Page 32 - EJMO-9-3

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

hepatic steatosis, hepatitis, and hepatic fibrosis through shown that circulating CXCL10 levels are correlated with
the activation of PPAR-α. Some clinical studies have the extent of lobular inflammation, which also serves
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demonstrated a correlation between only CXCL8 and the as an independent risk factor in NASH patients. For
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development of NAFLD and also found that there was a the initial instance, this research revealed CXCL10’s
direct relationship observed between the liver’s TLR2 crucial involvement in the development of experimental
expression and the expression levels of CXCL8, indicating steatohepatitis. In addition, certain clinical trials
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that inhibiting the expression of TLR2 might be able to suggested that CXCL10 expression correlates favorably
reduce the level of CXCL8 and thus achieve a decline in with disease severity, as well as the expression levels
liver inflammation. As NAFLD becomes more prevalent of alanine aminotransferase (ALT), Tumor necrosis
among youth, a study found that the concentrations of factor-α (TNF-α), monocyte chemotactic protein-1
CXCL8 and TNF-α in the supernatants of mercury- (MCP-1), and others; subsequent ordered logistic studies
exposed monocytes were more than 10-fold higher than showed that CXCL10 independently contributes to the
those of controls, by combining the epidemiological results risk of progressive liver damage and diabetes mellitus
of a multicenter mother-son cohort with the results of an and may serve as a non-invasive indicator of NAFLD
in vitro experiment. This suggests that the TNF-α/CXCL8 progression. The CXCL10/CXCR3 chemotaxis axis
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axis may represent an important target for limiting the can promote liver injury and fibrosis by recruiting
development of inflammation in NAFLD. macrophages. In addition, through a series of mouse
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experiments, Maina et al. found that steatosis and
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4.4. CXCL10
lobular inflammation were more prevalent in Th1- and
CXCL10 is alternatively known as interferon gamma- M1-oriented mice compared to Th2- and M2-oriented
inducible protein 10 (IP-10), which is maintained at low mouse models of NASH, and that Th1- and M1-oriented
levels in a homeostatic environment, but expression levels mice showed increased hepatic mRNA expression of
are upregulated in response to cytokine stimulation. macrophage M1-activated markers inducible nitric oxide
Functionally classified as a pro-inflammatory chemokine, synthase (iNOS) and CXCL10. Consistent with this, there
CXCL10 regulates the immune response by binding was a positive association between the expression levels
its specific receptor CXCR3 to activate and recruit of hepatic iNOS and CXCL10 mRNA and the occurrence
leukocytes, including T cells, monocytes, eosinophils, of hepatic necroinflammatory foci. CXCR3, the specific
and NK cells. CXCL10 can be secreted by different receptor for CXCL10, showed similar effects, and CXCR3
kinds of cells, including hepatocytes, macrophages, knockout was found to attenuate macrophage responses
monocytes, neutrophils, endothelial cells, fibroblasts, to IFN-γ in mouse experiments, thereby inhibiting the
dendritic cells, astrocytes, etc. CXCR3 has a preferential development of NASH. A protein known as fatty acid
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expression on monocyte, T-cell (mainly Th1), NK-cell, binding protein 4 (FABP4) has a strong association with
dendritic cell, and cancer cell surfaces. CXCL10 and its metabolic syndrome, and it has been shown that FABP4
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receptor CXCR3 are secreted mainly by the induction in hepatic sinusoidal endothelial cells may promote
of interferon-gamma (IFN-γ), which can also be weakly CXCL10-mediated macrophage M1 polarization and
induced by TNF-α. The primary secretion of CXCL10 CXCR3+ macrophage infiltration via the NF-κB/p65
occurs in hepatocytes and the endothelial cells within signaling pathway and thus promote the development of
the liver’s hepatic sinusoids, and the binding of CXCL10 NAFLD. Dysregulation of autophagy leads to hepatic
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to its specific receptor CXCR3 leads to the aggregation of inflammatory injury, and upregulation of CXCL10
activated CXCR3+ T-lymphocytes and macrophages into in NAFLD may impair the autophagic capacity of
the liver parenchyma, which gets involved in promoting hepatocytes by reducing the formation of autolysosomes,
inflammation, apoptosis, and fibrosis. Ibrahim et al. which inhibits the degradation of autophagic proteins
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demonstrated that during hepatocyte lipotoxicity, the and accumulation of ubiquitylated proteins, leading
activation of mixed-spectrum kinase 3 (MLK3) triggers the to the development of steatohepatitis, and the use of a
secretion of vesicles containing CXCL10 from hepatocytes, monoclonal antibody to CXCL10 can significantly restore
serving as a chemotactic agent for macrophages, thereby impaired autophagic capacity. MDA5, also known as
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increasing macrophage-associated inflammation in the melanoma differentiation-associated gene 5, is a member
liver. of the protein family of intracellular RNA deconjugating

CXCL10, recognized as a standard proinflammatory enzymes. Studies have shown that MDA5 actively controls
chemokine, plays a significant role in the emergence TNF-α-induced CXCL10 expression in a manner that is
of NAFLD. Research indicates a notable increase in both dependent on and independent of STAT1, which
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CXCL10 expression in cases of NAFLD. 65,66 It has been may be related to metabolic inflammation in the liver. 73

Volume 9 Issue 3 (2025) 24 doi: 10.36922/ejmo.8383