ISSN 0006-2979, Biochemistry (Moscow), 2024, Vol. 89, No. 11, pp. 1889-1903 © The Author(s) 2024. This article is an open access publication.
1889
REVIEW
Alcohol-Induced Activation of Chemokine System
and Neuroinflammation Development
Ekaterina V. Mikhalitskaya
1,a
*, Natalya M. Vyalova
1
, Nikolay A. Bokhan
1
,
and Svetlana A. Ivanova
1
1
Mental Health Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences,
634014 Tomsk, Russia
a
e-mail: Uzen63@mail.ru
Received May 15, 2024
Revised September 27, 2024
Accepted September 30, 2024
AbstractChemokines are immunoregulatory proteins with pleiotropic functions involved in neuromodulation,
neurogenesis, and neurotransmission. The way chemokines affect the CNS plays an important role in modulat-
ing various conditions that could have negative impact on CNS functions, including development of alcohol use
disorders. In this review, we analyzed the literature data available on the problem of chemokine participation
in pathogenesis, clinical presentation, and remission of alcohol use disorders both in animal models and in the
study of patients with alcoholism. The presented information confirms the hypothesis that the alcohol-induced
chemokine production could modulate chronic neuroinflammation. Thus, the data summarized and shown in
this review are focused on the relevant direction of research in the field of psychiatry, which is in demand
by both scientists and clinical specialists.
DOI: 10.1134/S0006297924110038
Keywords: alcohol use disorders, addiction, chemokines, neuroinflammation
Abbreviations: AUD, alcohol use disorders; GSK-3β, glycogen
synthase kinase-3 β; PND, postnatal days; TLR4, Toll-like
receptor  4.
* To whom correspondence should be addressed.
INTRODUCTION
Chemokines comprise a family of small-molecule
proteins that are chemoattractant cytokines with main
function being recruitment of leukocytes to the sites of
inflammation [1]. They play an important role in both
immune system and central nervous system (CNS)[2-4].
In the CNS, chemokines, along with cytokines, are in-
volved in a number of physiological processes, such as
neuroinflammation, changes in neuronal activity, com-
munication between neurons and glia, neuroendocrine
interaction, neurogenesis, and CNS development [5, 6].
More and more publications regarding the sub-
stance use disorders indicate that alcohol intake re-
sults in activation of immune response accompanied
with the development of chronic neuroinflammation
and change in chemokine regulation [7].
Selection, analysis, and generalization of the ex-
perimental material, as well as the accumulated data
of clinical observations on the changed content of
chemokines belonging to various families in the an-
imals exposed to alcohol, and in the patients with
various patterns of alcohol consumption and during
alcohol withdrawal combined in the single review is
important from the point of view of determination
of further vector of biomedical research involving, in
particular, search for biomarkers of the initial stages
of neuroinflammation and potential tools of pharma-
cological correction in alcohol use disorders (AUD).
Nevertheless, there have not been enough studies
focused on investigation of the changes in the chemok-
ine system during exposure to alcohol in recent years;
moreover, these studies largely include works with an-
imal models, and only one of them have been devoted
to studying humans. Therefore, this review includes
literature published from January 2004 to April 2024.
Our literature search was performed within
PubMed and eLIBRARY databases with the keywords
“alcoholism”, “alcohol use disorders” in combination
MIKHALITSKAYA et al.1890
BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
with one of the following search terms: “chemokine”,
“chemokine receptor”, “neuroinflammation”.
The aim of the review is to summarize and ana-
lyze the data available on the changes in chemokine
system in alcohol intoxication in animal models and
in the patients with alcohol dependence. These data
could be considered in further clinical and transla-
tional studies as pathologically relevant biomarkers or
therapeutic targets in the treatment of AUD.
CHEMOKINES AND THEIR FUNCTIONS IN CNS
Chemokines are important components of neu-
roimmune system and are involved in a number of
physiological processes, such as neuroinflammation,
change in neuronal activity, interaction between
neurons and glia, neuroendocrine interaction, neu-
rogenesis, and CNS development  [5,  6]. Proinflamma-
tory chemokines, such as CCL2, CCL7, CCL8, CCL12,
and CCL13 have been shown to induce chemotaxis of
proinflammatory cells to sites of CNS inflammation or
damage. Similarly, CX3CL chemokines are involved in
stimulating glial cell activation, secretion of proin-
flammatory cytokines, expression of ICAM-1 intracel-
lular adhesion molecules, and recruitment of CD4
+
T cells to CNS during neuroinflammatory process  [8].
Consequently, it has been suggested that dysregulation
of chemokine signaling and neuroinflammation con-
tribute to neurodegenerative and psychiatric diseases
[9]. For example, changes in chemokine circulation
[such as CCL2, also known as monocyte chemoat-
tractant protein-1 (MCP-1), CCL11 (eotaxin-1), CXCL8,
CXCL12] have been associated with neurodegenerative
disorders [10-13] and psychiatric disorders [8], such as
cocaine use disorders [14] affective disorders [15-19],
generalized anxiety disorder  [20], personality disor-
ders [20], schizophrenia [21-25], and also correlated
with the severity of psychopathological and cogni-
tive parameters [1]. In particular, CCL11 impairs hip-
pocampal function in aging, and prenatal exposure
to CXCL8 could disrupt early neurodevelopmental
periods [8].
Chemokines comprise a group of small 8-12  kDa-
proteins with similar tertiary structure including a se-
quence of 6-10 amino acids, followed by a long loop
(N-loop), a 3
10
helix, a three-stranded β-sheet, and
a C-terminal α-helix [26].
Depending on position of cysteine residues at
the N-terminus, chemokine molecules are classified
into four subfamilies: C, CC, CXC, and CX3C chemok-
ines  [27], while there are 27 CC chemokines, 17 CXC
chemokines, 2 XC chemokines, and 1 CX3C chemok-
ine  [26]. Chemokines mediate their effects through
G-protein-coupled transmembrane receptors (GPCRs),
which are designated as CR1, CCR1-11, CXCR1-5,
and CX3CR1 [4,  28,  29]. GPCRs transmit signals via
Gαi/o proteins, through which they inhibit adenylate
cyclase and reduce protein kinase A activity [30], as
well as through Gq proteins, due to which they can in-
crease intracellular levels of Ca
2+
and protein kinaseC
via the phospholipase C pathway [31-33].
Chemokines and their receptors are widely ex-
pressed on vascular bed cells, smooth muscle cells,
as well as on various types of leukocytes [34]. Chemo-
kines can reach the brain by crossing the blood-brain
barrier [35]. At the same time, they can be released
by neurons and glial cells directly in the brain
in response to physiological or pathological condi-
tions [36].
Regulation of chemokines and their receptors ex-
pression involves a complex and poorly understood
interaction both with each other and with other sys-
tems. For example, in the case of damage or inflam-
mation of CNS, mechanisms for increasing expression
of chemokines by cerebrospinal fluid lymphocytes and
T cells, migrating across the blood-brain barrier, as
well as by glial cells of the brain, especially astrocytes,
are triggered [37]. Moreover, in the CNS, individual
chemokines of all four families perform different, but
also overlapping functions.
C chemokines. The XC (or C) family includes only 2
very similar chemokines, XCL1 and XCL2, also known
as lymphotactin α and β, respectively. It is known that,
acting through the unique XCR1 receptor, XCL1 can
cause chemotaxis of lymphocytes, but not of mono-
cytes or neutrophils [38].
CC chemokines. Chemokines of this family have
a pro-inflammatory effect through macrophage che-
motaxis to the site of inflammation or damaged CNS
cells, and are also involved in regulation of neural
stem/progenitor cell migration  [39]. Monocytic che-
moattractant protein-1 (CCL2/MCP-1) is the first dis-
covered and most studied human CC chemokine. It is
one of the key chemokines that regulate recruitment
and activation of monocytes and microglia. Biologi-
cal function of CCL2 is mediated through the G pro-
tein-coupled CCR2 receptor. In addition to CCL2, CCR2
binds 4 more pro-inflammatory chemokines: CCL7,
CCL8, CCL12, and CCL13 [40].
CCL2s, like its receptor type  2 (CCR2), are expressed
in CNS neurons and cultured neuronal cell lines
[41-43]. CCL2 is constitutively expressed in neurons
of individual brain areas of rats, such as the cerebral
cortex, hippocampus, hypothalamus, substantia nigra,
cerebellum, and spinal cord  [44,  45]. Thus, CCL2/CCR2
signaling could regulate functions of neurons.
In addition to its role in immune system, CCL2/
CCR2 signaling is involved in the development of
various neuroinflammatory diseases, such as Alz-
heimers disease  [46], multiple sclerosis  [47], Parkin-
son’s disease [40], and ischemic brain damage  [48].
CHEMOKINES AND ALCOHOL CONSUMPTION 1891
BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
Although some studies have shown involvement of
CCL2 in the brain damage caused by alcohol [40], its
role in pathogenesis of AUD remains unclear to date.
Eotaxin-1 (CCL11), also known as the eosinophil
chemotactic protein, is another chemokine of the CC
family. After binding to CCR3 receptors expressed on
the cell surface of eosinophils, CCL11 activates a num-
ber of intracellular signaling cascades, which leads to
recruitment of eosinophils to the sites of inflammation
during allergic reactions that are thoroughly investi-
gated in asthma, allergic rhinitis, and other eosino-
phil-associated conditions. In particular, a systematic
literature review, including 30 studies, showed that
CCL11 concentrations in the blood and sputum were
consistently increased in the patients with asthma,
correlating negatively with lung function. This indi-
cates the possibility of potential use of CCL11 as a
biomarker for diagnosis and assessment of asthma
severity and control  [49]. In addition to eosinophils,
CCR3 chemokine receptor is expressed on basophils,
mast cells, and Th2 lymphocytes. Moreover, the last
ones are involved in the production of the so-called
Th2 cytokines (interleukins: IL-4, IL-5, IL-13), which
implies that CCL11 is also involved in directing im-
mune response towards the Th2 profile [1].
In the CNS, CCL11 is produced by epithelial cells
of the choroid plexus, pericytes, astrocytes, and mi-
croglia under the influence of inflammatory stimuli
[50]. In addition, CCL11 can enter the CNS, crossing
the blood-brain barrier [51]. One study showed in  vitro
that CCL11 inhibits reversibly proliferation of neu-
rons-progenitors in the isolated cells, neurospheres,
and hippocampal slice cultures without affecting their
ability to form both neurons and astrocytes [52]. Ithas
also been demonstrated that, although no direct effect
of CCL11 on neurons was found, this chemokine was
able to stimulate migration and activation of microglia
with subsequent production of reactive oxygen spe-
cies, which enhanced death of neurons caused by glu-
tamate  [53]. A number of works show relationship of
CCL11 with Alzheimers disease [10,  13], child and ad-
olescent psychopathology, including autism spectrum
disorders  [54,  55], major depression  [17], bipolar dis-
order [56], dysthymia [57], obsessive-compulsive dis-
order  [58], schizophrenia  [22,  25], and substance use
disorders  [59,  60], as well as relationship of the ele-
vated circulating CCL11 chemokine with progressive
clinical deterioration observed in these disorders  [61].
Thus, CCL11 is associated with a number of mental
and neurodegenerative disorders, as well as with the
degree of their clinical severity.
CXC chemokines. The main role of chemokines in
neuroinflammation is regulation of neutrophil chemo-
taxis. This is the key function of CXCL1-CXCL8 chemo-
kines, ligands of CXCR2, that are highly expressed on
neutrophils. The overall effect of these chemokines on
improving or worsening neuronal survival and recov-
ery under inflammatory conditions remains unclear.
In particular, there is evidence that most mice with
knocked out CXC family chemokines or chemokine
receptors are viable and are characterized by the ab-
sence of disturbances in the functioning of nervous
tissue [39].
CXCL9-CXCL11 chemokines, in contrast, exert a
more pronounced pro-inflammatory effect through
the CXCR3-mediated chemotaxis of natural Th1 killer
cells and associated macrophages. For example, block-
ade of CXCR3 has been shown to reduce Th1 and mac-
rophage infiltration, as well as tissue damage. More-
over, increase in the hippocampal neurogenesis has
been demonstrated in the adult mice with knockout
of the CXCR5
–/–
chemokine receptor (CXCL13 ligand),
while change in the structure of the cerebellum is ob-
served in the mice with knockout of the CXCL12 and
its CXCR4 receptor [8].
CX3C chemokines. CX3CL1 chemokine, also known
as fractalkine, is highly expressed in mature neurons
and astrocytes, while its CX3CR1 receptor is expressed
mainly on microglial cells, but, also, on mature neu-
rons [62,  63]. CX3CL1 has been shown to have multiple
effects on the CNS: on the one hand, it prevents exces-
sive activation of microglia in the absence of injury,
while promoting activation of microglia and astro-
cytes during neuroinflammatory processes, including
secretion of proinflammatory cytokines, expression of
ICAM-1, and recruitment of CD4
+
T cells in the CNS
[64-66].
Both soluble and membrane-bound forms of
CX3CL1 attenuate microglial activation and the lipopoly-
saccharide-induced increase in proinflammatory cyto-
kines in primary microglia and neuron cell cultures.
Thus, while a number of chemokines have been
shown to have significant effects on regulation of neu-
roinflammation, it is unclear for most of the chemok-
ines whether their functions have the same relevance
to regulation of chronic inflammation, which is as-
sumed to be one of the mechanisms of pathogenesis
in many psychiatric disorders.
STUDIES OF CHEMOKINE SYSTEM IN ANIMAL
MODELS OF ALCOHOL USE DISORDERS
C chemokines. Studies of this chemokine family
and their receptors are very few, including in animal
models. It was revealed that the C3AR1 receptor ex-
pression is induced by ethanol, which leads to the
change in phagocytosis of microglia [67]. Earlier stud-
ies have shown that the C5AR1 receptor is involved in
the alcohol-induced inflammation [68, 69].
In the study by Holloway et al. some potential
mechanisms by which the ethanol-induced neuroin-
MIKHALITSKAYA et al.1892
BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
flammation could contribute to the onset of neuropa-
thology were shown  [70]. Using the postnatal mouse
model of fetal alcohol syndrome equivalent to the
third trimester of human pregnancy, transcriptom-
ic changes caused by ethanol exposure at a dose of
4  g/kg/day were evaluated in the cerebellum on the
postnatal days 5 (PND5) and 6 (PND6), after 1 or 2
days of ethanol exposure, in order to detect chang-
es in the early stages of emergence and development
of this syndrome. In elucidating possible mechanisms
by which ethanol induces early immune activation,
Holloway  et  al.  [70] identified immune-associated tran-
scripts, expression of which was strongly altered by
ethanol. On the PND5 and PND6, upregulated tran-
scripts included C5AR1 and C3AR1 receptors, MSR1
(macrophage scavenger receptor  1), CCL3 chemok-
ine (macrophage inflammatory protein-1  α, MIP-1α),
and CD14.
CC chemokines. More studies are focused on in-
vestigation of the CCL2 chemokine belonging to this
family. Ethanol has been found to induce CCL2 ex-
pression in the animal models of AUD [70], and ge-
netic studies in animals show that the enhanced CCL2
signaling is accompanied by the increased alcohol
consumption [71].
CCL2/CCR2 signaling plays an important role in
the alcoholic neuropathology both in adult and de-
veloping CNS. Studies of the ethanol impact on the
developing spinal cord in a mouse model equivalent
to the third trimester of pregnancy  [72] found that
exposure to ethanol at a dose of 2.5  g/kg/day during
development caused irreversible loss of spinal cord
neurons, and CCR2 signaling played an important role
in ethanol neurotoxicity. The ethanol-induced apopto-
sis and neurodegeneration in dorsal horn neurons in
the mice in early postnatal period, which was accom-
panied by the glial activation, macrophage infiltration,
and increased CCR2 expression. The ethanol-induced
neuronal death during development resulted in irre-
versible loss of the spinal cord neurons in the adult
mice. The study revealed that ethanol-induced endo-
plasmic reticulum stress and oxidative stress, as well
as activated the glycogen synthase kinase-3  β (GSK-3β)
and c-Jun N-terminal kinase (JNK) pathways. Knock-
out of the CCL2 or CCR2 genes made mice resistant
to the ethanol-induced apoptosis, endoplasmic reticu-
lum stress, glial activation, GSK-3β and JNK activation.
Onthe other hand, knockout of the CCR2 gene provid-
ed much better protection against the ethanol-induced
spinal cord injury. Hence, the effect of ethanol on the
mouse embryonic development led to irreversible loss-
es of spinal cord neurons, and CCR2 signaling played
an important role in the ethanol neurotoxicity [72].
In the study by Chang et  al.  [73], pregnant rats
from the embryonic day 10 to 15 (during peak neu-
rogenesis) were orally administered ethanol at a mod-
erate dose (2  g/kg/day) or peripherally injected with
CCL2 or CCR2 antagonist to examine the role of the
CCL2/CCR2 system in the mechanisms of ethanol ef-
fects. Maternal administration of ethanol has been
demonstrated to increase the radial glia cell density
in embryos and simultaneous stimulation of the CCL2/
CCR2 system, and these effects are mimicked by the
maternal CCL2 administration and blocked by the
CCR2 antagonist. By stimulating colocalization of CCL2
with radial glia and neurons, but not microglia, eth-
anol increases amount of neuronal melanin-concen-
trating hormone (MCH) near radial glia cells and es-
tablishes contact along their processes protruding into
the lateral hypothalamus. Further tests identified that
the CCL2/CCR2 system in the neuroepithelium is the
primary source of ethanol sexual dimorphism. These
results provide new knowledge on how the inflamma-
tory chemokine pathway functions in neuroprogenitor
cells mediating long-lasting stimulatory effects of eth-
anol on neuropeptides linked to adolescent behavior
associated with alcohol consumption [73].
Several studies have shown that the CCL2/CCR2
signaling is also involved in the behaviors associated
with alcohol use. Thus, deletion of the CCR2 and CCL2
genes (in female mice) reduced preference for ethanol
in the case of free choice between ethanol solution
and water, while alcohol administration resulted in
the stronger conditional aversion to its taste in the
CCR2
–/–
and CCL2
–/–
mice  [68]. The study by Holloway
et al. [74] in mice showed that alcohol activates the
Toll-like receptor  4 (TLR4) signaling, leading to induc-
tion of proinflammatory cytokines and chemokines in
the CNS. Evaluation of mRNA expression with qRT-PCR
showed that ethanol induced increase of the levels of
IL-1β cytokines and TNF-α tumor necrosis factor, CCL2
chemokine, COX2 cyclooxygenase, as well as FosB and
JunB proteins in the cerebellum of the wild-type and
TLR4-deficient mice (TRIF). Although it is not exactly
clear how CCL2 regulates alcohol behavior, a possible
explanation is that CCL2 activates dopamine system
[75]. Based on the presented information it could
be concluded that CCL2/CCR2 signaling likely partic-
ipates in the alcohol-induced brain damage by regulat-
ing microglial activation and neurotransmission  [40].
In the study by June et al. [76] it has been reported
that the P-line rats preferring alcohol have innately
elevated levels of TLR4 and CCL2 chemokine, which
are localized in the neurons of the central nucleus of
amygdala (CeA) and ventral tegmental region (VTA).
To investigate potential role of the TLR4/CCL2 signal,
herpes simplex virus (HSV) vectors (amplicons) that
preserve neurotropism in vivo have been used. Intro-
duction of the TLR4 or CCL2 miRNA amplicons into
the CeA or VTA of the P rats inhibited expression of
the target genes and reduced alcohol dependence.
The similarly delivered amplicon of scrambled miRNAs
CHEMOKINES AND ALCOHOL CONSUMPTION 1893
BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
did not inhibit TLR4 or CCL2 expression or reduce al-
cohol overconsumption, thus identifying the neuronal
TLR4/CCL2 signal as the signal that regulates onset of
the voluntary self-administered alcohol consumption.
This signal was sustained during alcohol consump-
tion through increased expression of the corticotro-
pin-releasing factor (CRF) and its feedback regulation
of TLR4 expression, which, likely, contributed to the
transition to alcohol dependence [76].
In the study by Zhang et al. [77] exposure to eth-
anol was shown to increase expression of CCL2, but
not of CCR2, in the mouse brain on the PND4 and in
the microglial cells (SIM-A9). The CCL2 synthesis in-
hibitor, bindarite, and the CCR2 antagonist, RS504393,
inhibited ethanol-induced neuroapoptosis, microglial
activation, and expression of proinflammatory factors.
Further studies using the gene knockout mice con-
firmed that CCL2 or CCR2 deficiency made the mice
more resistant to the ethanol-induced neurodegenera-
tion. Moreover, ethanol and CCL2 caused greater neu-
ronal death in the neuron/microglia co-culture system
than in the neuronal culture alone. Blocking the CCL2/
CCR2 signaling protected primary cortical and cerebel-
lar neurons from the ethanol-induced death in co-cul-
tures of neurons and microglia. The TLR4 receptor
involved in innate immunity along with the GSK-3β
kinase were found to mediate the ethanol-induced ac-
tivation of microglia and proinflammatory cytokines
in the cultured microglia cells, and there was a signif-
icant interaction between the TLR4, GSK-3β, and CCL2/
CCR2 signaling in response to ethanol exposure  [77].
Also, Yang et  al.  [78] have shown using co-culture of
neurons and microglia that the CCL2-induced neuro-
toxicity requires microglia and that exogenous CCL2 is
able to activate and stimulate microglia to produce cy-
tokines. This study revealed that the neutralizing CCL2
antibodies inhibit the CCL2-induced microglial activa-
tion and neuronal death in the culture and thalamus.
The levels of CCL2 transcript are increased by ex-
posure to ethanol. CCL2 and CCL3, which are target
genes of the NF-κB transcription factor, are induced
by ethanol and are key mediators of CNS inflamma-
tion and alcohol-associated behavior [68,  69]. Ethanol
has previously been shown to induce CCL2 expression
in the animal models of fetal alcohol syndrome  [79]
and in the adult animal models of alcohol use disor-
ders [80].
Alcohol exposure activates microglia, increases
expression of CCL2 and other proinflammatory cyto-
kines, such as TNF-α, IL-6, and IL-1β, and leads to neu-
ronal death in the rats  [81-83]. Qin et  al.  [84] report-
ed that ethanol, administered at a dose of 5  g/kg/day
per  os, potentiated the lipopolysaccharide-induced
CCL2 increase and microglial activation in the brain
of adult mice. It was suggested that CCL2 reduces the
“threshold sensitivity” of microglia as a “priming”
stimulus and enhances synthesis of proinflammatory
cytokines in response to subsequent exposure [85].
In the experiment of Valenta et al.  [86] involv-
ing the CCL2 signaling enhancement through direct
injection of it into the brain, there was correlation
observed between the dose of CCL2 and consumption
of the sweetened ethanol solution by the Long-Evans
rats during the first 4 weeks (while pumps were
flowing) and during the entire 8-week experiment.
Animals receiving the highest dose of CCL2 (2  μg/day)
consumed the most ethanol during weeks 3 through 8.
This study proves that neuroimmune signaling could
increase directly chronic voluntary ethanol consump-
tion, and that this increase persists beyond the cyto-
kine administration. The ethanol-induced increase in
CCL2 or increase in CCL2 due to various other neu-
roimmune mechanisms could further facilitate etha-
nol consumption. Further investigation of this mech-
anism, particularly using alcohol dependence models,
could help to determine whether the effects on CCL2
signaling possess therapeutic potential in the treat-
ment of AUD. Bray et  al.  [87] in their work attribut-
ed increased CCL2 expression levels in the transgenic
mouse astrocytes to the increased alcohol consumption
in the alcohol consumption tests, and to spatial and
associative learning, thereby supporting the following
hypothesis that the increased CCL2 levels induce neu-
roadaptive changes, which, in turn, alter the alcohol
impact on CNS.
Lowe et  al.  [88] were searching for a potential
therapeutic approach in the treatment of alcohol-
associated neuroinflammation, and have suggested
that chronic alcohol consumption leads to infiltration
of peripheral immune cells into the CNS. Since chemo-
taxis through the CCL2/CCR2 signaling axis is critical
for recruitment of macrophages in the periphery and
center areas, it has also been hypothesized that block-
ade of the CCL2 signaling by the dual CCR2/5 inhib-
itor cenicriviroc would prevent the alcohol-induced
infiltration of peripheral macrophages into the CNS
and alter neuroinflammatory state of the brain caused
by chronic alcohol consumption. Investigation of the
female mice demonstrated that chronic alcohol con-
sumption caused microglial activation and infiltration
of peripheral macrophages in the CNS, especially in
the hippocampus. Cenicriviroc eliminated the ethanol-
induced recruitment of peripheral macrophages and
reversed partially microglial activation. In addition,
chronic alcohol consumption enhanced expression
of the pro-inflammatory markers in various brain
areas, including cortex, hippocampus, and cerebel-
lum. The CCR2/5 inhibition reduced alcohol-mediat-
ed expression of inflammatory markers. This fact is
considered by the authors as a potential therapeutic
approach in the treatment of alcohol-associated neu-
roinflammation. In another work, Lowe et  al.  [89]
MIKHALITSKAYA et al.1894
BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
revealed that alcohol consumption increased signifi-
cantly expression of the proinflammatory cytokines,
such as TNF-α, IL-17, and IL-23, CCL2 chemokine, and
Hmgb1 (high-mobility group box  1) cytokine mediator
in the brain and intestine. Thus, decrease in the bac-
terial load of intestine, resulted from the use of anti-
biotics, weakened expression of all pro-inflammatory
cytokines both in the brain and in the small intestine.
Alcohol consumption led to microglial activation and
morphological changes in the cortex and hippocam-
pus, characterized by the reactive phenotype. These
alcohol-induced changes were corrected after the pre-
scribed antibiotics weakened the intestinal microbi-
ome. Unexpectedly, antibiotic use led to the increased
expression of mRNAs of some inflammation compo-
nents in both brain and intestine [89].
The data obtained by Huang et  al.  [90] in humans
and mice, show that chronic alcohol consumption is
associated with the increased levels of the CCL11
chemokine. CCL11 levels correlate with severity of
alcohol dependence and could serve as its potential
indicator. The reduced CCL11 level after alcohol with-
drawal is associated with the relief in clinical symp-
toms. The authors conclude that CCL11 participates
in the neurobiological mechanisms underlying alcohol
dependence. Chronic and excessive ethanol adminis-
tration has also been shown to induce expression of
inflammatory molecules (CCL2) in the adult mice [83].
Specific sex-dependent effects of alcohol on mi-
croglia in the developing rat hippocampus were inves-
tigated to simulate acute effects following a single-day
alcohol exposure (2 feedings, 2  h apart, at a total eth-
anol dose of 5.25  g/kg) on PND4  [91]. Neuroimmune
response was evaluated by measuring microglia num-
ber and chemokine gene expression on the PND5 and
PND8. In many hippocampal subregions on the PND5,
the male pups had higher microglial number com-
pared to the females, but this difference disappeared
by the PND8, unless exposed to alcohol. After alcohol
exposure, the level of C-C motif chemokine ligand  4
(CCL4) was significantly increased in the female pups
on the PND5 and PND8. The results demonstrate clear
difference between the neuroimmune response to eth-
anol exposure in females and males [91].
Effects of alcohol on activation of immunity in
the aged animals has not been investigated extensive-
ly, despite the fact that alcohol abuse has a signifi-
cant impact on the health of the elderly population.
Kane et  al.  [92] compared influence of ethanol on
the chemokine and cytokine expression in the hippo-
campus, cerebellum, and cerebral cortex of the aged
C57BL/6 mice. The mice were gavaged with 6  g/kg of
ethanol for 10 days, tissue were harvested 1 day after
treatment. Ethanol exposure caused selective increase
of the CCL2 mRNA levels in the hippocampus and cer-
ebellum, but not in the cortex of the aged mice com-
pared to the control animals. According to this para-
digm, ethanol did not affect the mRNA levels of the
cytokines IL-6 or TNF-α in any of the studied brain
areas of aged animals. Collectively, these data indi-
cate area-specific susceptibility to ethanol regulation
of neuroinflammatory and addiction-associated mol-
ecules in the aged mice. The authors conclude that
these studies could be of great importance regarding
to alcohol-induced neuropathology and alcohol depen-
dence in older adults [92].
The level of CCL2 in microglia obtained in animal
models of AUD with forcible ethanol administration
is a major marker of neuroinflammation. However,
there is conflicting evidence on whether the CCL2 lev-
els increase in the case of voluntary ethanol intake.
Thus, the key role of CCL2 in stimulating motivation
to consume ethanol is challenged. In the study of
Berríos-Cárcamo et  al.  [93] the levels of CCL2 mRNA
levels were studied in the brain areas of the C57BL/6-
line mice associated with motivation to consume
alcohol, particularly in the prefrontal cortex, hippo-
campus, and striatum, as well as in the cerebellum,
which is the brain area highly sensitive to ethanol; all
experiments were carried out with the animals that
consumed ethanol voluntarily for two months. A signif-
icant increase in the CCL2 mRNA levels was found in
the cerebellum of mice exposed to ethanol compared
to the control animals. At the same time, no significant
changes were observed in the prefrontal cortex, hip-
pocampus, striatum, and microglia isolated from the
hippocampus and striatum. These results suggest that
stimulation of the voluntary ethanol consumption by
the C57BL/6 mice does not require neuroinflammation
in the areas associated with motivation. Moreover, cer-
ebellar susceptibility to neuroinflammation could be
the cause of cerebellar degeneration in humans after
chronic ethanol consumption [93].
CXC chemokines. It was revealed in the recent
study with mice that overexpression of CXCL14, as-
sessed by qPCR and ELISA, enhances alcoholic liver
damage, as evidenced by the measurements of ALT (al-
anine aminotransferase) and AST (aspartate transami-
nase) levels in the plasma, as well as of triglycerides
in the liver  [94]. In addition, co-expression of BRG1
(Brahma-related gene  1) and CXCL14 genes was found
to be positively correlated with the neutrophil infiltra-
tion in this study. In the work by Kusumanchi et al.
[95] a novel role of the FKBP5 gene (encoding FK506-
binding protein  51) in pathogenesis of the alcoholic
liver disease was identified. FKBP5 loss alleviates the
alcohol- induced liver damage through the CXCL1 sig-
naling, indicating its potential role as a target in the
treatment of alcohol-induced liver damage.
The alcohol-induced changes in circulating chemo-
kines have also been studied in preclinical models
of alcohol consumption using male Wistar rats [59].
CHEMOKINES AND ALCOHOL CONSUMPTION 1895
BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
The rats subjected to repeated ethanol administration
(3  g/kg, gavage) had lower CXCL12 concentrations and
higher CCL11 concentrations relative to the control
group. Moreover, the elevated CCL11 concentrations
in the ethanol-exposed rats were further increased by
the prior stress exposure. Accordingly, acute ethanol
exposure caused changes in the CXCL12 and CCL11
levels, similarly to the effect of repeated exposure.
Another study showed that the moderate prenatal
ethanol exposure stimulates chemokine system of
CXCL12/CXCR4 in the radial glial progenitor cells in
hypothalamic neuroepithelium and also in neuropep-
tide system in the lateral hypothalamus of embryo
and postnatal rat offsprings [96].
A study conducted with adult male cynomolgus
macaques evaluated plasma protein levels during
the 32-month experimental protocol: at baseline, in-
duction of water and ethanol (4%  w/v in water) self-
administration, after 4 months, after 12 months of
simultaneous 22-hour daily access to ethanol and wa-
ter [97]. Chronic ethanol intake in primates has been
shown to result in the allostatic state of physiological
compromise with regards to circulating proteins as-
sociated with immunity and stress in the NF-κB and
STAT/JAK-associated pathways, which correlates with
the altered endocrine activity.
In another animal model, Danio  rerio fish, par-
ticipation of the CXCL2a/CXCR4b chemokine system
in mediating the stimulating effect of ethanol on
neuron density in the hypothalamus of embryos was
studied. The results provide clear evidence that the
stimulating effects of ethanol in small and moderate
doses on the number of hypothalamic neurons in the
early stages of development are mediated, in part, by
enhanced transcription and intracellular activation
of the CXCL2a/CXCR4b chemokine system, probably
due to autocrine CXCL2a signaling to the CXCR4b re-
ceptor on neurons [98].
CX3C chemokines. It was shown in the work by
García-Marchena et  al.  [59] that there was no signifi-
cant difference in the CX3CL1 chemokine concentra-
tions in the plasma of male Wistar rats between the
group subjected to repeated ethanol exposure (3  g/kg,
gavage) and the control group.
Investigation of gender differences in the inflam-
matory chemokine profiles caused by the excessive
ethanol consumption during adolescence revealed that
in the female wild-type adolescent mice, intermittent
ethanol administration increased the CCL2, CCL3, and
CXC3CL1 chemokine levels in the prefrontal cortex
and serum (CCL2 and CCL3), but significant differenc-
es in the CX3CL1 levels in the prefrontal cortex were
observed only in the male mice. In the ethanol-treat-
ed TLR4 genetic knockout mice, male or female, no
changes in the chemokine levels were found in the
serum or prefrontal cortex. These results showed that
the females are more vulnerable to the inflammatory
effects of binge ethanol consumption than the males;
and suggested that TLR4 is an important target of the
ethanol-induced inflammation and neuroinflamma-
tion in adolescence [99].
Pascual et  al.  [100] in their work revealed that
chronic ethanol consumption increased the CX3CL1
chemokine levels in striatum and serum of the wild-
type mice. Twenty-four hours after ethanol withdraw-
al, high CX3CL1 level was maintained in the striatum.
The authors associate this with the increase in anxiety
behavior assessed with the light/dark transition and
elevated plus maze tests. Notably, the mice lacking
TLR4 or TLR2 receptors are largely protected from
the ethanol-induced chemokine release, as well as
from the behavioral effects during the alcohol with-
drawal. These data confirm the role of TLR4 and TLR2
responses in neuroinflammation and anxiety-associ-
ated behavioral effects during ethanol deprivation.
Thisevidence also proves that chemokines could serve
as biomarkers of the ethanol-induced neuroimmune
response [100].
Thus, the results of the above-mentioned studies
in animal models suggest involvement of chemokines
in the mechanisms of AUD. Majority of the studies
involve CCL2 chemokine and its receptor. CCR2 sig-
naling has been shown to play an important role in
the ethanol neurotoxicity. The results of the presented
works support the general neuroimmune hypothesis
of dependence. The alcohol-induced chemokine pro-
duction could modulate alcohol impact on regulation
of chronic inflammation.
CHANGES IN THE HUMAN
CHEMOKINE SYSTEM UNDER
THE INFLUENCE OF ALCOHOL
There is sufficient evidence in the literature to
support involvement of many chemokines in patho-
genesis of AUD. At the same time, most of the studies
are focused on the research in animal models, while
only few studies have been conducted with biomate-
rial from the patients with AUD.
Alcohol has been shown to stimulate inflamma-
tory pathways by activating microglia in the CNS in
both adult and developing brain [101]. Recent studies
indicate that chemokines are key mediators of the
ethanol-induced neuroimmune response and neuro-
adaptive changes in the CNS, together with cytokines,
such as IFN-2α [102], TNF-α, IL-1β, IL-6, IL-10 cyto-
kines [103].
In particular, the study of postmortem brain tis-
sues of 5 people with alcoholism revealed that CCL2
concentration in the ventral tegmental area, substan-
tia nigra, hippocampus, and amygdala of the brain
MIKHALITSKAYA et al.1896
BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
Fig. 1. Contribution of chemokines to neuroinflammation in alcohol intoxication. Ethanol exposure (EtOH), affecting liver
and CNS cells, leads to the increased expression (↑) of some chemokines and their receptors (CCL2, -11, C3AR1, CXCL1, -2,
-4, -5, -6, -8, -10) and decreased expression (↓) of others (CXCL12, CX3CL1). Chemokines, in turn, interacting with their GPCR
receptors on the surface of microglia and neurons, contribute to activation (!) of microglia, chemotaxis, and infiltration
of neutrophils and macrophages into the inflammation site, as well as to activation of oxidative stress and expression of
anumber of pro-inflammatory factors. Altered expression of chemokines in the CNS also leads to activation of the dopamine
system and increased alcohol consumption, which, in turn, results in an even greater change in the chemokine expression.
Thus, the development of neuroinflammation leads to impaired neurogenesis, neurodegeneration, and apoptosis of neurons.
was increased in the alcoholic patients with compared
to the control group  [69]. Another research of the
postmortem brain tissues of 10 men with AUD  [104]
showed increase in the expression of CCL8, CCL7,
CCL13, CCL5, CXCL8, CXCL12 chemokines and their re-
ceptors (CCR1 and CCR2, CXCR3 and CXCR4) in orbitof-
rontal cortex of the patients compared to the control
group. Although the sample size in these two studies
is rather small, the demonstrated data suggest that the
ethanol-induced increased expression of chemokines
and their receptors in the brain could modulate the
effects of alcohol exposure/withdrawal on synaptic
function, as well as contribute to AUD [105]. In the
study by García-Marchena etal. [59] content of a num-
ber of chemokines (CXCL8 and -12, CX3CL1, CCL2, -3,
and -11) was examined and the statistically significant
association of just a few chemokines with AUD was
demonstrated: plasma concentrations of CXCL12 and
CX3CL1 chemokines were lower in the patients com-
pared to the control group.
In the same work, the topic of gender differences
in terms of immune response to alcohol overconsump-
tion was noted. In particular, plasma concentration of
CCL11 was much lower in the women with alcoholism
than in the men  [59]. Experiments conducted in ado-
lescents (humans and mice) by Pascual etal. [99] also
showed that women are more vulnerable to the in-
flammatory effects of ethanol overconsumption than
men: at equivalent blood alcohol levels, cytokine and
chemokine levels (IFN-γ, IL-10, IL-17A, IL-1β, IL-2, IL-4,
IL-6, IL-8, CX3CL1, CCL2, and CCL3) in the plasma were
found to be higher in the adolescent women than in
the male adolescents after severe alcohol intoxication.
Thus, in addition to the structural and functional gen-
der differences in the effects of ethanol on the brain
of adolescents [106], new evidence suggests existence
of sex differences also in the immune and neuroim-
mune responses induced by ethanol [107].
A study of the blood plasma of 151 patients with
alcohol dependence showed that the CCL11 levels
CHEMOKINES AND ALCOHOL CONSUMPTION 1897
BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
were higher in the patients than in the control group,
and the CCL11 levels decreased during detoxification.
In addition, the CCL11 levels were shown to correlate
positively with the alcoholism severity assessed by the
SADQ scale (The Severity of Alcohol Dependence Ques-
tionnaire) [90]. In another work focused on analysis of
the serum of male patients with excessive alcohol con-
sumption, higher levels of CCL2 were observed along
with the increased levels of IL-6 and IFN-γ, as well as
lower levels of TGF-β1 (transforming growth factor  β1)
compared to the control group [108]. Moreover, rela-
tionship between the CCL2 plasma concentration and
clinical remission in the patients was shown: increase
in the number of days since last drink was associ-
ated with the lower CCL2 concentration  [109], while
the higher CCL2 concentration was associated with
greater cravings for alcohol  [110]. Higher CCL2 levels
were also associated with poor sleep quality, higher
rates of anxiety and depression, as well as with the in-
crease of the following parameters: number of drink-
ing days, average amount of alcohol drunk per day,
number of days of excessive alcohol consumption, and
total amount of alcohol consumed [111].
When examining cerebrospinal fluid of 28 alco-
holics and 13 healthy volunteers, the researchers
found that CCL2 concentration in the patients was
significantly higher both on the 4th and 25th day af-
ter detoxification. The CCL2 concentration also cor-
related positively with activity of the liver enzymes:
GGT (gamma-glutamyl transpeptidase) and AST  [112].
These data support the hypothesis that the CCL2-me-
diated neuroinflammation could be associated with
alcohol-dependent liver inflammation.
Hence, it seems reasonable to suggest that in the
AUD, chemokines are usually evaluated particularly in
the context of alcoholic hepatitis [113-115]. Moreover,
along with the IL-1 inhibitors and pan-caspases, CCL2
inhibitors are currently considered as new therapeutic
drugs in the treatment of alcoholic hepatitis [116].
In particular, increased expression of CXC (CXCL8,
CXCL2, CXCL5, CXCL6, CXCL10, and CXCL4) and CC
(CCL2, but not CCL5) chemokines was observed in the
liver cells of the patients with alcoholic hepatitis in
comparison with the control [115]. In addition, higher
expression levels of CXCL8, CXCL5, CXCL2, and CXCL6
were associated with the worst disease prognosis
[115]. Another study performed using RNA sequenc-
ing also showed that activity of the CXCL chemokines
(CXCL1, CXCL6, and CXCL8) was increased in the liver
of patients with alcoholic hepatitis  [117]. A weighted
gene coexpression network analysis (WGCNA) showed
that the individual members of the CXC chemokine
(CXCL8) and CC chemokine (CCL20) families were
highly associated with alcoholic hepatitis, compared
to the controls, but have no relationship with the liver
diseases of another etiology [118].
Taken together, this evidence suggests potential
mechanisms through which the ethanol-induced neu-
roinflammation could contribute to neuropathology in
both the developing and adult organism.
CONCLUSION
To date, there are not many works in the liter-
ature focused on investigation of chemokines in the
context of alcohol dependence. Most of them include
studies in animal models, and only few study patients
with AUD.
Based on the presented data, we propose a dia-
gram illustrating contribution of the ethanol-induced
activation of chemokine system to the development of
neuroinflammation (Fig. 1).
Generally, in the context of alcohol abuse, most of
the chemokines have not been explored and not rep-
resented sufficiently in the literature, especially in the
studies performed with patients. Feasibility of using
these proteins as pathologically relevant biomarkers
or therapeutic targets should be considered in future
clinical and translational studies.
Contributions. S.A.I. developed the concept, pre-
pared primary version of the manuscript; E.V.M. and
N.M.V. conducted search and analysis of the literature
date; N.A.B. developed the concept, edited the manu-
script.
Funding. This work was financially supported
by the Russian Science Foundation (project no.23-15-
00338, “Comparative study of the role of immunoin-
flammation and neuroprotection in the pathogenesis
and clinic of affective disorders and alcohol addiction”).
Ethics declaration. This work does not describe
any studies involving humans or animals as objects
performed by any of the authors. The authors of this
work declare that they have no conflicts of interest in
financial or any other sphere.
Open access. This article is licensed under a Cre-
ative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution,
and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s)
and the source, provide a link to the Creative Com-
mons license, and indicate if changes were made.
Theimages or other third party material in this article
are included in the article’s Creative Commons license,
unless indicated otherwise in a credit line to the mate-
rial. If material is not included in the article’s Creative
Commons license and your intended use is not permit-
ted by statutory regulation or exceeds the permitted
use, you will need to obtain permission directly from
the copyright holder. To view a copy of this license,
visit http://creativecommons.org/licenses/by/4.0/.
MIKHALITSKAYA et al.1898
BIOCHEMISTRY (Moscow) Vol. 89 No. 11 2024
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