Article Type : Research Article
Authors : Ali S, Sangwan S, Srivastava P, Khan S, Raghuvanshi V, Kumar A, Nawani A, Vishal C and Yadav P
Keywords : Chronic obstructive pulmonary disease (COPD); Atherosclerosis; Cardiovascular disease; Macrophage polarization; Multiple sclerosis; Immune response
Cytokines, tiny proteins secreted by
cells, play a critical role in mediating communication and interactions between
cells. They also function as immunomodulating agents, adjusting immune
responses. When released into the bloodstream or tissues, cytokines bind to
specific receptors on target immune cells, triggering cellular responses.
Cytokines are implicated in various diseases, including asthma, COPD, HIV
infection, and multiple sclerosis. This review delves into the intricate
interplay between cytokines and macrophages, focusing on their roles in
inflammation and the immune response. Macrophages, which are scavenger cells of
the immune system, exhibit remarkable heterogeneity, reside in diverse tissues,
and play crucial roles in both innate and acquired immunity. They can be activated
for proinflammatory or anti-inflammatory functions, contributing to tissue
destruction or regeneration. Cytokines influence macrophage activation and
polarization, impacting the inflammatory process. Dysregulated cytokine
production and macrophage activation are observed in various diseases. For
example, in asthma, an imbalance in macrophage phenotypes contributes to airway
hyperresponsiveness. Understanding the complex interplay between cytokines and
macrophages is crucial for developing novel therapeutic strategies for
inflammatory diseases. Future research directions include utilizing humanized
animal models, single-cell sequencing, and immunomodulatory therapies to
further decipher the intricate roles of cytokines and macrophages in health and
disease. Ultimately, elucidating these interactions holds immense potential for
improving human health outcomes.
Cytokines, proteins secreted by cells, play pivotal
roles in mediating intercellular communication and interactions. These proteins
are also referred to as “lymphokines,” “monokines,” “chemokines,” and
“interleukins” (when produced by one leukocyte and acting on other leukocytes).
The term ‘cytokine’ originates from the Greek words ‘cyto’ (cell) and ‘kinos’
(movement) [1]. Recently, cytokines have been referred to as ‘immunomodulatory
agents’ due to their ability to adjust immune responses. Cytokines are released
into the bloodstream or directly into tissues, where they bind to their target
immune cell receptors, triggering specific cellular responses. Inflammatory
pathogen-associated molecular patterns (PAMPs), such as heat shock proteins
(HSPs), peptidoglycans (PGNs), and lipopolysaccharides (LPS), as well as DAMPs,
such as HMGB1 and adenosine triphosphate, are key players in this process [1].
These molecules, originally intracellular proteins or nucleic acids are not
typically found outside the cell. Pattern recognition receptors (PRRs)
recognize PAMPs and DAMPs. The primary PRRs involved in inflammatory pathways
are TLR, NLR, and MBL. Upon engagement, PRRs transmit signals within the cell,
for instance, through MAP kinase signalling pathways to the nucleus, where
various transcription factors are activated. Additionally, two polypeptide
chains are present: a cytokine-specific ? subunit and a signal-transducing ?
subunit. Upon binding to these receptors, cytokines can induce cellular and
humoral immune responses and inflammatory responses, regulate hematopoiesis,
control cell proliferation and differentiation, and promote wound healing [2].
In the context of bronchial asthma, research has indicated that cytokine
production by T cells, rather than the eosinophil concentration or IgE
synthesis, is typically associated with altered airway behaviour. An increase
in the number of CD4+ Th cells of the Th2 subtype has been observed in the
airways. In chronic obstructive pulmonary disease (COPD), there is increased
expression of IL-4 in bronchoalveolar lavage (BAL) fluid from patients, which
is pivotal in the immune response and influences the differentiation of Th0
cells into Th2 cells, which could trigger allergen sensitivity [3]. IFN-?, a
key cytokine in patient inflammation, facilitates the lung infiltration of Th1
and Tc cells by enhancing the expression of the chemokine receptor CXCR3 on
these cells and promoting the secretion of CXCR3-activating chemokines such as
CCL9, CCL10, and CCL11 [4]. In the context of HIV infection, cytokines play a
vital role in maintaining immune system homeostasis. There was a marked
decrease in the release of Th1 cytokines, including IL-2 and IFN-?, concurrent
with an increase in the production of Th2 cytokines (IL-4 and IL-10) and
proinflammatory cytokines (IL-1, IL-6, IL-8, and TNF-?) during HIV infection.
Moreover, cytokines such as TNF-?, TNF-?, IL-1, and IL-6 have been found to
stimulate HIV replication in lymphocytes and monocyte-derived macrophages
(MDMs). In the case of multiple sclerosis (MS), neurodegeneration is a direct
result of demyelination, leading to the formation of plaques in the white
matter, a hallmark pathology of the disease. The cytokines IL-6 and IFN-?
instigate an inflammatory response in the brain’s white matter, contributing to
plaque development. Notably, the administration of IFN-? exacerbates MS
symptoms. However, IFN-? treatment has demonstrated some efficacy in reducing
the relapse rate among MS patients. Considering the pivotal role of cytokines
in these diseases, as corroborated by the referenced data and articles, it is
essential to further explore the therapeutic potential of cytokines.
Consequently, this study aimed to elucidate the role of cytokines and
macrophages in several of the most common diseases. A comprehensive literature
search was conducted using a variety of keywords, resulting in a plethora of
articles. The most pertinent and relevant articles were meticulously selected
for this systematic review.
Macrophages
Macrophages, which are sentinels of the immune system,
exhibit remarkable tissue tropism and strategically position themselves in
lymphoid organs, mucosal interfaces, and other pivotal sites. These versatile
cells act as resident custodians, wielding their phagocytic ability to maintain
tissue homeostasis [5]. These cells diligently scavenge apoptotic and necrotic
debris while simultaneously standing guard against invading pathogens. In
addition to being mere scavengers, macrophages are key players in both innate
and adaptive immunity. The innate arsenal of these viruses includes immediate
neutralization of foreign microorganisms and orchestration of leukocyte
recruitment. These proteins meticulously regulate the delicate balance between
antigen presentation and clearance through phagocytosis and subsequent
degradation. This intricate interplay with T and B lymphocytes, facilitated by
a diverse repertoire of cytokines, chemokines, and bioactive molecules,
dictates the trajectory of the immune response [6]. Macrophage activation, a
dynamic process influenced by contextual cues, can skew toward proinflammatory
or anti-inflammatory functions. This versatility allows them to orchestrate
tissue destruction during infection, followed by a switch toward regenerative
and wound healing processes. Ultimately, macrophages act as crucial
orchestrators, initiating, instructing, and even terminating the adaptive
immune response, ensuring delicately balanced and dynamic defenses against
diverse immunological challenges [7].
Classically activated
macrophages
M1 macrophage polarization is orchestrated by the
coordinated symphony of IFN-? and microbial stimuli, particularly LPS. IFN-?,
the lone maestro of type II IFNs, interacts with a dedicated orchestrator
conductor, IFNGR, a heterodimer formed by two ligand-capturing IFNGR1 subunits
and two signal-transducing IFNGR2 subunits. This exquisite interplay triggers a
cascade of molecular events directing macrophage differentiation toward the
robust effector repertoire of M1 macrophages [8].
Tumor-associated
macrophages
Environmental cues within the TME orchestrate
intricate leukocyte infiltration, proliferation, and polarization, thereby
dictating the functional repertoire of recruited macrophages. Among these, TAMs
exhibit a protumorigenic phenotype and thus harbor a potent arsenal of
proangiogenic and tumor-promoting chemokines, such as CCL2/MCP-1. Hypoxia, a
defining hallmark of the TME, further sculpts TAM functionality, igniting a
proangiogenic program that amplifies tumour-driven vascularization in an
indirect yet potent manner [9]. However, not all macrophage contributions
favour tumour progression. In a murine model, tumor-derived GM-CSF induced
macrophage-mediated degradation of the extracellular matrix via upregulation of
MMPs, concurrently stimulating angiostatin production, ultimately leading to
suppressed metastatic growth [10].
Role of cytokines and
macrophages in inflammation
The intricate nature of inflammation relies on the
delicate balance between proinflammatory and resolving signals. Disruption of
this equilibrium leads to uncontrolled inflammation, causing cellular and
tissue damage [11]. Macrophages, the stalwart foot soldiers of the mononuclear
phagocyte system, orchestrate this intricate dance, playing a pivotal role in
initiation, maintenance, and resolution. Elie Metchnikoff, a Nobel laureate,
initially christened these phagocytic warriors as "white blood cells"
for their frontline defenses against infection. In 1924, Aschoff refined the
nomenclature, coining the term "macrophage" for this diverse lineage
encompassing monocytes, macrophages, and histiocytes. During inflammation,
macrophages carry out three essential steps: antigen presentation,
phagocytosis, and immunomodulation through cytokine and growth factor
orchestration [12]. Activated by a symphony of signals, including cytokines
such as IFN-?, GM-CSF, and TNF-?; bacterial lipopolysaccharide; and matrix
cues, macrophages ignite the inflammatory response. Resolution, the
counterpoint to inflammation, necessitates the silencing of these inflammatory
conductors and their effector cells. Deactivation of macrophages, achieved
through diverse mechanisms, allows tissue repair and restoration [13].
Neutrophilic granulocytes, the rapid responders of the acute inflammatory
phase, extravasate through a fleeting set of endothelial adhesion molecules
orchestrated by cytokine-induced upregulation. Intriguingly, the duration of
inflammation appears to differ between preterm deliveries and term deliveries,
with elevated proinflammatory cytokine and proteinase levels preceding cervical
dilation. Similarly, chorioamnionitis patient’s exhibit elevated
proinflammatory cytokines across various compartments, potentially contributing
to preterm contractions. The role of inflammation in atherosclerosis is a
captivating research avenue. Recent studies have investigated ate interplay
between proinflammatory cytokines such as IL-1, IL-18, and OPN and their
anti-inflammatory counterparts, including IL-1 receptor antagonists, IL-10, and
IL-18-binding proteins [14]. Additionally, the contribution of chronic
infections such as Helicobacter pylori and Chlamydophila pneumoniae to
persistent inflammation has garnered significant attention.
Cytokine therapeutic uses
IL-1 and IL-2 have demonstrated potential as
consistent immunostimulants for combating AIDS. Empirical studies have
substantiated the hypothesis that immunostimulatory cytokines can counteract
the immunosuppressive characteristics of cancer. The synthesis of IL-10, TGF-?,
and PGE2 by ovarian cancer and Cap (3) cells contributes to the comprehensive
inhibition of antitumor activities. IL-10 facilitates the differentiation of
monocytes into mature macrophages and impedes their differentiation into
dendritic cells. The alarming inflammatory response of humans to cytokines such
as IL-1, IL-2, IL-3, IL-4, IL-6, IL-12, and TNF-? has resulted in adverse
effects. The first cytokine approved for cancer treatment was IL-2, but its
proinflammatory effects are poorly tolerated, thereby limiting its efficacy in
conditions such as melanoma and renal cell carcinoma. IL-10 has emerged as a
promising candidate for various autoimmune diseases because it not only
suppresses the production of IFN-?, IL-1, TNF-?, and IL-6 but also has other
anti-inflammatory effects. However, several trials of recombinant human IL-10
have demonstrated limited effectiveness in treating psoriasis, rheumatoid
arthritis, and Crohn’s disease, and this cytokine has not been approved for
therapeutic use [15]. The FDA has approved the cytokines IL-2 and IFN-?, with
IL-2 being used for the treatment of metastatic melanoma and renal cell
carcinoma in high-dose boluses and IFN-? serving as an adjuvant treatment for
stage III melanoma, hematologic malignancies, AIDS-related Kaposi’s sarcoma,
and in combination with bevacizumab as an antiangiogenic agent for advanced
renal cancer. Recently, various cytokines, including IL-7, IL-12, IL-15, IL-18,
IL-21, and GM-CSF, have been tested in clinical trials for advanced cancer.
Macrophages in acute
lung disease
Acute respiratory distress syndrome (ARDS) is a
critical condition characterized by the rapid onset of diffuse alveolar damage
and impaired gas exchange [16]. Diverse primary and secondary mechanisms can
trigger ARDS, including shock, severe sepsis, pulmonary contusion,
gastroesophageal reflux, pneumonia, drug toxicity, transfusion, and acute
pancreatitis [17]. Iatrogenic or physical injury from mechanical ventilation
can further contribute to ARDS development. The pathogenesis of this disease
commences with the rupture of alveolar septa, disruption of the
epithelium?capillary interface, release of protein-rich fluid, secretion of
proinflammatory chemokines and cytokines, and infiltration of inflammatory
cells such as monocytes and neutrophils. ALI is characterized by an amplified
M1 response and impaired M2-mediated repair, while chronic diseases such as
fibrosis and cancer are dominated by hyper responsive, alternatively activated
M2 cells.
Macrophages in various
infections
During the initial phase of bacterial infection, macrophages exhibit an M1 phenotype. Delayed regulation of macrophage-mediated inflammation results in a cytokine storm, contributing to the pathogenesis of severe sepsis. During inflammatory responses, macrophages exhibit two key strategies for resolution: programmed cell death (apoptosis) or phenotypic reprogramming toward an M2 state. These mechanisms safeguard the host from excessive tissue damage and initiate the critical transition from inflammation to tissue repair. Apoptosis eliminates potentially harmful proinflammatory macrophages, while the M2 phenotype promotes debris clearance, angiogenesis, and collagen deposition, ultimately facilitating wound healing.
Figure 1: The cytokines in immune processes. [Source: (Kang et al., 2021)].
Figure
2: The
diagram is summarizing the three chronic inflammatory airway diseases. [source:
(Garth et al., 2018)].
Figure 3: Macrophage Subtypes in Atherosclerosis. [source: (Macrophages: Structure, Immunity, Types, Functions, n.d.)].
Figure 4: Current and future specific treatment strategies of cytokines. [source: (Garth et al., 2018)].
Macrophage counts in bronchiectasis
In bronchiectasis, a chronic pulmonary pathology characterized
by persistent inflammation, bacterial colonization, and specific commensal
bacteria, such as Stromatosus mucilaginosus, exacerbates disease progression.
S. mucilaginosus facilitates the establishment of opportunistic pathogens,
notably Pseudomonas aeruginosa, by fostering a conducive microenvironment
within compromised airways [18]. This bacterium specifically activates
Toll-like receptor 2 (TLR2) on host immune cells, particularly M1 macrophages,
triggering a proinflammatory cytokine cascade that perpetuates tissue damage
and infection susceptibility.
Macrophages in asthma
Asthmatic inflammation hinges on a precarious balance
between proinflammatory and anti-inflammatory pulmonary macrophage functions.
While M2 macrophages, champions of tissue repair and lung microenvironment
homeostasis, normally serve as allies, their dysregulation unleashes a cascade
of pathological events. This dysregulation manifests as airway
hyperresponsiveness, fuelled by augmented cell recruitment and mucus hypersecretion,
potentially orchestrated by aberrant miRNA expression [19]. Recent
investigations have shed light on the intriguing nexus between specific miRNAs
and alleviating asthmatic symptoms. For instance, miR-145 exhibits therapeutic
potential by dampening the expression of proinflammatory cytokines (IL-13 and
IL-5), thereby curbing inflammation [20]. Similarly, miR-146a orchestrates
multiple processes by suppressing an array of proinflammatory cytokines and
chemokines, effectively eliminating the inflammatory storm. Furthermore, miR-21
strategically neutralizes IL-21, a pivotal player in Th1 cell polarization, by
disrupting a key pathogenic pathway. The intricate link between asthma and
miRNAs is further underscored by the observation that let-7 downregulation amplifies
the levels of IL-13, a pivotal orchestrator of allergic responses, potentially
influencing Th2 skewing [21].
Macrophages in chronic obstructive
pulmonary disease (COPD)
Progressive inflammatory and structural derangements
orchestrate the pathogenesis of COPD. Chronically inhaled noxious stimuli
trigger diverse responses in lung epithelial cells, culminating in a
maladaptive cascade [22]. Epithelial senescence accelerates, the pulmonary
capillary vasculature undergoes progressive destruction, and airway remodelling
ensues. This architectural disarray manifests as decreased lung compliance, the
hallmark functional signature of COPD. The inflammatory cascade in COPD
involves a repertoire of key mediators. Cytokines such as TNF-?, IL-1?, and
GM-CSF act in both autocrine and paracrine fashions, perpetuating the
inflammatory milieu [23]. TGF? orchestrates the nefarious transformation of
fibroblasts into myofibroblasts, fueling the fibrotic crescendo of airway
remodelling. Recent insights implicate miRNA dysregulation in this macabre
dance, with downregulation of miR-152 liberating MMP12, a potent maestro of
emphysematous destruction [24].
Macrophages in tuberculosis (TB)
Mycobacterium tuberculosis (Mtb), the causative agent
of the ubiquitous infectious disease tuberculosis (TB), faces its initial
barrier within the alveoli. Alveolar macrophages, the sentinels of pulmonary
immunity, engulf Mtb droplets via phagocytosis. Within the phagolysosome, a
potent arsenal of reactive oxygen species (ROS) unleashes oxidative mayhem upon
invaders [25]. This initial skirmish triggers the recruitment of mononuclear
leukocytes, bolstering the immune response. These professional phagocytes
constitute the first line of defense, actively engaging and eliminating
mycobacterial threats. Among these leukocytes, classically activated
macrophages (M1) are central to combating intracellular parasites [26]. Their
potent microbicidal arsenal, fueled by enhanced antigen presentation and
inflammatory cytokine production, spearheads the antimycobacterial response.
Alternatively, activated M2 macrophages adopt a different paradigm. These
versatile cells prioritize tissue repair, suppress inflammation, and promote
wound healing, contributing to a more orchestrated immune response. This dynamic
interplay between M1 and M2 macrophages underscores the complex immunological
landscape of TB. Understanding these intricate orchestrations paves the way for
novel therapeutic strategies aimed at tipping the balance toward pathogen
eradication and tissue preservation [27].
Kidney diseases
In chronic kidney disease (CKD), infiltrating immune
cells transcend passive bystanders, morphing into detrimental actors within the
pathogenic orchestration [28]. These inflammatory elements actively propel
disease progression, orchestrating a nefarious symphony of nephron attrition
and fibrotic encasement. This insidious immune-mediated assault elevates CKD to
the ominous ranks of chronic inflammatory diseases, demanding novel therapeutic
strategies that not only eliminate inflammation but also disarm the nefarious
orchestrators of renal devastation [29]. Anti-inflammatory strategies have
emerged as common therapeutic targets for renal disorders, given that patients
with early-stage CKD exhibit subclinical inflammation and activation of
circulating immune cells. Recent investigations have illuminated the
versatility and complexity of immune cell roles [30]. Monocytes/macrophages, a
critical type of immune cell, are innate immune system phagocytes found across
various organs.
Autoimmune disease
Interleukin-6 (IL-6) is a pleiotropic cytokine that
critically influences diverse pathological processes, encompassing autoimmune
disorders, bacterial infections, and metabolic dysregulations. Composed of four
?-helices, this 184-amino acid protein has multiple functions, transcending its
initial characterization as a B-cell stimulatory factor. Notably, IL-6 has
potent immunomodulatory effects, promoting CD4+ T-cell expansion via IL-21
induction and guiding CD4+ T-cell differentiation toward the Th2 and Th17
lineages [31-34].
Cardiovascular disease
Cytokines and macrophages are instrumental in the
onset and progression of CVD. Cytokines, signalling molecules produced by
various cells, including immune cells such as macrophages, regulate immune
responses, inflammation, and cell growth and differentiation [35,36]. In CVD,
cytokines such as TNF-alpha, IL-6, and IL-1beta contribute to the development
of atherosclerosis, a primary cause of CVD. Macrophages, a type of immune cell,
play a pivotal role in atherosclerosis. In its early stages, macrophages
infiltrate the arterial wall and take up modified lipids such as oxidized LDL
to form foam cells. These foam cells contribute to the formation of fatty
streaks, the earliest visible signs of atherosclerosis. Macrophages also
secrete cytokines and other inflammatory mediators that promote inflammation
and atherosclerosis progression. In advanced atherosclerosis, macrophages can
form a necrotic core by undergoing apoptosis and releasing their contents,
including cholesterol and proinflammatory cytokines. This can lead to plaque
instability and rupture, triggering acute cardiovascular events such as
myocardial infarction or stroke [37].
Cancer
In cancer, cytokines can exhibit both protumor and
antitumour effects. Some cytokines, such as IL-6 and TNF-alpha, promote tumour
growth by stimulating cell proliferation, inhibiting cell death, and promoting
angiogenesis [38]. Conversely, other cytokines, such as IFN-gamma and tumour
necrosis factor-beta (TNF-beta), exhibit antitumor effects by promoting cell
death and activating immune cells to attack cancer cells. Macrophages play a
key role in the early stages of cancer and help recognize and eliminate cancer
cells. However, as the tumour grows, macrophages can become “reprogrammed” to
adopt a protumor phenotype. These “tumour-associated macrophages” (TAMs)
promote tumour growth by secreting cytokines and growth factors that stimulate
cell proliferation and angiogenesis, suppress the immune response, and remodel
the extracellular matrix to promote metastasis [39]. Targeting cytokines and
macrophages is a promising strategy for cancer therapy. For instance, drugs
that block cytokine signalling, such as anti-IL-6 or anti-TNF-alpha antibodies,
are currently undergoing clinical trials for various types of cancer.
Additionally, there is growing interest in developing therapies that target
TAMs, either by depleting them or reprogramming them to adopt an antitumor
phenotype.
Investigating the complex interplay between cytokines
and macrophages in inflammation poses several significant challenges. First,
the sheer diversity of cytokines involved complicates the identification of
specific actors in individual cases. Overlapping and sometimes redundant functions
of certain cytokines further enhance this complexity, demanding sophisticated
tools for discerning their unique contributions [40]. Determination of the
concentrations of many cytokines in biological samples necessitates highly
sensitive assays, such as flow cytometry or ELISA, for accurate quantification.
Macrophages, a heterogeneous cell population, present another critical hurdle.
The diverse tissue-specific phenotypes of these viruses exhibit distinct gene
expression profiles and functional properties, necessitating tailored isolation
techniques. Fluorescence-activated cell sorting (FACS) or magnetic-activated
cell sorting (MACS) have become essential tools for differentiating these
nuanced subsets [41]. Maintaining macrophage viability throughout an
experiment, especially during cytokine stimulation studies, can be delicate due
to the high sensitivity of macrophages to environmental changes and the
tendency for rapid activation or apoptosis. Deciphering the intricate
signalling pathways activated by cytokines within macrophages is yet another
challenge. Western blotting and gene expression profiling have become crucial
tools for revealing the molecular cascades triggered by specific cytokines,
allowing for a deeper understanding of their downstream effects [42]. Both
cytokines and macrophages exhibit pronounced heterogeneity, further adding
layers of complexity to their roles in inflammation [43]. Understanding the
tissue-specific nuances of different macrophage subsets and the diverse effects
of cytokine combinations is crucial for dissecting their precise contributions
to the inflammatory process. Additionally, cytokine storms, characterized by a
hyperactive immune response with excessive cytokine production, pose a
potentially fatal threat, leading to widespread tissue damage and organ
failure. Elucidating the mechanisms triggering such events holds immense
clinical significance [44]. Finally, immunosenescence, the age-related decline
in immune function, further complicates the picture. Understanding how these
changes impact cytokine profiles and macrophage polarization patterns is vital
for developing effective strategies to combat age-related infections, cancers,
and autoimmune diseases. By addressing these significant challenges,
researchers can elucidate the intricacies of cytokine–macrophage interactions
in inflammation, paving the way for novel therapeutic interventions and
improved human health outcomes.
The emergence of humanized animal models constructed
by engrafting human cells or tissues into nonhuman hosts has revolutionized
biomedical research and drug discovery [45]. These models offer unparalleled
advantages over traditional in vitro or in silico approaches by enabling the
investigation of human pathophysiology in vivo, evaluating potential
therapeutic efficacy, and providing a more accurate representation of disease
progression than conventional methods. By serving as a preliminary testing
ground for new drugs, humanized models can streamline the drug development process
by identifying potential safety or efficacy concerns early on. Continued
advancements in technology hold promise for the creation of even more
sophisticated and precise humanized models, potentially paving the way for the
development of more effective disease treatments [46]. Single-cell sequencing,
while a powerful tool for understanding cellular heterogeneity, faces several
challenges. Isolation of individual cells from complex tissues or rare cell
populations can be difficult, impacting subsequent analysis. The quality and
quantity of isolated cells significantly influence the accuracy and reliability
of the generated data. Additionally, the high-dimensional nature of single-cell
sequencing data necessitates a meticulously designed analysis pipeline to
manage technical variability and biological heterogeneity. Amplification,
required to generate sufficient DNA or RNA for sequencing, introduces potential
biases that can distort results, highlighting the importance of robust quality
control measures. Macrophage polarization plays a pivotal role in regulating
inflammation. Inducing M2 polarization through IL-4 and IL-13 has potential for
mitigating inflammation in diseases such as asthma [47]. Emerging
immunomodulatory therapies, such as senolytics and immune checkpoint
inhibitors, offer promising avenues for combating immunosenescence. Senolytics
selectively eliminate senescent cells, which contribute to age-associated
inflammation, while immune checkpoint inhibitors enhance immune function by
negating immunosuppressive signals. In the context of COVID-19, cytokine
inhibitors such as tocilizumab and baricitinib have shown efficacy in managing
cytokine storms by targeting specific proinflammatory cytokines. Despite the
identification and study of numerous cytokines and macrophage subsets, the
landscape has not been fully elucidated. Future research should focus on
discovering novel entities and elucidating their roles in inflammation and the
immune response [48-51]. Dysregulated cytokine production is a hallmark of
chronic inflammatory diseases. Deciphering the regulatory mechanisms governing
cytokine production in macrophages and other immune cells provides fertile
ground for identifying novel therapeutic targets. Similarly, the diverse
spectrum of macrophage polarization states warrants further investigation to
identify specific targets for modulating inflammation in various diseases.
While the pivotal roles of cytokines and macrophages in inflammation and the
immune response are well established, their specific contributions too many
diseases remain unclear. Current imaging techniques provide limited information
about cytokine and macrophage activity in vivo. The development of novel
imaging modalities with the potential to visualize these activities in real
time holds immense promise for advancing our understanding of inflammation and
the immune response, paving the way for the development of more targeted and
effective therapeutic strategies (Figures 1-4).
In conclusion, macrophages exhibit remarkable
heterogeneity and play a crucial role in both innate and adaptive immunity. The
diverse activation states of M1 and M2 macrophages contribute to tissue repair,
inflammation resolution, and disease progression depending on the specific
context. Cytokines, signalling molecules produced by macrophages and other
immune cells, further orchestrate these complex processes. Understanding the
intricate interplay between cytokines and macrophages in inflammation holds
immense potential for developing novel therapeutic interventions for various
diseases, including cancer, autoimmune disorders, and chronic inflammatory
conditions. Future research efforts should focus on deciphering the regulatory
mechanisms governing cytokine production and macrophage polarization,
identifying novel therapeutic targets, and developing advanced imaging
modalities to visualize these activities in vivo. By addressing these
challenges and revealing the secrets of cytokine–macrophage interplay, we can
pave the way for a healthier future.
Funding
This research was unfunded by any public, commercial,
or not-for-profit agency.
Ethical Approval and Consent to
Participate
Not applicable.
Guarantor
The article’s full responsibility lies with PY, who is
the corresponding author and the third author on the list.
Author contributions
SA, PS, SS, AK, and VR were responsible for manuscript
conceptualization, writing - original draft, consent, and sample collection. PY
participated in the writing, review and editing.
Acknowledgments
Due to space constraints, some pertinent publications
could not be found.
Availability
of data and materials
All the data have been truly cited in the articles.
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for publication
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manuscript.