Unlike lymphocytes, monocytes and macrophages do not express recombinant antigen-receptor genes; they express pattern recognition receptors (PRRs). PRRs can recognize the structure of foreign antigens-PAMPs. Furthermore, DAMPs, and endogenous hazard signals, generate corresponding responses [15, 16]. PRRs may be involved in immune memory response. After BCG injection, intracellular PRR nucleotide-binding oligomerization domain 2 (PRRNOD2) participates in the protective effect of monocytes against secondary infection [17]. Prestimulation of monocytes with multiple PRRs ligands, such as dectin-1 ligand β-glucan, NOD2 ligand cytomyodyl dipeptide, and toll-like receptor 5 (TLR5) ligand flagellin, resulted in the production of large amounts of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) on secondary stimulation. However, TLR4 ligand LPS and flagellin stimulation (10 μg/mL) can induce long-term tolerance of monocytes and reduce the production of pro-inflammatory factors [18]. The IIM involved in forming cell surface receptors will not be lost with cell differentiation. Macrophages differentiated from hematopoietic stem cells, and progenitor cells that are tolerant to TLR2 ligands produce less inflammatory factors and reactive oxygen species in subsequent inflammatory stimulation [19]. This evidence suggests that PRRs may be widely involved in forming IIM. Further research is needed to clarify which PRRs and how they are involved in the process of IIM of specific macrophages.

During the generation of innate immunity, cellular metabolism in innate immune cells changes, which is associated with the above epigenetic changes [29] and is also an essential mechanism of IIM. Metabolic pathways change when immune cells are activated. Taking macrophage polarization as an example, the metabolic pathways of macrophages with classically activated M1 phenotype and those with alternative activated M2 phenotype are different: M1-type macrophages produce energy by glycolysis [30, 31]. M2 macrophages generate energy mainly through oxidative phosphorylation and have a complete tricarboxylic acid cycle [32]. In response to β-glucan and BCG, a critical link in cellular metabolism is the transition from oxidative phosphorylation to aerobic glycolysis dependent on the Akt/mechanistic target of rapamycin (mTOR)/hypoxia-inducible factor-1α (HIF-1α) pathway [21, 33, 34]. However, macrophages will undergo an intense and transient glycolysis process during the acute response phase [30]. After the stimulus fades, its metabolic mode rapidly changes to oxidative phosphorylation, and deacetylase-1 and deacetylase-6 deacetylate histone deacetylases form an immune tolerance phenotype [35].

In the process of IIM, there is a relationship between histone modification and intermediate products of cellular metabolism. Histone acetylation requires a critical metabolic intermediate, acetyl-coenzyme A (acetyl-CoA), whose elevated levels are in trained monocytes [21]. Tricarboxylic acid cycle intermediates such as fumarate, succinic acid, and α-ketoglutaric acid may regulate the production of IIM. The accumulation of Tamara inhibits the activity of demethylase in the protein of the group [36], induces cholesterol synthesis, leads to the accumulation of mehydroxyprotanic acid, and promotes epigenetic reprogramming during the generation of IIM of monocytes/macrophages by activating the mTOR pathway [37]. The breakdown of glutamine leads to the accumulation of succinic acid and α-ketoglutaric acid, cofactors of an important epigenetic enzyme family. In the process of macrophages producing solid immune memory, succinic acid and α-ketoglutaric acid inhibit lytic acid-specific demethylase 6 (KDM6, also known as JMJD3), resulting in the enhancement of M2-related gene H3K27me3, which inhibits the expression of these genes and makes memory macrophages in an anti-inflammatory phenotype [38, 39]. In classical LPS-induced endotoxin tolerance, α-ketoglutaric acid promotes macrophage M1 activation [39]. These results suggest that cellular metabolism is involved in solid immune memory production. However, the direct evidence that cellular metabolism intermediates affect histone modification enzymes is still needed to find further.

The innate immune system is critical to microbial and antiviral defense. As part of the innate immune system, monocytes/macrophages help fight off infections from bacteria and viruses. Memory macrophages play a protective role in both primary and secondary infection of the same or different pathogens. Staphylococcus aureus is a significant reason of skin and skin structure infection (SSSI). Macrophages with IIM function are protective in the recurrent mouse SSSI model. It reduces the severity of skin damage. Stimulated macrophages can still provide in vivo protection after adoptive transfer to the original skin [40]. In the secondary infection of mice previously infected with Staphylococcus aureus, the stimulated macrophages recruited monocytes faster, increased bacterial killing rate, accelerated healing speed and enhanced resistance to the second infection [41]. Alveolar macrophages (AMs) can be induced by primary infection (e.g., respiratory tract virus infection) with two different pathogens. Memory AMs are reprogrammed with high expression of major histocompatibility complex (MHC)-II molecules and increased glycolysis metabolism. In the case of secondary infection with Streptococcus pneumoniae and Escherichia coli, memorizing AMs produces more chemokines and chemotactic neutrophils to reach the lungs to enhance the body’s resistance to bacterial infection [42]. LPS stimulated macrophages can show more vigorous killing activity when encountering Staphylococcus aureus [23]. In conclusion, macrophage IIM plays an essential role in resistance to re-infection.

Chronic allograft rejection has long been linked to the role of monocytes/macrophages in generating inflammation and modulating adaptive immunological responses [43–45]. In recent years, researchers have found that macrophages’ IIM is involved in transplant rejection [46]. After the adoptive transfer of macrophages prestimulated by alloantigen into MHC matched immune-deficient mice, the latter acquired a strong specific ability to reject skin grafts for at least 120 days. Acquiring this ability requires the assistance of CD4 ⁺ T cells [47, 48]. Macrophages can also recognize specific molecules and generate memory. For example, mouse macrophages can obtain the memory of specific recognition of MHC-I molecules. These memory responses involve MHC-I receptors [type A paired immunoglobulin-like receptors (PIR-A)]. In mouse models of kidney and heart transplantation, deletion of recipient PIR-A or blocking the binding of PIR-A to donor MHC-I molecules can block the memory response and alleviate the rejection reaction [49]. The memory of innate immunity is also present in human transplant cases. In liver transplantation, mononuclear phagocytes (MNPs) from recipient blood are partially reprogrammed to obtain strong expression of CD68/CD206 in human leukocyte antigen (HLA)-mismatch allograft [50]. It is suggested that these cells may influence the recipient’s tolerance to the graft. Macrophages can acquire IIM for recognizing alloantigens or specific molecules, and blocking this memory may be a potential means to improve the effect of transplantation.

Monocytes and macrophages play critical roles in all stages of atherosclerosis [51], and their IIM also plays a vital role in disease progression. In addition to classical innate immune inducers β-glucan, BCG, and LPS, endogenous non-microbial atherogenic stimulus such as oxidized low-density lipoprotein (oxLDL) and lipoprotein(a) [Lp(a)] also induce IIM in monocytes/macrophages [52]. Transient stimulation of oxLDL and Lp(a) in vitro induced human monocytes to become macrophage phenotypes. When stimulated by TLR2 and TLR4 ligands again, the production of pro-atherogenic factors such as TNF-α and IL-6 in monocytes/macrophages increased significantly [52, 53]. oxLDL-stimulated macrophages can produce more collagenases such as matrix metalloproteinases 2 (MMP-2) and MMP-9, which play an essential role in the instability of atherosclerosis plaque [52]. High cholesterol can also induce immune memory production. Monocytes in patients with familial hypercholesterolemia are characterized by increased TNF-α production. Their promoters are rich in H3K4me3 markers, which cannot be eliminated after 3 months of cholesterol-lowering statins [54], suggesting that these patients are at increased risk of atherosclerosis. Therefore, the IIM of monocytes/macrophages plays a role in atherosclerosis, and its specific mechanism needs to be further explored.

In autoinflammatory diseases, pathogenic inflammation is mainly caused by the overactivation of antigen-independent immune pathways [55], in which the IIM of macrophages plays an important role (Figure 2). A significant feature of autoinflammatory diseases is the excessive production of IL-1β, so anti-IL-1 therapy has become a broad-spectrum approach for treating autoinflammatory diseases [56]. IL-1β is a critical disease factor and an essential inducer of IIM production. Studies have shown that the mortality of mice reinfected with bacteria after injection of IL-1β is significantly reduced [57]. Human monocytes prestimulated by IL-1β in vitro produced more IL-6 and TNF-α under LPS stimulation, and further studies showed elevated H3K4me3 levels in the promoter regions of IL-6 and TNF-α [58]. These findings suggest that IL-1β can induce the production of IIM and may lead to excessive inflammation, suggesting that IL-1β may play an essential role in autoimmune diseases. In addition to IL-1β, β-glucan is also a classical inducer of IIM. β-glucan can reprogram macrophages in patients with inflammatory disease, reducing the production of IL-1β mediated by nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing-3 (NLRP3) inflammasome and inhibiting inflammation [59], suggesting that β-glucan can reprogram macrophages to obtain immune memory and reduce pathogenic inflammation. The function of macrophage IIM in autoimmune diseases needs to be further explored.

Innate immune cells play different roles in tumor progression and finally show two opposite results: inhibiting and promoting tumors. When the innate immune system is activated effectively, it can play an anti-tumor role, and IIM can also play an important role in anti-tumor immunity. β-glucan, for example, induces an IIM of granulocytes that lasts for at least 28 days. Neutrophils can be reprogrammed into anti-tumor phenotype through transcription and epigenetic changes during the process of neutrophils producing IIM to exert anti-tumor activity and inhibit tumor growth. This process requires to type I interferon signaling and is independent of host adaptive immunity [60]. There are significant differences between tumor-associated macrophages (TAMs) and tumor-associated neutrophils in the mode of action, mechanism of action, duration of action, and effect on tumor progression. The innate memory of immunity may also be different between the two. Macrophage IIM can also play an anti-tumor role. Existing studies speculated that BCG-induced macrophage IIM might play a role in the tumor microenvironment. The anti-tumor effect of BCG has long been known. BCG can be used to treat bladder cancer [61], melanoma [62], and other malignant tumors and reduce the risk of leukemia [63] and lymphoma [64]. Further studies have revealed that this effect is achieved by providing non-specific protection through innate immune-dependent mechanisms involving histone H3K4me3, which is related to the generation of IIM of monocytes/macrophages [13, 17]. Long-term IIM of macrophages induced by BCG therapy may also play an essential role in preventing tumor recurrence.

In many cases, innate immune cells contribute to tumor progression. Innate immune cells invade the area around the tumor and become part of the tumor microenvironment. Inflammatory microcells in the tumor microenvironment usually promote tumor progression, and they can promote tissue remodeling, angiogenesis, and fibrosis, creating a microenvironment conducive to tumor growth [65]. The tumor microenvironment can functionally reprogram disease-free cells to counteract anti-tumor effects and promote the production of inflammatory states that are often associated with disease progression [66]. Epigenetic reprogramming of TAM in the tumor microenvironment is a core feature of TAM differentiation due to long-term histone modification. For example, changes in H3K4me3 and H3K9me3 in the promoter regions of IL-6 and TNF-α lead to increased TAM pro-inflammatory factors, expressed as tumor-promoting gene expression profiles [67]. The role of macrophage IIM in the tumor microenvironment remains further explored.