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\begin{document}

\title{Macrophage memory: Types, Mechanisms, and Its Role in Health and Disease}



\author[1]{Ai-Hua Liao}%
\author[1]{Xu-Hui Fang}%
\author[1]{Zhi-Jing Li}%
\author[1]{Chun-Yan Liu}%
\author[1]{Gil Mor}%
\affil[1]{Huazhong University of Science and Technology Tongji Medical College}%


\vspace{-1em}



  
  \date{May 21, 2024}


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\selectlanguage{english}
\begin{abstract}
On the basis of the mechanisms of action and characteristics of immune
effects, immunity is generally divided into innate and adaptive
immunity. Adaptive immunity is associated with the response to non-self
entities and is characterized by high specificity and memory. In
contrast, innate immunity is believed to lack memory. However, an
increasing number of studies have sought to challenge this traditional
immunological dogma and have shown that innate immune cells respond to
secondary stimulation more strongly and rapidly than to the primary
triggers, thus providing evidence of the immune memory in innate
immunity. Macrophages, which are among the most important innate immune
cells, can also acquire memory that facilitates the mediation of recall
responses. Macrophage memory is a relatively new concept that is
revolutionizing our understanding of macrophage biology and
immunological memory and could lead to a new class of vaccines and
immunotherapies. In this review, we describe the characteristics and
mechanisms of macrophage memory, as well as its key roles in various
diseases.%
\end{abstract}%



\sloppy


\textbf{Title: Macrophage memory: Types, Mechanisms, and Its Role in
Health and Disease}

\textbf{Authors:} Xu-Hui Fang\textsuperscript{1}, Zhi-Jing
Li\textsuperscript{1}, Chun-Yan Liu\textsuperscript{1}, Gil
Mor\textsuperscript{1, 2}, Ai-Hua Liao\textsuperscript{1,*}

\textbf{Affiliations:}

\textsuperscript{1}Institute of Reproductive Health, Center for
Reproductive Medicine, Tongji Medical College, Huazhong University of
Science and Technology, Wuhan, P.R. China

\textsuperscript{2}C.S. Mott Center for Human Growth and Development,
Wayne State University School of Medicine, Detroit, MI, USA

\textsuperscript{\textbf{*}}\textbf{Corresponding author:}

Institute of Reproductive Health, Center for Reproductive Medicine,
Tongji Medical College, Huazhong University of Science and Technology,
Wuhan, 430030, China.

\textbf{E-mail address} :\emph{aihua\_liao@hust.edu.cn}

\textbf{Funding information} : The research was supported by the grants
from the National Natural Science Foundation of China (No. 82220108008
to A.H. Liao), and Strategic Developmental Project for Foreign Experts
by the Ministry of Science and Technology (No. G2022154027L to A.H.
Liao).

\textbf{Conflict of interest:} The authors have declared that no
competing interest exists.

\textbf{Author contributions:} Xu-Hui Fang: manuscript draft and
revision. Zhi-Jing Li, Chun-Yan Liu and Gil Mor: manuscript revision.
Ai-Hua Liao: concept, text revision, and final approval.

\textbf{Data availability statement:} Data sharing is not applicable as
no new data were created or analyzed in this paper.

\textbf{Abbreviations:} NK, natural killer; LPS, lipopolysaccharide;
BCG, Bacillus Calmette-Gu\selectlanguage{ngerman}érin; PRR, pattern recognition receptor; PAMPs,
pathogen-associated molecular patterns; DAMPs, danger-associated
molecular patterns; TLR, toll like receptor; TNF-\selectlanguage{greek}α, \selectlanguage{english}tumor necrosis
factor-a; \selectlanguage{english}IL, interleukin; H3K4me3, tri-methylation of histone H3 at
lysine 4; ox-LDL, oxidized low-density lipoprotein; miRNAs, microRNAs;
mTOR, mammalian target of rapamycin; HIF-1\selectlanguage{greek}α, \selectlanguage{english}hypoxia-inducible
factor-1\selectlanguage{greek}α; \selectlanguage{english}PIR-A, paired immunoglobulin-like receptor-A; MHC, major
histocompatibility complex; TAM, tumor-associated macrophage

\textbf{ORCID:} Xu-Hui Fang, 0000-0001-5380-3956; Ai-Hua Liao,
0000-0001-8533-8315

\textbf{Abstract}

On the basis of the mechanisms of action and characteristics of immune
effects, immunity is generally divided into innate and adaptive
immunity. Adaptive immunity is associated with the response to non-self
entities and is characterized by high specificity and memory. In
contrast, innate immunity is believed to lack memory. However, an
increasing number of studies have sought to challenge this traditional
immunological dogma and have shown that innate immune cells respond to
secondary stimulation more strongly and rapidly than to the primary
triggers, thus providing evidence of the immune memory in innate
immunity. Macrophages, which are among the most important innate immune
cells, can also acquire memory that facilitates the mediation of recall
responses. Macrophage memory is a relatively new concept that is
revolutionizing our understanding of macrophage biology and
immunological memory and could lead to a new class of vaccines and
immunotherapies. In this review, we describe the characteristics and
mechanisms of macrophage memory, as well as its key roles in various
diseases.

\textbf{Keywords:} macrophage memory; trained immunity; endowed
immunity; epigenetic reprogramming



\textbf{Introduction}

Depending on the types of participating cells, recognition patterns, and
effector mechanisms, immunity is traditionally divided into two
categories, namely, innate and adaptive immunity. The former is mediated
by phagocytes, such as monocytes, macrophages, and neutrophils, as well
as natural killer cells (NK cells), and is characterized by a rapid and
non-specific immune response, whereas the latter is mainly mediated by T
and B lymphocytes and is characterized by a slower, albeit highly
specific, response. It is generally believed that the immunological
memory is associated exclusively with adaptive immunity, and not innate
immunity. Nevertheless, it has long been debated as to whether innate
immunity also has memory feature, and the recent findings have indeed
indicated that immunological memory is not an exclusive hallmark of
adaptive immunity \textsuperscript{1, 2}. For example, plants and
invertebrates, which lack adaptive immunity, are protected against
secondary infections, and invertebrates can also exhibit transplant
rejection\textsuperscript{3-6}. Macrophages, which are key innate immune
cell types, participate in innate immunity by phagocytizing foreign
bodies, and initiate adaptive immunity by capturing and processing
antigens, which are subsequently presented to lymphocytes, thereby
playing a central role in immune responses \textsuperscript{7, 8}.
Moreover, macrophages exhibit certain immune memory-related properties
that are traditionally attributed to adaptive T and B cells. However,
compared with the memory of adaptive immunity, macrophage memory remains
comparatively unknown. Herein, we describe two types of macrophage
memory, namely, trained immunity (innate immunological memory) and
endowed immunity (adaptive immune-like memory) (Figure 1), as well as
the essential roles these play in a range of diseases.

\textbf{Trained immunity (innate immune memory)}

In 2011, Netea et al. \textsuperscript{3} first proposed the concept of
``trained immunity'' to describe the ability of mammalian innate
immunity to exhibit immune memory, monocytes/macrophages, NK cells, and
granulocytes that show altered immune responses to secondary stimulation
originating from exogenous or endogenous insults. In terms of cell
populations and molecular mechanisms, there are important differences
between trained immunity and classic adaptive immune memory. While
adaptive immune memory generally implies high specificity and cascade
amplification, trained immunity is a non-specific or semi-specific
phenomenon that is mainly characterized by alterations in the number
and/or function of innate immune cells, and subsequently involves the
initiation of a pro-inflammatory or anti-inflammatory secondary immune
response \textsuperscript{3, 9, 10}. Depending on the nature and the
dose of the primary stimulus, trained immunity responds to the secondary
challenge via one of two contrasting functional programs, with enhanced
immunological imprinting being manifested as training, and the
suppressed program contributing to tolerance \textsuperscript{10, 11}.

\textbf{Discovery and characteristics of trained immunity}

Freudenberg et al. \textsuperscript{12} reported that in mice,
macrophages primarily stimulated by sepsis or high-dose
lipopolysaccharide (LPS) induce immune tolerance and exhibit a
suppressed immune response to avoid the development of a state of
excessive inflammation on secondary challenge. Quintin et
al.\textsuperscript{13} also showed that whereas macrophages can be
trained by \selectlanguage{greek}β-\selectlanguage{english}glucan (the main cell wall structural component of the
yeast\emph{Candida albicans} ), mice lacking functional T and B
lymphocytes are protected against reinfection of multiple pathogens such
as \emph{C. albicans} and \emph{Staphylococcus aureus} . Indeed,
increasing number of studies have indicated that bacterial, fungal,
parasitic, and viral infections can train monocytes/macrophages to
promote the secretion of inflammatory cytokines and enhance phagocytosis
in response to secondary stimulation, thereby confirming the
universality of macrophage memory\textsuperscript{13-17}. In addition to
studies using animal models, a study on childhood vaccination reported
that the Bacillus Calmette-Gu\selectlanguage{ngerman}érin (BCG) vaccination can enhance the
defense against infections other than those caused by mycobacteria in a
monocyte-dependent manner, thereby leading to an overall reduction in
child mortality \textsuperscript{18}. Furthermore, accumulating
epidemiological data indicates that live vaccines, such as the measles,
smallpox, and polio vaccines, provide non-specific protective effects
against a broad range of infections other than those caused by the
respective target viruses \textsuperscript{19-22}.

These studies have revealed two important characteristics of trained
immunity. Firstly, trained immunity is a non-specific or semi-specific
phenomenon, with its specificity being lower than that of adaptive
immunity; and as such, it can provide cross-protection against a wide
range of pathogens. Secondly, trained immunity primarily stimulated by
infections or vaccines induces a pro-inflammatory or anti-inflammatory
secondary immune response independent of classical T/B cell adaptive
immunity.

\textbf{Mechanisms of trained immunity}

Unlike the classical adaptive immune memory, which is dependent on
antigen-specific gene rearrangement, the mechanisms underlying trained
immunity mainly include \selectlanguage{english} altered pattern recognition receptor (PRR)
expression, \selectlanguage{english} epigenetic reprogramming, and \selectlanguage{english} metabolic reprogramming.
Moreover, these mechanisms may be characterized by a degree of
synergism, rather than functioning completely independently.

\textbf{Altered pattern recognition receptor expression}

In response to a primary challenge, macrophages acquire an immune memory
phenotype and upregulate PRR expression to promote the recognition of
diverse foreign antigen-derived pathogen-associated molecular patterns
(PAMPs) and self-derived danger-associated molecular patterns (DAMPs),
and subsequently produce an altered immune memory
response\textsuperscript{23-25}. Following stimulation by different PRR
ligands such as the dectin-1 ligand \selectlanguage{greek}β-\selectlanguage{english}glucan, Toll like receptor 2
(TLR2) ligand lipoteichoic acid, TLR4 ligand LPS, and nucleotide-binding
oligomerization domain-containing protein 2 (NOD2) ligand muramyl
dipeptide, monocytes/macrophages modify the secretion of
pro-inflammatory cytokines tumor necrosis factor-a \selectlanguage{english}(TNF-\selectlanguage{greek}α\selectlanguage{english}) and
interleukin (IL)-6, and initiate an altered immune response on secondary
encounter \textsuperscript{26}. In addition, the macrophage memory
induced by cell surface receptors may be retained following cell
differentiation. The findings of a recent study have revealed that
macrophages derived from mice or human hematopoietic stem and progenitor
cell subsets that are exposed to a TLR2 agonist prior to or during
macrophages differentiation, develop immune tolerance during the
secondary response and produce lower levels of the inflammatory
cytokines TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-6, and IL-1\selectlanguage{greek}β \selectlanguage{english}\textsuperscript{27}.

\textbf{Epigenetic reprogramming}

Epigenetic reprogramming of innate immune cells is among the most
important mechanisms associated with trained immunity. Epigenetic
reprogramming involves multiple mechanisms, among which histone
modification plays a key role in the induction of macrophage memory.

In the case of \emph{Candida} infections, monocytes/macrophage memory
trained by \selectlanguage{greek}β-\selectlanguage{english}glucan has been found to be associated with epigenetic
changes involving the enhanced tri-methylation of histone H3 at lysine 4
(H3K4me3) \textsuperscript{13}. In addition, in vitro stimulation of
human monocytes with oxidized low-density lipoprotein (ox-LDL) has been
observed to promote H3K4me3 and the upregulated expression of different
inflammatory cytokines associated with atherosclerosis, including IL-6,
IL-8, IL-18, and TNF-\selectlanguage{greek}α \selectlanguage{english}\textsuperscript{28}. On the basis of
inflammatory status (the expression of pro-inflammatory mediators, such
as TNF-\selectlanguage{greek}α \selectlanguage{english}and IL-6), LPS exposure and \selectlanguage{greek}β- \selectlanguage{english}glucan priming have been shown
to induce distinct functional programs of macrophage memory, namely,
tolerance and training. The contrasting functional changes in
macrophages are associated with specific epigenetic changes such as
H3K4me1 and H3K27ac. However, whereas H3K27ac, which marks active
promoters and enhancers, is a dynamic modification that gradually
disappears after the stimulation subsided, the distal regulatory element
(enhancer) marker H3K4me1 remains accessible \textsuperscript{11}. In
conclusion, H3K4me1 may serve as a marker that contributes to
maintaining the immunological memory of macrophages.

Additionally, when macrophages are stimulated with low-dose LPS, latent
enhancers that are normally inactive, label-free, and unbound by
transcription factors are selectively activated and acquired H3K4me1
marks after the resolution of stimulation, and once having been
unveiled, the histone marks persist and mediate a stronger
pro-inflammatory response upon subsequent
stimulation\textsuperscript{29}. Whereas monocytes/macrophages can be
stimulated in response to high-dose LPS, the induction of macrophage
memory involves H3K9me2 and H3K27me2 modification \textsuperscript{30}.
Kleinnijenhuis et al. \textsuperscript{31} have also reported that
TLR4-NOD2 is involved in the protective effect of monocytes against
secondary reinfection after primary BCG vaccination in healthy
volunteers. The enhanced function of monocytes in this case was found to
be mediated by H3K4me3, with the production of the inflammatory
cytokines IFN-\selectlanguage{greek}γ, \selectlanguage{english}TNF, and IL-1\selectlanguage{greek}β \selectlanguage{english}increasing several-fold in response to
infections by non-specific bacterial and fungal pathogens. Moreover, the
inhibition of histone methyltransferase was found to be associated with
a significant reduction in BCG-induced macrophage memory.

Further factors that play important roles in the induction of macrophage
memory are microRNAs (miRNAs), which serve as key regulators of immune
cell development and function \textsuperscript{32}. In this regard,
Seeley et al. \textsuperscript{33} have reported that prolonged exposure
to LPS in mice led to an increase in the expression of miRNA-221 and
miRNA-222, followed by transcriptional silencing of certain inflammatory
genes through switch/sucrose non-fermentable (SWI/SNF) and signal
transducer and activator of transcription (STAT)-mediated chromatin
remodeling. This in turn was found to promote immune tolerance to
secondary challenge, thereby indicating the regulatory effects of miRNAs
in the functional reprogramming of macrophage memory. An enhancement in
the expression of miRNA-221 and miRNA-222 has also been established to
be associated with immunoparalysis and heightened organ damage in
patients with sepsis. In addition to miRNAs, it is conceivable that long
non-coding RNAs (lncRNAs) also play roles in macrophage memory. Indeed,
Fanucchi et al. \textsuperscript{34} found that the newly identified
immune gene initiation lncRNA (IPL) directed WD repeat-containing
protein 5 (WDR5)-mixed lineage leukemia protein 1 (MLL1) histone
methyltransferase complex formation and subsequent H3K4me3 accumulation
on the promoters of IL-6, IL-8, and CXCL1, thereby resulting in a
stronger inflammatory response in \selectlanguage{greek}β-\selectlanguage{english}glucan-induced trained immunity.

\textbf{Metabolic reprogramming}

Trained immunity has also been established to involve changes in cell
metabolism, as indicted by the different metabolic pathways of two types
of activated macrophage, namely the classically activated M1 macrophages
and alternatively activated M2 macrophages. Whereas M1 macrophages tend
to utilize glycolytic metabolism for energy generation, M2 macrophages
are primarily dependent on oxidative phosphorylation for ATP
biogenesis\textsuperscript{35, 36}. In this context, Cheng et
al.\textsuperscript{37} have reported that the metabolic basis of
trained immunity triggered by the\emph{C. albicans} cell wall
constituent \selectlanguage{greek}β-\selectlanguage{english}glucan is the induction of aerobic glycolysis dependent on
an AKT-mammalian target of rapamycin (mTOR)-hypoxia-inducible factor-1\selectlanguage{greek}α
\selectlanguage{english}(HIF-1\selectlanguage{greek}α\selectlanguage{english}) pathway. Furthermore, trained human monocytes have been shown
to be characterized by high glucose consumption, high lactate
production, and a high ratio of nicotinamide adenine dinucleotide
(NAD\textsuperscript{+}) to nicotinamide adenine dinucleotide (NADH),
reflecting a shift in cell metabolism from oxidative phosphorylation to
aerobic glycolysis. Similar changes in glucose metabolism have also been
observed in BCG-induced trained immunity \textsuperscript{38}. Such
changes in cell metabolism facilitate the rapid conversion of glucose to
lactic acid in the cytoplasm, thereby yielding the energy necessary to
mount a rapid response to secondary challenge \textsuperscript{39}.
Furthermore, in the case of LPS-induced immunological memory,
macrophages have been observed to display strong and transient
glycolytic metabolism during the acute response, whereas after the
stimulation subsided, the metabolic polarity shifts back to oxidative
phosphorylation, and histones in the transcriptional region of the
genome are deacetylated by deacetylase-1 and deacetylase-6, thereby
establishing the immune tolerance memory of
macrophages\textsuperscript{40}. In addition, intermediate metabolites
have also been established to be involved in the regulation of
macrophage memory. For example, the metabolite mevalonate has been shown
to induce trained immunity by activating IGF1-R and mTOR and subsequent
histone modifications in inflammatory pathways \textsuperscript{41}.
Furthermore, the tricarboxylic acid cycle (TCA) metabolite fumarate
provides a link integrating immune and metabolic circuits to induce the
epigenetic reprogramming of monocytes by downregulating KDM5 histone
demethylases \textsuperscript{42, 43}. Additionally, glutamine
metabolism has been demonstrated to promote a high accumulation of
\selectlanguage{greek}α-\selectlanguage{english}ketoglutarate, and a corresponding elevation in the
\selectlanguage{greek}α-\selectlanguage{english}ketoglutarate/succinate ratio was found to be sufficient to regulate
H3K27me3 modification and ten-eleven translocation-dependent DNA
demethylation, which contribute to the induction of macrophage
memory\textsuperscript{42-44}.

\textbf{Endowed immunity (adaptive immune-like memory)}

Studies on transplant rejection provide a fundamental basis for
challenging the assumption that innate immune cells acquire immune
memory independent of adaptive immunity. In endowed immunity,
macrophages are endowed with adaptive immune-like memory that
facilitates the recall of primary immune responses. However,
high-specificity endowed immunity responses to secondary stimuli
necessitate the assistance of helper T cells \textsuperscript{45}.

\textbf{Discovery and characteristics of endowed immunity}

Dai et al. \textsuperscript{46} showed that mice monocytes/macrophages
can acquire an alloantigen-specific memory in response to secondary
encounters, and identified that paired immunoglobulin-like receptor-A
(PIR-A), a major histocompatibility complex (MHC)-I receptor, was
necessary for the induction of macrophage memory. Either deleting PIR-A
or blocking the PIR-A-MHC-I combination was demonstrated to suppress
memory and attenuate the allograft rejection in kidney and heart
transplantation. Similarly, Liu et al. \textsuperscript{47} have
reported that during secondary challenge, macrophages have the capacity
to recognize and reject allogeneic antigens, which requires two signals,
namely, priming with allogeneic antigens and the assistance of
CD4\textsuperscript{+}T cells. Chu et al. \textsuperscript{48} also
showed that macrophages primed with allogeneic antigens mounted an acute
response to skin allografts with a certain degree of antigen
specificity, which is similar to the characteristics of adaptive immune
cells. The authors demonstrated that immunodeficient recipient mice
showed no signs of rejection to allogeneic skin grafts, which is
consistent with the findings of previous studies that have established
that innate immune cells alone are insufficient to facilitate the
rejection of allogeneic organ grafts. However, they found that
immunodeficient recipient mice, which received antigen-immunized
macrophages (primed macrophages) from immunocompetent mice, were able to
efficiently reject the same allogeneic skin grafts, although not
third-party skin grafts, or showed significantly slower rejections of
the grafts. In summary, when primed macrophages in immunocompetent mice
are exposed to the same allogeneic antigen secondarily, primed
macrophages undergo pronounced proliferation, expand during the immune
response and exert a direct graft-rejection effect, at least partially,
via a perforin-dependent pathway.

In addition, the assistance of helper CD4\textsuperscript{+}T cells, but
not CD8\textsuperscript{+}T cells, during the priming period was found
to be essential for na\selectlanguage{ngerman}ïve macrophages to gain the ability to distinguish
allografts and thus promote rejection \textsuperscript{48-50}. In a
follow-up study, the same authors reported that the specific memory of
primed macrophages in the rejection of allogeneic cells and skin grafts
was long-term and persisted for at least 4 months (until the end of the
experimental period) \textsuperscript{51}. In conclusion, macrophages
can become endowed with memory that facilitates the recognition of
allogeneic antigens or specific molecules, and thereby induce an
inflammatory response on secondary encounter. Accordingly, suppressing
this memory may represent a potential therapeutic strategy for improving
transplantation outcomes. However, in a study of mouse alveolar
macrophages, Yao et al. \textsuperscript{52} found that the induction of
macrophage memory after respiratory viral infection required the
assistance of effector CD8\textsuperscript{+} T cells, but not
CD4\textsuperscript{+} T cells.

Taken together, the findings of the aforementioned studies indicate that
functional endowed immunity may require the assistance of different
types of T cells in different disease models. Hence, further studies are
needed to determine which T cell subsets facilitate the induction of
macrophage memory under different conditions. Although endowed immunity
may be associated with the secretion of inflammatory effectors and
amplified adaptive immune responses \textsuperscript{45, 53}, the
precise nature of the underlying molecular mechanisms remain unclear and
necessitate further study.

\textbf{The essential role of macrophage memory in disease responses}

Macrophage memory is closely associated with various diseases. As a
novel strategy for diseases prevention and treatment, macrophage memory
is beneficial for promoting host immune response against infections. In
contrast, this type of memory may be maladaptive or potentially
detrimental in the context of transplant rejection or immune-mediated
and chronic inflammatory diseases, such as rheumatoid arthritis and
atherosclerosis \textsuperscript{10, 54, 55}.

\textbf{Infections}

In a mouse model of recurrent skin and skin structure infections,
macrophage memory reduced the severity of skin damage and promote an
increase in the production of cytokines associated with skin protection
and prevention of dissemination. Furthermore, the adoptive transfer of
trained macrophages into naïve skin has also been established to afford
protective efficacy \textsuperscript{56}. In addition, trained
macrophages of mice that had previously been infected with\emph{S.
aureus} , have been observed to be associated with more rapid monocyte
recruitment, enhanced bactericidal effects, improved healing, and the
enhanced resistance of these mice to secondary infections
\textsuperscript{57}.

\textbf{Atherosclerosis}

In addition to microbial products, endogenous non-microbial stimulus
ox-LDL and lipoprotein (a) also induce monocyte/macrophage immune memory
and play important roles at different stages of
atherosclerosis\textsuperscript{28, 58}. In this context, trained human
monocytes have been found to switch to an enduring pro-atherogenic
macrophage phenotype via epigenetic histone modifications associated
with the downregulation of H3K4me3 on the promoters of pro-inflammatory
cytokines and a metabolic shift toward increased glycolysis. When
stimulated secondarily by TLR2 and TLR4 ligands, there is a substantial
increase in the production of pro-atherogenic factors, such as TNF-\selectlanguage{greek}α,
\selectlanguage{english}IL-1\selectlanguage{greek}β, \selectlanguage{english}IL-6, and monocyte chemoattractant protein-1 (MCP-1), which may
lead to arteriosclerotic plaque instability and exacerbate
atherosclerosis\textsuperscript{28, 59-61}.

\textbf{Inflammatory diseases}

A distinctive feature of inflammatory diseases, IL-1\selectlanguage{greek}β \selectlanguage{english}also serves as an
inducer of immunological memory. For example, it has been demonstrated
that IL-1\selectlanguage{greek}β \selectlanguage{english}pre-treatment protects mice against lethal
\emph{Pseudomonas}infection, and has also been reported to mediate the
immune response in human BCG vaccination, thereby indicating that this
cytokine may play an important role in the macrophage memory associated
with inflammatory diseases \textsuperscript{62-64}. This supposition in
indeed supported by the fact that \selectlanguage{greek}β-\selectlanguage{english}glucan-induced macrophage memory can
contribute to inhibiting IL-1\selectlanguage{greek}β-\selectlanguage{english}mediated inflammation. \selectlanguage{greek}β-\selectlanguage{english}glucan is
recognized as a classical immune memory inducer that can also activate
NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome,
the biochemical function of which is to activate cysteine-requiring
aspartate proteinase-1 (caspase-1) and subsequent IL-1\selectlanguage{greek}β \selectlanguage{english}production,
thereby establishing macrophage memory and a marked attenuation of IL-1\selectlanguage{greek}β
\selectlanguage{english}secretion in NLRP3-associated inflammatory diseases \textsuperscript{65,
66}.

\textbf{Cancer}

Immunological memory has also been established to play a central role in
tumor progression. For example, \selectlanguage{greek}β-\selectlanguage{english}glucan-induced mouse granulocyte
immune memory is reportedly associated with diminished tumor growth,
with this anti-tumor effect being attributed to a reprogramming of
neutrophils toward an anti-tumor phenotype, a process dependent on type
I interferon signaling, although independent of host adaptive
immunity\textsuperscript{67}. Indeed, innate immune cells may play
opposing roles by displaying both tumor-suppressing and tumor-promoting
properties. For example, in terms of suppression, BCG treatment has long
been known to eradicate malignancies such as bladder cancer and melanoma
and reduce the risk of leukemia and lymphoma \textsuperscript{68-71}.
Furthermore, \selectlanguage{greek}β-\selectlanguage{english}glucan has also been used in clinical trials for cancer
therapy such as that for non-small cell lung, breast, and colorectal
cancers \textsuperscript{72}. The findings of further studies have
revealed that such anti-tumor effects may be attributable to the
non-specific protection triggered by epigenetic reprogramming and is
associated with the induction of monocyte/macrophage
memory\textsuperscript{31, 73}.

With respect to the tumor-promoting effects of macrophage memory,
tumor-associated macrophage (TAM), which serves as important immune
regulatory element in tumor progression, has been shown to be involved
in the development of an immunosuppressive tumor microenvironment and
facilitate tumor immune escape, growth, and
metastasis\textsuperscript{74, 75}. The salient feature of TAM
differentiation is epigenetic reprogramming involving histone
modification, such as H3K4me3 and H3K9me3 alterations in the promoter
regions of IL-6 and TNF-\selectlanguage{greek}α, \selectlanguage{english}thereby inducing the production of
pro-inflammatory cytokines and expression of tumor-associated gene
profiles \textsuperscript{76}. For example, predominant functional
changes in thyroid cancer (TC)-induced macrophage memory enhance
inflammatory properties and the modification of cell metabolism. This
functional reprogramming has been established to be partially mediated
by TC-derived lactate via AKT1/mTOR-dependent aerobic glycolysis,
resulting in long-term epigenetic modifications at histone methylation
levels, such as H3K4me3 and H3K9me3 in the promoters of IL-6 and TNF-\selectlanguage{greek}α,
\selectlanguage{english}thereby leading to increases in the expression of genes characteristic
of cancer tumor profiles, and an increase in the production of TAM
pro-inflammatory factors \textsuperscript{76, 77}.

\textbf{Other diseases}

Human and mouse macrophages trained by low-dose LPS attenuate the
inflammatory phenotype of endometriotic cells via an IL-10-dependent
pathway, and significantly upregulated H3K4me3 on the IL-10 promoter and
altered inflammatory cytokine production have been observed
simultaneously in endometriosis \textsuperscript{78}. In addition,
evidence of macrophage memory has also been obtained with respect
neurodegenerative disorders, such as Alzheimer's disease, Parkinson's
disease, and autism spectrum disorder \textsuperscript{55}. In a mouse
model of Alzheimer's pathology, LPS-induced immune training has been
demonstrated to exacerbate cerebral \selectlanguage{greek}β-\selectlanguage{english}amyloidosis, whereas this could be
alleviated by immune tolerance, attributable to microglial
(brain-resident macrophage) memory, along with altered inflammatory
cytokine production and H3K4me1 and H3K27ac
enrichment\textsuperscript{79}. Furthermore, in respiratory diseases
such as allergic asthma, allergen-triggered macrophages have been
observed to acquire a TNF-dependent inflammatory memory and show an
excessive mediator response upon stimulation, thereby resulting in a
shift toward an M2-like macrophage phenotype and the production of
diverse inflammatory cytokines. Conversely, TNF blockade or genetic
ablation has been found to prevent the inflammatory imprinting of
macrophages\textsuperscript{80}. The concept of macrophage memory
presents a new perspective for better understanding of disease
pathology, and elucidating the precise underlying mechanisms may provide
relevant insights for the development of novel therapeutic strategies.

\textbf{Conclusion \& perspectives}

Trained or primed macrophages exhibit immune memory similar to that of
adaptive immunity when challenged with secondary triggers. There are two
types of macrophage memory, namely, trained and endowed immunity.
Trained macrophages acquire memory via epigenetic and metabolic
reprogramming, induce trained immunity, and facilitate an altered immune
response upon secondary stimulation. Similarly, primed macrophages can
acquire memory, which leads to the development of endowed immunity and
allogeneic rejection in response to stimulation with the same allogeneic
antigen. The discovery of macrophage memory has challenged traditional
dogma regarding the limitations of immunological memory and enriched our
understanding of macrophage-mediated immune responses. More importantly,
unraveling macrophage memory provides a more comprehensive perspective
on the pathogenesis of immune-mediated diseases, and may lead to
establishing a new class of vaccines and the development of novel
immunoprophylactic and therapeutic strategies.

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\textbf{Figure legend}

\textbf{Figure 1} . There are two types of macrophage memory: trained
and endowed immunity. In trained immunity, macrophages acquire an immune
memory phenotype via epigenetic and metabolic reprogramming and exhibit
an enhanced (training) or suppressed (tolerance) host defense response
toward a secondary challenge. In endowed immunity, macrophages primed by
allogeneic antigens acquire the potential ability to reject allogeneic
grafts bearing the same antigen, with the assistance of helper
CD4\textsuperscript{+} T cells, although lack the capacity to reject
third-party grafts. In adaptive immunity, T and B cells display a highly
specific immune memory subsequent to primary exposure to antigens and
produce a rapid, robust, and enduring immune response.\selectlanguage{english}
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