXCR2-mediated intracellular calcium mobilization and further neutrophil trafficking; biomarkers of cirrhosis progression; uncontrolled neutrophilic accumulation.

CXCR2 antagonist on neutrophil dysregulation and pro-inflammation states to prevent further cirrhosis.

[87, 109, 110]

Hepatitis B and C

CXCL8, IL-1, 6, 10, 18, TNF-α

Increased IL-8 accumulated neutrophils to the liver; decreased CXCR2 expression correlates with disease severity.

Inhibitors on IL-8 or CXCR2 downregulated inflammation response and alleviated hepatitis.

[20, 71, 111]

I/R injury

CXCL8, IL-1, 6, 11, 12, 13, 18, TNF- α

Neutrophil recruitment & activation; ligands production directly related to the duration of reperfusion; angiogenesis.

Blockade of CXCLs or CXCR2 and Cxcr2^−/− mice decreased local and systemic inflammation and promoted liver proliferation.

[13, 15, 112]

ACLF

CXCL8, ROS, IL-6, 17, 23, CCL-20, GM-CSF

Neutrophil chemotaxis to the site of inflammation/injury with high CXCR1/2 expression mediates the hepatic immune response.

Cxcr1/2 antagonist alleviated the production of inflammatory mediators and reduced cell death.

[20, 111, 113]

Sepsis

CXCL1, 2, 5, 8, TNF- α, ROS, iNOS, NETs

Neutrophil migration and its overstimulation led to CXCR2 internalization, microbial dissemination, uncontrolled systemic inflammation, and host death; the detection of CXCL8 predicted severity and evolution to organ failure.

Signaling prevents neutrophils’ failure to migrate to restore the sufficient levels of CXCR2 on their surface, including blockade or inhibition of PI3Kγ, and administration of IL-33 leads to better control of systemic inflammation and decreasing mortality.

[105, 114,115,116,117,118,119,120]