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Resveratrol-driven macrophage polarization: unveiling mechanisms and therapeutic potential

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Frontiers in Pharmacology
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Resveratrol, a polyphenolic compound known for its diverse biological activities, has demonstrated multiple pharmacological effects, including anti-inflammatory, anti-aging, anti-diabetic, anti-cancer, and cardiovascular protective properties. Recent studies suggest that these effects are partly mediated through the regulation of macrophage polarization, wherein macrophages differentiate into pro-inflammatory M1 or anti-inflammatory M2 phenotypes. Our review highlights how resveratrol modulates macrophage polarization through various signaling pathways to achieve therapeutic effects. For example, resveratrol can activate the senescence-associated secretory phenotype (SASP) pathway and inhibit the signal transducer and activator of transcription (STAT3) and sphingosine-1-phosphate (S1P)-YAP signaling axes, promoting M1 polarization or suppressing M2 polarization, thereby inhibiting tumor growth. Conversely, it can promote M2 polarization or suppress M1 polarization by inhibiting the NF-κB signaling pathway or activating the PI3K/Akt and AMP-activated protein kinase (AMPK) pathways, thus alleviating inflammatory responses. Notably, the effect of resveratrol on macrophage polarization is concentration-dependent; moderate concentrations tend to promote M1 polarization, while higher concentrations may favor M2 polarization. This concentration dependence offers new perspectives for clinical treatment but also underscores the necessity for precise dosage control when using resveratrol. In summary, resveratrol exhibits significant potential in regulating macrophage polarization and treating related diseases.
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Resveratrol-driven macrophage
polarization: unveiling
mechanisms and therapeutic
potential
Panting Wang
1
,
2
, Zixi Li
3
, Yixuan Song
3
, Bowei Zhang
4
* and
Chaofeng Fan
1
,
2
*
1
Department of Neurosurgery West China Hospital, Sichuan University, Chengdu, China,
2
West China
School of Nursing Sichuan University, Chengdu, China,
3
School of Pharmacy, Chengdu University of
Traditional Chinese Medicine, Chengdu, China,
4
Southwest Institute of Technical Physics, Chengdu,
China
Resveratrol, a polyphenolic compound known for its diverse biological activities,
has demonstrated multiple pharmacological effects, including anti-inammatory,
anti-aging, anti-diabetic, anti-cancer, and cardiovascular protective properties.
Recent studies suggest that these effects are partly mediated through the
regulation of macrophage polarization, wherein macrophages differentiate into
pro-inammatory M1 or anti-inammatory M2 phenotypes. Our review highlights
how resveratrol modulates macrophage polarization through various signaling
pathways to achieve therapeutic effects. For example, resveratrol can activate
the senescence-associated secretory phenotype (SASP) pathway and inhibit the
signal transducer and activator of transcription (STAT3) and sphingosine-1-
phosphate (S1P)-YAP signaling axes, promoting M1 polarization or suppressing
M2 polarization, thereby inhibiting tumor growth. Conversely, it can promote
M2 polarization or suppress M1 polarization by inhibiting the NF-κBsignaling
pathway or activating the PI3K/Akt and AMP-activated protein kinase (AMPK)
pathways, thus alleviating inammatory responses. Notably, the effect of
resveratrol on macrophage polarization is concentration-dependent; moderate
concentrations tend to promote M1 polarization, while higher concentrations may
favor M2 polarization. This concentration dependence offers new perspectives for
clinical treatment but also underscores the necessity for precise dosage control
when using resveratrol. In summary, resveratrol exhibits signicant potential in
regulating macrophage polarization and treating related diseases.
KEYWORDS
resveratrol, macrophage polarization, M1/M2 phenotypes, cancer, inammation
OPEN ACCESS
EDITED BY
Chiara Bolego,
University of Padua, Italy
REVIEWED BY
Marc Christophe Karam,
University of Balamand, Lebanon
Chandra C. Ghosh,
Beth Israel Deaconess Medical Center and
Harvard Medical School, United States
*CORRESPONDENCE
Bowei Zhang,
bowilzhang@163.com
Chaofeng Fan,
914609141@qq.com
RECEIVED 24 October 2024
ACCEPTED 23 December 2024
PUBLISHED 13 January 2025
CITATION
Wang P, Li Z, Song Y, Zhang B and Fan C (2025)
Resveratrol-driven macrophage polarization:
unveiling mechanisms and
therapeutic potential.
Front. Pharmacol. 15:1516609.
doi: 10.3389/fphar.2024.1516609
COPYRIGHT
© 2025 Wang, Li, Song, Zhang and Fan. This is
an open-access article distributed under the
terms of the Creative Commons Attribution
License (CC BY). The use, distribution or
reproduction in other forums is permitted,
provided the original author(s) and the
copyright owner(s) are credited and that the
original publication in this journal is cited, in
accordance with accepted academic practice.
No use, distribution or reproduction is
permitted which does not comply with these
terms.
Abbreviations: STAT, signal transducer and activator of transcription; JNK, c-Jun N-terminal kinase;
TLR2, toll-like receptors 2; BMSC-Exos, Bone Marrow Stromal Cell-derived Exosomes; SASP,
Senescence-Associated Secretory Phenotype; LPS, lipopolysaccharide; NO, nitric oxide; ROS,
oxygen species; VEGF-B, vascular endothelial growth factor B; MSN, mesoporous silica
nanoparticles; MSN-RSV, mesoporous silica nanoparticles loaded with resveratrol; TNF-α, tumor
necrosis factor-alpha; INOS, inducible nitric oxide synthase; S1P, sphingosine-1-phosphate; AMPK,
AMP-activated protein kinase; IL-10, interleukin 10; IRF-3, interferon regulatory factor 3; C/EBPβ,
CCAAT/enhancer binding protein beta; PINK1, PTEN induced putative kinase 1; THP-1, Tohoku
Hospital Pediatrics-1; ARG1, arginase-1; SPHK1, sphingosine kinase 1; MyD88, myeloid differentiation
primary response protein 88; DHR, dihydroresveratrol; SLNs, lipid nanoparticles; NLCs, nanostructured
lipid carriers; AUC, area under the curve; Cmax, maximum concentration.
Frontiers in Pharmacology frontiersin.org01
TYPE Review
PUBLISHED 13 January 2025
DOI 10.3389/fphar.2024.1516609
1 Introduction
Resveratrol (C₁₄H₁₂O) is a distinguished non-avonoid
polyphenolic phytoalexin (Galiniak et al., 2019)thatfunctions
as a natural defense mechanism in plants. This compound is
prevalent in various dietary sources, including grapes, peanuts,
blueberries, lingonberries, cranberries, and purple grape juice
(Tian and Liu, 2020;Ispiryan et al., 2024). Notably, red wine
contains an average of approximately 1.9 ± 1.7 mg/L of
resveratrol, with certain batches exhibiting higher
concentrations. In contrast, white and rosé wines possess
signicantly lower resveratrol levels, ranging from 0 to
1.089 mg/L and around 0.29 mg/L, respectively (Weiskirchen
and Weiskirchen, 2016), with the summary provided by Tian
and Liu (2020). Extensive research has consistently elucidated
that resveratrol exhibits a myriad of therapeutic properties,
encompassing anti-inammatory (Huang et al., 2024;
Vestergaard and Ingmer, 2019), anti-aging (Shahcheraghi
et al., 2023;Shari-Rad et al., 2022), anti-diabetic (Youjun
et al., 2023), anti-cancer (Lafta et al., 2023;Zhang et al.,
2023), and cardiovascular protective effects (Brown et al.,
2024;Zivarpour et al., 2022). These compelling ndings
underscore the considerable potential of resveratrol as a
pivotal agent in promoting health and mitigating a spectrum
of diseases.
Macrophage polarization is a dynamic and crucial process
that occurs when macrophages are activated by a variety of
stimuli (Zhou et al., 2022), such as pathogens, inammatory
signals, cytokines, or specic physicochemical factors. This
activation results in the differentiation of macrophages into
two distinct subtypes: the pro-inammatory M1 macrophages
and the anti-inammatory M2 macrophages (Kerneur et al.,
2022;Mantovani et al., 2022). These specialized phenotypes
play essential roles in orchestrating effective bactericidal
andanti-tumorresponses,aswellasinmodulatingthe
initiation and resolution of diseases through intricate signal
transduction pathways (Li Y. et al., 2024;Wang et al., 2021;
Wang S. et al., 2024). The delicate balance between M1 and
M2 macrophage polarization is vital for the maintenance of
immune homeostasis. In the context of acute inammation,
macrophages differentiate into the M1 subtype, which is
characterized by a robust production of cytokines that are
instrumental in the elimination of invading pathogens. Once
the pathogens have been cleared, macrophages undergo a
transition to the M2 subtype (Chang et al., 2020). This
shift is marked by the secretion of anti-inammatory
cytokines, which serve to dampen inammation, facilitate
tissue repair, and restore tissue integrity (Chen S. et al.,
2023;Wynn et al., 2013). The intricate mechanism
between M1 and M2 polarization is essential for the proper
resolution of inammatory responses and the maintenance of
overall health.
In recent years, signicant strides in understanding the
mechanisms of macrophage polarization have brought
resveratrol to the forefront as a promising clinical
interventionfordiseasessuchasinammation and cancer
(Chen and Musa, 2021;Ren et al., 2021). Emerging research
suggests that resveratrol is capable of modulating macrophage
polarization via multiple pathways, which could be
instrumental in managing conditions like inammation,
GRAPHICAL ABSTRACT
This review explores the therapeutic potential of resveratrol in disease management by assessing its ability to modulate macrophage polarization
towards the M1 and M2 phenotypes.
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diabetes, and cancer (Malaguarnera, 2019). A review of the
literature indicates a growing interest in the study of
resveratrols effects on macrophage polarization, highlighting
the importance of its regulatory role on the M1/M2 balance as a
subject of intensive scientic investigation. Despite the
considerable progress made in elucidating the interplay
between resveratrol, macrophage polarization, and the
pathogenesis of various diseases, comprehensive overviews
that integrate these ndings are still relatively rare. This
article endeavors to bridge this gap by summarizing the
mechanisms through which resveratrol regulates macrophage
polarization (Figures 1,2). By doing so, it aims to provide novel
FIGURE 1
Resveratrol polarizes macrophages into M1 and M2 phenotypes with distinct therapeutic functions. By modulating macrophage polarization,
resveratrol exerts its pharmacological effects: M1-polarized macrophages demonstrate anticancer and anti-aging activities, while M2-polarized
macrophages exhibit anti-diabetic and anti-inammatory actions.
FIGURE 2
The polarization process of macrophages and its triggering targets. M0 macrophages, upon stimulation with factors such as LPS and IFN-γ, activate
signaling pathways including STAT1, NF-κB, and JNK, leading to polarization into the M1 phenotype. This polarization induces inammatory responses
and cytotoxicity. Conversely, exposure of M0 macrophages to cytokines like IL-4, IL-13, and TGF-βactivates pathways such as AmTAR, STAT3, and NF-
κB, promoting polarization into the M2 phenotype to mitigate inammation. Additionally, M1 macrophages can transition to the M2 phenotype
following the clearance of pathogens.
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therapeutic insights for diseases where macrophage polarization
plays a critical role, potentially paving the way for more effective
treatment strategies in the future.
2 Research progress on the mechanism
of macrophage polarization in
disease treatment
2.1 The role of macrophage M1 polarization
in inammatory responses and cytotoxicity
Studies have demonstrated that by modulating signaling
pathways such as NF-κB, STAT1, c-Jun N-terminal kinase
(JNK), and IFN-γ/JAK/STAT1, the polarization of macrophages
into the M1 phenotype is promoted or the M2 polarization is
inhibited, thereby triggering inammatory responses and
cytotoxicity.
The polarization of macrophages towards the M1 phenotype is a
critical process in the immune response, and it is heavily inuenced by
the activation of key signaling pathways. The NF-κBand
STAT1 pathways are particularly importantinthiscontext,astheir
activation is crucial for driving the M1 polarization. This process
enhances the macrophagescytotoxic effects and pro-inammatory
capabilities, which, while essential for pathogen elimination, can also
result in tissue damage if not properly regulated (Li et al., 2023;
Mussbacher et al., 2023;Wang et al., 2014). Interestingly, the
inhibition of the JNK signaling pathway has been observed to
initiate M1 macrophage polarization, highlighting the complex
interplay between signaling pathways in macrophage biology.
Additionally, the activation of the Notch and Akt1 pathways has a
dual role in macrophage polarization by promoting the M1 phenotype
while concurrently suppressing the M2 phenotype, which is typically
associated with anti-inammatory and reparative functions.
Furthermore, IFN-γ, an endogenous activating factor, plays a
signicant role in M1 macrophage polarization by activating
STAT1 through the IFN-γ/JAK/STAT1 signaling pathway (Cheng
et al., 2019;Li et al., 2021). This activation is particularly effective in
inducing the M1 phenotype, further underscoring the importance of
IFN-γin the pro-inammatory activities of M1 macrophages. These
insights into the signaling pathways that regulate macrophage
polarization provide a deeper understanding of the mechanisms
underlying inammation and tissue damage, offering potential
targets for therapeutic intervention in diseases characterized by
inappropriate macrophage activation.
Recent advancements in research have revealed that the targeting of
TRIM25 has been shown to play a role in modulating macrophage
polarization. Specically, TRIM25 catalyzes the ubiquitination of
XRCC1, which in turn promotes M1 macrophage polarization and
induces programmed cell death (Blagov et al., 2023;Jing et al., 2023;Wu
et al., 2024). This process is known to exacerbate atherosclerosis, further
emphasizing the importance of understanding the intricate
mechanisms behind macrophage polarization. These groundbreaking
ndings not only expand our understanding of the role macrophages
play in immune responses and disease progression but also hold the
potential to inform the creation of new therapeutic strategies. By
targeting key regulatory genes and proteins involved in macrophage
polarization, it may be possible to develop treatments that specically
address cytotoxicity-related diseases, offering hope for more effective
clinical interventions in the future.
2.2 Research on the molecular mechanisms
of macrophage M2 polarization in the
treatment of inammation
In contrast to M1 polarization, macrophage M2 polarization is
regulated by signaling pathways such as NF-κB, MAPK, PI3K/AKT,
STAT3, STAT6, peroxisome proliferator-activated receptor gamma
(PPARγ), p50 NF-κB, and C/EBPβ, which collectively promote
M2 polarization and aid in the treatment of inammation.
The synergistic interaction between AmTARS and toll-like
receptors 2 (TLR2) has been demonstrated to effectively activate
the MAPK and PI3K/AKT signaling pathways. This activation
leads to a signicant increase in interleukin 10 (IL-10) production,
which is accompanied by the inhibition of the pivotal inammatory
mediator NF-κB. Consequently, this biological response results in the
amelioration of pathological manifestations in mouse models of colitis
(Kim et al., 2023). Furthermore, IL-4 and IL-13 are identied as key
cytokines that foster M2 macrophage polarization by engaging the
STAT3 and STAT6 signaling pathways. These pathways are essential
for the establishment of immune tolerance and the initiation of tissue
repair mechanisms. Building uponthis, IL-10 is recognized for its role
in advancing M2 polarization by enhancing the activity of p50 NF-κB
homodimers, c-Maf, and STAT3 (Wang et al., 2014;Xia et al., 2023).
PPARγ, a lipid-activated transcription factor in macrophages,
emerges as a signicant player, with its dual function in lipid
metabolism and the modulation of inammatory responses. The
collaborative interaction between STAT6 and PPARγfacilitates
DNA binding, which subsequently regulates the expression of
genes that are integral to the formation of M2 macrophage
markers. Adding to this intricate regulatory network, interferon
regulatory factor 3 (IRF-3) and IRF-4 are highlighted for their
inuential roles in M2 polarization. CCAAT/enhancer binding
protein beta (C/EBPβ), a component of the C/EBP family, is noted
for its ability to stimulate macrophage activation and the expression of
genes specic to the M2 phenotype (Cheng et al., 2019). These
discoveries provide a comprehensive view of the complex signaling
events that underpin M2 macrophage polarization and offer
promising avenues for therapeutic strategies aimed at modulating
macrophage function in various disease contexts.
Recent studies have shed light on the role of Bone Marrow
Stromal Cell-derived Exosomes (BMSC-Exos) in modulating the
polarization of synovial macrophages. By inhibiting the PTEN
induced putative kinase 1 (PINK1)/Parkin signaling pathway,
BMSC-Exos have been shown to suppress the M1 polarization and
promote the M2 polarization in the synovium. This regulatory
mechanism leads to a reduction in cartilage damage in
osteoarthritis rats. Concurrently, there is a decrease in the serum
expression levels of pro-inammatory cytokines such as IL-6, IL-1β,
and tumor necrosis factor-alpha (TNF-α), while the level of the anti-
inammatory cytokine IL-10 increases (Li B. et al., 2024). These
ndings underscore the therapeutic potential of macrophage
polarization in disease treatment and highlight the importance of
precise regulation of macrophage polarization in managing
inammatory diseases. The ability to modulate macrophage
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polarization presents a promising avenue for developing novel
therapeutic strategies that could revolutionize the treatment of
various inammatory conditions.
3 Research on the pharmacological
action of resveratrol in regulating
macrophage polarization for the
treatment of tumors and
inammatory diseases
After examining the diverse mechanisms of macrophage
polarization into M1 and M2 phenotypes and their roles in
diseases such as inammation and tumors, we turn our attention
to how resveratrol inuences these polarization processes to exert its
pharmacological effects (Supplementary Table S1; Figure 3).
Resveratrol has garnered extensive research interest for its ability
to modulate macrophage polarization, particularly in the context of
tumor and inammatory disease treatment.
3.1 Resveratrols anti-tumor mechanism: the
synergistic effect of promoting macrophage
M1 polarization or inhibiting M2 polarization
The SASP is a hallmark of cellular senescence, whereas STAT3 is
a transcription factor pivotal in signal transduction (Li et al., 2023;
Wang H. et al., 2024). Resveratrol can modulate macrophage
polarization towards the M1 phenotype by activating the SASP
pathway or by inhibiting the STAT3 and S1P-YAP signaling axis,
thereby suppressing cancer cell growth and proliferation.
Sun and colleagues have uncovered the intricate effects of
resveratrol on macrophage polarization, revealing its potential in
cancer therapy. Their research indicates that resveratrol modulates
cytokine levels, with a decrease in IL-10 and an increase in IL-12 and
TNF-α. Notably, a concentration of 20 μM resveratrol was found to
downregulate the expression of M2 markers such as MRC1, CCL24,
Chi3l3, and Retnla, highlighting its inuence on M2 polarization. In
vivo studies have corroborated these ndings, demonstrating that
resveratrol signicantly inhibits tumor growth, a response that is
FIGURE 3
Mechanisms by which resveratrol regulates macrophage polarization through multiple signaling pathways. Resveratrol can regulate the M1 or
M2 polarization of macrophages individually, or it can promote M1 polarization while inhibiting M2, or conversely, promote M2 polarization while
inhibiting M1. Resveratrol promotes M1 polarization by activating the SASP and inhibiting S1P and phos phorylated STAT3. Conversely, resveratrol induces
M2 polarization by activating the PI3K/Akt/mTOR pathway, enhancing VEGF expression, and stimulating AMPK to suppress the NF-κB pathway.
Additionally, AMPK activation leads to JAK2-mediated upregulation of STAT3, while resveratrol inhibits TLR-4 to suppress MyD88, further promoting
M2 polarization. Resveratrol also activates STAT1 to either stimulate AMPK or inhibit the NF-κB pathway, thereby reinforcing M2 macrophage polarization.
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associated with reduced p-STAT3 expression in tumor tissues (Sun
et al., 2017;Zhang and Sioud, 2023). This suggests that resveratrols
impact on macrophage polarization may be linked to the inhibition
of STAT3 activation, a key regulator of immune responses. Further
research has shown that resveratrol promotes M1 macrophage
polarization by diminishing IL-6 production and suppressing
STAT3 activation. It also hinders M2 macrophage polarization
and impairs the differentiation of Tohoku Hospital Pediatrics-1
(THP-1) cells into the M2 phenotype, as evidenced by reduced
arginase-1 (ARG1) expression, thereby limiting the proliferation of
breast cancer cells (Cheuk et al., 2022). Resveratrols ability to
modulate THP-1 cell polarization is further exemplied by its
activation of the SASP pathway, leading to increased expression
and secretion of IL-6 and IL-8, and inducing M1 macrophage
polarization that results in senescence in clear cell renal cell
carcinoma cells (Chen Z. et al., 2023).
In addition to the transformation of macrophages from M0 to M1,
resveratrol can also regulate theshift of macrophages from M2 toM1.
In the context of lymphoma treatment, resveratrol administration in
an obesity-lymphoma mouse model has been shown to increase the
F4/80+MHCII + cell subset, associated with M1 macrophages, and
decrease the F4/80+CD206+ cell subset, associated with
M2 macrophages. This indicates a shift in macrophage phenotype
from M2 to M1, which is accompanied by downregulation of aberrant
sphingosine kinase 1 (SPHK1), phosphorylated YAP, and the YAP
target gene CTGF in obesity-lymphoma mice (Wang et al., 2023).
These ndings underscore resveratrols role in combating cancer by
targeting the S1P-YAP signaling axis and inuencing macrophage
polarization. By promoting the M1 phenotype and inducing cell
senescence, resveratrol exerts immune-modulating effects and
demonstrates signicant antitumor efcacy, positioning it as a
promising agent in cancer therapy.
In a short, resveratrol modulates macrophage polarization by
promoting the M1 phenotype and inhibiting the M2 phenotype
through the activation of the senescence-associated secretory
phenotype (SASP) signaling pathway and suppression of the
STAT3 and S1P-YAP pathways. These mechanisms confer
signicant immunomodulatory and senescence-inducing effects,
thereby exerting antitumor activity and highlighting resveratrols
potential as a cancer therapeutic agent. Numerous clinical trials have
substantiated the efcacy of resveratrol in oncology, demonstrating
its applicability in the prevention and treatment of various cancer
types. Owing to its exceptionally low toxicity and ability to
target mutated molecules and key signaling pathways across
multiple tumors, resveratrol emerges as an ideal anticancer
compound. Furthermore, it may exhibit synergistic effects when
combined with diverse chemotherapeutic agents and targeted
therapies, enhancing antitumor efcacy (see Section 4)(Ko
et al., 2017).
3.2 Resveratrols anti-inammatory
mechanism: the dual role of inhibiting
M1 macrophage polarization or promoting
M2 polarization
In contrast to its effects on the M1 phenotype, resveratrol
regulates macrophage polarization towards the M2 phenotype
through pathways such as NF-κB and AMPK/PI3K/Akt,
upregulating anti-inammatory factors and downregulating pro-
inammatory factors. This regulation helps combat inammation,
diabetes, and cardiovascular and cerebrovascular diseases.
3.2.1 NF-κB pathway: a pivotal node in resveratrol-
induced M2 polarization or inhibited
M1 polarization
The transcription factor NF-κB is a master regulator in the
activation of the inammasome and the modulation of
inammatory responses (Mussbacher et al., 2023). Within the
context of macrophage biology, the specic activation of NF-κB
is a critical determinant of their polarization state (Songkiatisak
et al., 2022). Resveratrol has been shown to modulate macrophage
polarization by inhibiting NF-κB activation, thereby exerting its
anti-inammatory effects.
Macrophage polarization is increasingly recognized for its
benecial impact on blood sugar regulation. Resveratrol aids in
the polarization of macrophages towards the M2 phenotype by
inuencing the NF-κB signaling pathway, which in turn inhibits
inammation. In scenarios of insulin resistance and obesity, there is
an increase in the proportion of M1 macrophages, which exacerbates
inammation. Recent studies have indicated that resveratrol
possesses therapeutic effects on inammation caused by insulin
resistance. Gao et al. (2022) discovered that resveratrol signicantly
reduced serum levels of pro-inammatory cytokines, such as TNF-α
and IL-6, by activating the SIRT1/NF-κB signaling pathway. This led
to a decrease in the proportion of M1 macrophages in epididymal
white adipose tissue and an increase in M2 macrophages, thus
ameliorating insulin resistance. Under high glucose conditions,
resveratrol can regulate macrophage polarization through the
NF-κB signaling pathway. During lipopolysaccharide (LPS)
stimulation, resveratrol signicantly reduced nitric oxide (NO)
production and the expression of pro-inammatory cytokines IL-
1 and IL-6 mRNA in LPS-stimulated macrophages. Resveratrol
achieves these effects by inhibiting the NF-κB signaling pathway
and activating the mTOR signaling pathway, thus promoting
M2 macrophage polarization (Manríquez-Núñez et al., 2023).
However, the low oral bioavailability of resveratrol can diminish
its pharmacological efcacy (de Vries et al., 2018). To overcome this
challenge, resveratrol can be formulated into nanoparticles. For
example, RES@PPD NPs, which are self-assembled nanoparticles
from resveratrol and PPD, have been shown to inhibit the NF-κB
signaling pathway, regulate host immunity, inhibit M1 macrophage
polarization, and promote M2 macrophage polarization, thus
treating periodontitis (Huangfu et al., 2023). These ndings
provide novel insights into the potential of resveratrol for
treating blood sugar and dental-related inammation, and they
pave the way for improving its bioavailability. The strategic use
of resveratrol, particularly through nanoparticle formulation, may
offer a promising therapeutic approach for managing inammation
in metabolic and oral health disorders.
3.2.2 AMPK pathway: resveratrols key to energy
metabolism and anti-inammatory effects
AMPK is a key regulator in cellular energy metabolism and is
associated with the balance of macrophage polarization (Cheng et al.,
2023). Resveratrol exerts its anti-inammatory effects by activating
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the AMPK signaling pathway. Within macrophages, this
mechanism promotes energy balance and metabolic regulation,
thereby indirectly inhibiting inammatory processes. It positively
affects the polarization state of macrophages, helping to regulate
inammatory responses and alleviate symptoms of
related diseases.
Resveratrols ability to modulate macrophage polarization is
further supported by its effects on AMPK phosphorylation and the
downregulation of p38 MAPK and JNK phosphorylation. These
actions lead to a reduction in the expression of pro-inammatory
cytokines, thereby alleviating skeletal muscle inammation in
obese mice. Resveratrol prevents the accumulation of
intracellular fat in skeletal muscle by suppressing the expression
of toll-like receptors TLR2 and TLR4 (Shabani et al., 2020). Li et al.
also revealed vascular endothelial growth factor B (VEGF-B) as a
new target for resveratrols therapeutic action. Through the VEGF-
B/AMPK/NF-κB signaling axis, resveratrol inhibits
M1 macrophage polarization, which is crucial in the treatment
of isoproterenol-induced myocardial injury. In vitro studies using
RAW264.7 cells conrm that resveratrol decreases the levels of
M1 markers and pro-inammatory cytokines, while upregulating
M2 markers, further contributing to the amelioration of
myocardial injury (Li et al., 2020). By targeting AMPK,
resveratrol promotes M2 macrophage polarization, which holds
signicant therapeutic potential for the treatment of periodontitis,
skeletal muscle inammation, and myocardial injury.
Tan and colleagues have conducted a groundbreaking study that
demonstrates the efcacy of mesoporous silica nanoparticles (MSN)
loaded with resveratrol (MSN-RSV) in the treatment of
periodontitis. This novel approach diverges from previous
research by highlighting a dual mechanism of action: MSN-RSV
not only suppresses the NF-κB signaling pathway, which is well-
known for its role in inammation, but also activates the SIRT1/
AMPK pathway, a less explored avenue in anti-inammatory
therapy (Tan et al., 2022;Wicinski et al., 2023). The synergistic
effect of these two pathways not only enhances the stability of
resveratrol but also extends its therapeutic window and improves
bioavailability. This innovative dual-targeting strategy has been
shown to inhibit M1 macrophage polarization, which is
associated with pro-inammatory responses, while promoting the
alternative M2 polarization, which is anti-inammatory and
reparative. This research provides a compelling case for the use
of MSN-RSV as a novel therapeutic agent with a unique dual-action
mechanism, offering a promising avenue for future clinical
applications in the management of these conditions.
3.2.3 PI3K/Akt pathway: inducing M2 polarization
or inhibiting M1 polarization for enhanced immune
regulation
The PI3K/Akt pathway is a crucial regulator of macrophage
responses to inammatory signals (Yang et al., 2023). Resveratrol
promotes the polarization of M2 macrophages by activating the
PI3K/Akt pathway, enhancing the expression of anti-inammatory
cytokines and thereby strengthening the cells anti-inammatory
and immune regulatory capabilities.
Resveratrol has been the subject of extensive research due to its
potential therapeutic effects. Studies have revealed that
resveratrols activation of the PI3K/Akt signaling pathway plays
a crucial role in modulating the inammatory response.
Specically, it has been shown to suppress the secretion of pro-
inammatory factors such as TNF-α, inducible nitric oxide
synthase (iNOS), and IL-1β. Concurrently, resveratrol enhances
the expression of M2 macrophage markers, including Arg-1 and
CD206, which are associated with anti-inammatory and tissue
repair functions (Ding et al., 2022;Hassanshahi et al., 2022). This
dual action of resveratrol in regulating inammation is particularly
benecial in the context of diabetic wound healing. By reducing the
inammatory response in wound tissue, resveratrol accelerates the
healing process, which is often impeded in diabetic patients due to
chronic inammation and impaired tissue repair mechanisms. In
addition to its effects on wound healing, resveratrol has also been
demonstrated to have a signicant impact on corneal transplant
rejection. Xu et al. (2023) have reported that resveratrol can
alleviate rejection by mediating the PI3K/Akt signaling pathway.
This mechanism works by reducing the levels of pro-inammatory
cytokines in the corneal graft, thereby decreasing the proportion of
dendritic cells in the ipsilateral cervical lymph nodes. This
reduction in dendritic cells inhibits the recruitment of corneal
macrophages and the polarization towards the pro-inammatory
M1 phenotype. The ndings by Xu et al. are particularly
noteworthy as they provide a novel approach to preventing
corneal transplant rejection.BytargetingthePI3K/Akt
pathway, resveratrol may offer a promising strategy for
immunomodulation in corneal transplantation, potentially
improving graft survival rates and patient outcomes.
In conclusion, resveratrols ability to modulate the PI3K/Akt
signaling pathway offers a multifaceted approach to managing
inammation and promoting tissue repair. Its potential
applications in both diabetic wound healing and corneal
transplant rejection highlight the importance of further research
into this polyphenols therapeutic potential.
3.2.4 Exploring the diverse pathways: resveratrols
broad impact on macrophage polarization
Resveratrol, a polyphenolic compound with established anti-
inammatory properties, exerts its immunomodulatory effects
through a variety of mechanisms, including the modulation of
macrophage polarization. Beyond the PI3K/Akt pathway, resveratrol
inuences macrophage behavior by impacting metabolic pathways, the
SASP pathway, and the TLR4/Myeloid differentiation primary response
protein 88 (MyD88) receptor pathway. Resveratrols ability to modulate
macrophage polarization is particularly evident in its capacity to reduce
the production of pro-inammatory cytokines such as IL-12 and NO,
while simultaneously promoting the polarization towards the anti-
inammatory M2 phenotype. This effect is mediated through the
alteration of macrophage metabolic pathways, which has been
shown to alleviate arthritis in experimental models (Chen C. et al.,
2023;Nedunchezhiyan et al., 2022;Wang and He, 2022;Zhang L. et al.,
2021). Further studies have indicated that resveratrol enhances
M2 polarization by increasing the expression of PPARγ,akey
transcription factor associated with M2 macrophage polarization.
This is accompanied by the upregulation of Arg-1, mannose
receptor C type 1 (MRC-1), CCL-17, which are markers of
M2 macrophages. These changes prevent obesity-related low-grade
inammation, suggesting a potential role for resveratrol in managing
metabolic disorders (Ryyti et al., 2022). Yu and colleagues have
Frontiers in Pharmacology frontiersin.org07
Wang et al. 10.3389/fphar.2024.1516609
demonstrated that resveratrol can modify the microenvironment by
upregulating IL-10, a cytokine that promotes M2 polarization. This
leads to an increase in the expression of Mrc1, Mrc2, CD163, and Arg1,
while reducing the levels of iNOS, TNF-α,andMCP1.Thesechanges
are associated with improved outcomes in CCL4-induced liver brosis
in mice, highlighting resveratrols potential in treating brotic diseases
(Yu et al., 2019).
Additionally, resveratrol has been shown to reduce the
expression of NO, IL-6, TNF-α, and proteins and mRNA
related to the TLR4 pathway at concentrations of 2, 4, and
M(Fan et al., 2021). This suggests that resveratrol promotes
M2 macrophage polarization via the TLR4/MyD88 signaling
pathway, thereby regulating the immune system and reducing
inammation. Under hypoxic conditions, resveratrol facilitates
M2 macrophage polarization through the phosphorylation of
JAK2-STAT3, which suppresses inammatory mediators (Liu
et al., 2019;Wicinski et al., 2018). This nding is signicant for
the treatment of myocardial infarction, where resveratrol could
potentially aid in the resolution of inammation and promote
tissue repair. In summary, resveratrolsmultifacetedapproachto
macrophage polarization and immune modulation offers a
promising avenue for the treatment of a variety of
inammatory and brotic diseases. Its ability to target multiple
pathways and receptors underscores the potential therapeutic
value of this natural compound in modulating the immune
response and promoting health.
Resveratrol exhibits potent anti-inammatory, anti-diabetic,
and cardioprotective properties by modulating intracellular
signaling pathways. Precisely, the intervention of resveratrol on
key pathways such as NF-κB, AMPK, and PI3K/Akt plays a
critical role in inducing M2 polarization or inhibiting
M1 polarization, contributing to the treatment of related diseases.
4 Discussion and prospect
Macrophage polarization states are indeed crucial for their
functions, with the M1 phenotype closely associated with anti-
cancer properties. Notably, M1 macrophages can exert cytotoxic
effects, which are vital for combating the growth and spread of
cancer cells. Studies have shown that resveratrol can promote
the polarization of macrophages towards the M1 phenotype or
inhibit polarization towards the M2 phenotype, thereby
exhibiting potential anti-cancer effects. This process often
involves the activation of the SASP pathway or by inhibiting
the activation of STAT3 and S1P-YAP signaling axes, which are
key regulators of macrophage polarization. On the other hand,
the M2 polarization of macrophages primarily plays an anti-
inammatory role, which is essential for preventing or
alleviating inammatory responses. M2 macrophages release
anti-inammatory cytokines and play an important role in
promoting tissue repair and immune regulation. Interestingly,
resveratrol can also induce the polarization of macrophages
towards the M2 phenotype or inhibit polarization towards
the M1 phenotype, a process that can be achieved by
inhibiting the NF-κB and TLR4/MyD88 signaling pathways,
which are typically associated with pro-inammatory
responses. Alternatively, this polarization can be achieved by
activating the PI3K/Akt and AMPK signaling pathways, which
are well-known for suppressing inammatory responses and
maintaining the bodys immune balance. Therefore, the
multifaceted effects of resveratrol on macrophage polarization
underscore its prospects as a therapeutic candidate for
modulating immune responses.
4.1 Development of novel technologies to
enhance resveratrol bioavailability
Resveratrols ability to modulate macrophage polarization offers
a promising strategy for disease intervention. Determining the
optimal intake of resveratrol remains a contentious issue in
scientic research, with current studies proposing an
experimental dose of approximately 1 g per day. However, the
clinical application of resveratrol is primarily hindered by its low
bioavailability. Although approximately 75% of orally administered
resveratrol is absorbed in the small intestine, extensive metabolism
in the gut and liver reduces its bioavailability to below 1% (Jabłońska
et al., 2024). In vitro analyses demonstrate that resveratrol maintains
relative stability during simulated gastric digestion; however, its
concentration and antioxidant activitysuch as DPPH radical
scavengingsubstantially decline during the intestinal phase.
This reduction is attributed to drastic pH shifts from the
stomach to the small intestine and the pH elevation induced by
bile salts. Furthermore, digestive enzymes including α-amylase,
pepsin, and pancreatic enzymes may hydrolyze resveratrol,
compromising its structural integrity and bioactivity. Despite
exhibiting some stability during in vitro digestion, the antioxidant
efcacy of resveratrol diminishes, likely due to structural
modications and decreased bioavailability (Lee et al., 2020).
Recent investigations have highlighted the role of gut microbiota
in metabolizing resveratrol precursors into resveratrol and its
derivatives. Specic microorganisms, such as Slackia equolifaciens
and Adlercreutzia equolifaciens, can convert resveratrol into
dihydroresveratrol (DHR) (Wang et al., 2022), indicating that
alterations in the digestive system signicantly inuence
resveratrols bioactivity and bioavailability. Consequently,
enhancing resveratrol bioavailability has become a focal point of
research. Current strategies to achieve this include the development
of resveratrol derivatives, co-administration with other agents, and
the utilization of advanced delivery technologies (Salla et al., 2024).
For example, co-administration with piperine inhibits resveratrol
glucuronidation, thereby decelerating its degradation and increasing
its systemic exposureresulting in a 229% increase in area under the
curve (AUC) and a 1544% increase in maximum concentration
(Cmax) (Johnson et al., 2011). Additionally, nanotechnological
approaches, such as solid lipid nanoparticles (SLNs) and
nanostructured lipid carriers (NLCs), have been shown to
effectively enhance resveratrol bioavailability (Neves et al., 2013).
4.2 Combined therapy of resveratrol: a new
strategy to boost efcacy
To maximize its therapeutic impact and widen its application,
resveratrol can be encapsulated in various pharmaceutical
Frontiers in Pharmacology frontiersin.org08
Wang et al. 10.3389/fphar.2024.1516609
formulations or combined with other medications. One such
innovative approach involves the integration of resveratrol into a
state-of-the-art core-shell nanocomposite, QRu-PLGA-RES-DS
NPs, which uses photothermal effects to stimulate
M2 macrophage polarization. This strategy is particularly
advantageous for managing rheumatoid arthritis and also
improves the drugs release prole (Chen et al., 2019).
Additionally, a novel injectable thermosensitive hydrogel system
has been engineered to include resveratrol and dexamethasone-
loaded carbonate hydroxyapatite microspheres. This system is
adept at promoting the repair of osteoporotic bone defects. It
not only fosters the osteogenic differentiation of bone marrow
mesenchymal stem cells but also mitigates the buildup of
intracellular reactive oxygen species (ROS) and regulates
macrophage polarization to reduce inammation. The strategic
pairing of resveratrol with dexamethasone not only amplies the
drugs therapeutic impact but also diversies its clinical
applications (Li J. et al., 2024). This combination transcends the
realm of anti-inammatory treatments, extending to the
promotion of osteogenic differentiation in bone marrow-derived
stem cells, and thereby expanding the therapeutic horizons of
resveratrol in clinical practice.
4.3 Expansion of resveratrols clinical
applications in macrophage research
Clinical studies have demonstrated that resveratrol exhibits
tissue specicity and dose dependency in cancer treatment.
Notably, its metabolites accumulate in the normal tissue of
prostate cancer patients (Patel et al., 2010), and higher
resveratrol intake is inversely correlated with breast cancer
risk (Levi et al., 2005). In obese postmenopausal women,
resveratrol signicantly increases sex hormone-binding
globulin (SHBG) levels, which are negatively associated with
breast cancer risk, without markedly affecting serum estrogen
and testosterone concentrations (Chow et al., 2014).
Additionally, resveratrol regulates the methylation of
proteins implicated in breast cancer (Singh et al., 2015).
Regarding obesity-related metabolic parameters, research
ndings are inconsistent. Some studies report improvements
in glucose metabolism and lipid proles (Timmers et al., 2011),
whereas others nd no signicant anti-obesity effects (Poulsen
et al., 2013). These discrepancies may stem from variations in
study design, intervention duration, and resveratrol dosing. In
the context of diabetes and its complications, resveratrol has
shown potential therapeutic benets by enhancing insulin
sensitivity and lowering blood glucose levels (Tomé-
Carneiro et al., 2013). However, outcomes vary due to
factors such as racial differences and treatment duration
(Fujitaka et al., 2011;Walker et al., 2019). Specically,
in diabetic patients with periodontitis, some studies report
signicant reductions in insulin resistance without notable
changes in fasting blood glucose levels (Crandall et al., 2012;
Méndez-Del Villar et al., 2014;Zare Javid et al., 2017),
while others observe a decrease in fasting blood glucose
(Bhatt et al., 2012;Movahed et al., 2013). These
inconsistencies may be attributable to differences in study
design and sample size, highlighting the need for future
research to address variables such as resveratrol purity,
dosage, and administration methods.
Despite signicant advancements in understanding resveratrols
pharmacological properties, clinical studies involving human
participants, particularly those focusing on macrophages,
remain limited. Current clinical data are constrained by short
trial durations, small sample sizes, and a lack of studies explicitly
evaluating health outcomes. The complexity of human
physiology necessitates comprehensive investigations into the
mechanisms of resveratrol action. For instance, further research
is required to elucidate the molecular pathways through which
resveratrol regulates blood glucose levels and ameliorates
diabetes complications. Additionally, potential interactions
between resveratrol and medications metabolized by enzymes
such as CYP3A4 and CYP2E1 are not well understood, as many
trials exclude participants on concurrent medications (Brown
et al., 2024). Therefore, there is an urgent need to advance
resveratrol-based therapies to ensure their efcacy and safety
in clinical settings. Furthermore, studies have revealed that IL-4
induces the polarization of macrophages from the M0 to the
M2 phenotype, a transition that is accompanied by notable
alterations in metabolic pathways, specically those reliant on
glucose or lactate in the tricarboxylic acid cycle (Noe et al., 2021).
The buildup of lactate, a dening feature of solid tumors, is
intricately linked to the immunosuppressive traits of immune
cells that inltrate tumors. The potential involvement of
mitochondrial metabolism of glucose or lactate in the
M2 macrophage polarization induced by resveratrol remains
an open mechanistic questionthatrequiresfurther
investigation to elucidate its role in modulating the tumor
microenvironment.
Signicantly, a review of the literature reveals a distinct dose-
dependent effect of resveratrol. At moderate concentrations,
resveratrol has been shown to downregulate the expression of
numerous inammatory factors, facilitating a transition of
macrophages from the pro-inammatory M1 phenotype to
the anti-inammatory M2 phenotype. In contrast, at higher
concentrations, resveratrol upregulates inammatory factors,
effectively reversing the polarization to the M1 phenotype.
This concentration-dependent dichotomy highlights the
importance of establishing precise pharmacological thresholds
through comprehensive clinical studies. Furthermore, this
intriguing phenomenon suggests new therapeutic
opportunities for addressing a variety of diseases within
clinical practice.
5 Conclusion
In this review, we have thoroughly explored the multifaceted
mechanisms by which resveratrol regulates macrophage
polarization through various signaling pathways, revealing its
considerable potential in cancer prevention and anti-
inammatory treatments. Our ndings underscore the pivotal
role of resveratrol in modulating immune cell functions,
thereby afrming its broad applicability and efcacy in diverse
medical applications.
Frontiers in Pharmacology frontiersin.org09
Wang et al. 10.3389/fphar.2024.1516609
Author contributions
PW: Writingoriginal draft, Writingreview and editing. ZL:
Methodology, Visualization, Writingoriginal draft. YS: Software,
Visualization, Writingreview and editing. BZ: Software,
Writingreview and editing. CF: Conceptualization, Writingreview
and editing.
Funding
The author(s) declare that no nancial support was
received for the research, authorship, and/or publication of
this article.
Acknowledgments
The gures in this review were partly illustrated with the
assistance of BioRender.
Conict of interest
The authors declare that the research was conducted in the
absence of any commercial or nancial relationships that could be
construed as a potential conict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the
creation of this manuscript.
Publishers note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their afliated organizations,
or those of the publisher, the editors and the reviewers. Any product
that may be evaluated in this article, or claim that may be made by its
manufacturer, is not guaranteed or endorsed by the publisher.
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