The liver in humans receives 1.5 L of blood every minute, originating from two sources: the portal vein and the hepatic artery. This blood supply carries an enormous antigenic load, consisting of harmless dietary and commensal products that the hepatic immune system must tolerate [35]. Simultaneously, the immune system in the liver must respond to a variety of blood-borne pathogens, such as viruses, bacteria, and parasites, as well as metastatic cells that frequently target the liver [36]. To address this challenge, the liver requires tight immune regulation, or the so-called LPS/endotoxin tolerance [37]. In essence, the liver has a complex and unique system that enables it to manage the dual challenge of tolerating harmless antigens and responding appropriately to pathogenic challenges [36,38]. Several cellular mechanisms, such as immunosuppressive cells and molecules, including cytokines and ligands, are present in abundance in the liver to ensure that pathogen products and antigens typically do not stimulate immune responses.

To begin with, numerous non-parenchymal cells (NPCs) including liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs) and dendritic cells (DCs) have the ability to present antigens to T cells in ways that promote exhaustion [39,40], leading to the expression of inhibitory receptors on T cells such as programmed cell death protein 1 (PD-1) and T-cell Ig mucin domain-containing protein 3 (Tim-3) [41]. Secondly, another key mechanism of immune tolerance in the liver involves liver DCs. The liver contains multiple subsets of DCs, including myeloid DCs (mDCs) and plasmacytoid DCs (pDCs). These cells are specialized for antigen presentation and can induce either a state of tolerance or effective immunity [42]. In the liver, mDCs express programmed cell death ligand-1 (PD-L1), which drives the activation and expansion of classic FoxP3⁺ CD25⁺ CD4⁺ T regulatory (Treg) cells [43], which have been shown to suppress liver allograft rejection. DCs can also promote Treg development through their expression of indoleamine-pyrrole 2,3-dioxygenase (IDO), an enzyme that catabolizes tryptophan and generates an immunosuppressive product (kynurenine) [44]. Another important mechanism of immune tolerance in the liver is the role of KCs, which are resident macrophages of hepatic sinusoids. KCs can endocytose fragments of damaged hepatocytes, which convey transforming growth factor (TGF)-β1 and cause KCs to secrete IL-10 [45]. IL-10 acts in an autocrine manner, leading KCs to induce a variety of immunosuppressive mechanisms, including both effector T cell suppression and Treg cell promotion [40,46]. KCs also express B7-H1 (PD-L1), a ligand that engages the PD-1 receptor on activated T cells, resulting in clonal exhaustion [47]. Continuous exposure to LPS from the intestine may cause the down-regulation of TLR4-signaling pathways in KCs, resulting in LPS tolerance. This tolerance is partly induced by iIRAK-M [48]. Regarding LSECs, they respond to LPS initially by expressing TLR4/CD14, but with repeated stimulation, they become unresponsive to LPS while still retaining their scavenger activity. The LPS tolerance observed in LSECs is marked by a decrease in the nuclear translocation of NF-κB upon subsequent LPS exposure, which is intricately associated with the production of prostanoids. LPS tolerance in LSECs results in reduced leukocyte adhesion following LPS rechallenge and improved sinusoidal microcirculation in the liver, contributing to the local hepatic control of inflammation [49]. The molecular mechanisms that have been associated with the suppression of TLR4 signaling after prolonged LPS stimulation [50] involve changes in gene expression, signaling pathways, and epigenetic modifications and are analyzed in depth elsewhere [37]. These mechanisms include reduced LPS-induced MyD88-TLR4 association [51], reduced IRAK activity [51], enhanced nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor α (IkBα) degradation [52] and reduced activation of p38, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and/or NF-κB [53]. Additionally, negative feedback regulators of TLR4 signaling, such as A20 [54,55] and IRAK-M [56], have been found to delay the onset of LPS tolerance and could contribute to the suppression of gene expression during tolerance [37]. Moreover, NF-κB subunits and other transcription factors that are activated by LPS are also altered during tolerance. In naive cells, LPS stimulation leads to the loss of histone H3K9 demethylation [57] and an increase in H4 acetylation, allowing for SWItch/sucrose non-fermentable (SWI/SNF) complex recruitment and gene transcription. However, in tolerized cells, a Trichostatin A (TSA)-sensitive histone deacetylase may prevent H4 acetylation. Sirt1 facilitates the recruitment of RelB to promoters of tolerizable genes [58,59], subsequently engaging G9a to inhibit the expression of tolerizable genes by countering H3K9 demethylation [60]. For non-tolerizable gene promoters, G9a demethylates H3K9 in naive cells through the basal association of Atf7 [61]. Subsequent to tolerization, Atf7, and G9a are eliminated from these promoters, leading to the loss of H3K9 demethylation, which permits gene expression. Furthermore, latent enhancers might allow for the rapid expression of some genes during tolerance [62]. It is important to note that these changes have been directly shown to occur for only particular subsets of tolerizable and non-tolerizable genes and specific gene subsets, which likely differ in the specifics of their regulation, although the general paradigms of histone modification and transcription factor recruitment may be broadly applicable [37]. TLR4-signaling pathway alterations during LPS tolerance are summarized in Figure 3.