Page 29 - EJMO-9-3

Eurasian Journal of
Medicine and Oncology Role of common CXC chemokines in NAFLD

and microbial factors, and the molecular mechanisms kinase, or phospholipase β signaling pathway by binding
underlying the progression from NAFLDs to NASHs are to the receptor CXCR2, thereby inducing neutrophil
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poorly understood. The widely accepted theory that NASH infiltration to high-concentration sites, participating
is a complicated multifactorial disease whose development in inflammatory responses, and even leading to tissue
is facilitated by metabolic factors, immune abnormalities, destruction. In the liver, CXCL1 was expressed at the
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chemokines, cytokines, bacterial lipopolysaccharides, highest levels in hepatocytes and at a lower level in hepatic
and other factors is the “multiple parallel hits theory.” It stellate cells and hepatic sinusoidal endothelial cells. It has
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has been shown that chemokines promote inflammation been proposed that the heightened expression of CXCL1 in
by coordinating the recruitment of immune cells during liver cells correlates with a rise in the levels of free fatty
obesity, Type 2 diabetes, and cardiovascular disease in both acids in the liver and is dependent on the regulation of
mice and humans. 20 extracellular signal-regulated kinase 1/2, c-Jun N-terminal
kinase (JNK), and nuclear factor κ light chain enhancer
3. CXC chemokines (NF-κB). Tang et al. have attempted at upregulating or
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Chemokines have a part to play in hematopoiesis, innate downregulating CXCL1 expression levels by using adeno-
and adaptive immune responses, and inflammatory associated viruses in an established mouse model of acute
processes to a large extent by mediating the migration of and chronic liver failure and found that knockdown of
leukocytes, and they are grouped into four subfamilies: CXCL1 reduced neutrophil infiltration and lowered the
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CXC, CC, C, and CX3C, based on the position of the first expression of inflammatory cytokines in the mouse liver
two cysteines in the primary sequence, and perform their and also significantly downregulated the generation of
corresponding functions by binding to their respective reactive oxygen species (ROS) and the caspase3-associated
G protein-coupled seven transmembrane structural apoptosis of hepatocytes, thereby ameliorating liver injury
domain receptors. CXC chemokines, small secreted in acute and chronic liver failure.
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proteins, possess four remarkably conserved cysteine The invasion of neutrophils into the liver stands out as a
amino acid residues, with the first two separated by one major pathological symptom of liver damage, and CXCL1
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non-conserved amino acid residue. On the basis of is a major chemokine that mediates neutrophil recruitment
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the presence or absence of Glu-Leu-Arg (ELR) motifs at (Figure 1). CXCL1 expression has been shown to be
the NH2 terminus, the CXC chemokine family can be dramatically elevated in patients with NASH in previous
subdivided into two isoforms, ELR+ CXC chemokine and studies, whereas it is essentially normal in patients with
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ELR- CXC chemokine. ELR+ CXC chemokines include steatohepatitis and in high-fat diet-induced steatohepatitis
CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, model mice. Hwang et al. found that elevated levels of
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CXCL8, and CXCL17, while ELR- CXC chemokine include CXCL1 alone can accelerate the development of NASH
CXCL4, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, through ROS from neutrophils and trigger stress kinases, a
CXCL14, and CXCL16. CXC chemokine ligands are process that interleukin (IL)-22 can reverse by stimulating
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associated with trimeric G proteins (Gαβγ), and the role metallothionein production. Saturated fatty acids (sFAs)
of four different types of Gα subunit types determines increase NF-κB, ERK MAPK, and JNK MAPK-dependent
intracellular activation. Given that ELR+ CXC Kupffer cell (KC) expression in hepatocytes, in which
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chemokines have the ability to attract neutrophils from CXCL1 plays a key pivotal role. Through contrasting the
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the blood to areas of infection and inflammation, they are supernatants from primary human and mouse liver cells
categorized as inflammatory chemokines, and ELR- CXC exposed to inflammatory cytokines, it was found that
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chemokines may have a homeostatic role in the regulation mouse hepatocytes lacked IL-8 expression and had low
of the movement of neutrophils from the bone marrow
into the bloodstream. Since the inflammatory response expression of tumor necrosis factor-alpha (TNF-α) and
is important in the development of NASH and CXC IL-1β-induced CXCL1, which could explain the difficulty
chemokine receptors are G-protein-coupled receptors that in establishing a NASH model in high-fat diet-fed mice.
mediate the inflammatory response, the search for specific Subsequent research indicated that the heightened
CXC chemokine targets for action in NAFLD disease is a expression of CXCL1 leads to NASH by producing ROS
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logical and attractive goal (Table 1). and triggering the stress kinase p38α. E-selectin (Sele) is
crucial as a binding molecule for neutrophils in adipose
4. Impact of key CXC chemokines on NAFLD tissue, and it was found that knockdown of Sele might
slow down the development of NASH by impairing the
4.1. CXCL1 adhesion between neutrophils and sinusoidal endothelial
CXCL1, as an ELR+ CXC chemokine, is one of the selective cells and reducing CXCL1-induced neutrophil transport
ligands for CXCR2, which can activate the PI3K/Akt, MAP to the liver. Under normal physiological conditions,
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Volume 9 Issue 3 (2025) 21 doi: 10.36922/ejmo.8383