Macrophages serve as crucial components in the innate immune system. As the primary cells involved in phagocytosis, macrophages are fully equipped with diverse pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and scavenger receptors (SRs), adding powerful lysosomal enzymes to engage, recognize, and eliminate pathogenic agents (Janeway and Medzhitov, 2002; Nagata, 2018). The functions and phenotypes of macrophages vary widely, depending on physiologic and/or pathologic conditions (Gordon and Taylor, 2005; Gordon et al., 2014). For example, macrophages can polarize into two subsets: proinflammatory classically activated macrophages (M1) and anti-inflammatory alternatively activated macrophages (M2) (Murray and Wynn, 2011; Locati et al., 2020).

Two main categories of macrophages are present in the liver: liver-resident Kupffer cells (KCs) and circulating monocyte-derived macrophages (MoMφs) (Varol et al., 2015; Dou et al., 2019). In general, KCs are responsible for sensing and processing biochemical signals, such as pathogen components, cell fragments, and endo/exogenous metabolites (Diehl et al., 2020; Li W. et al., 2022). They can trigger primary inflammation and secrete chemokines to recruit MoMφs for further inflammatory responses (Wen et al., 2021; Zhou J. et al., 2022). Hepatic macrophages can also regulate inflammatory responses when stimulated with anti-inflammatory factors. Hence, the signaling pathways associated with macrophage activity and heterogeneity induced by different agents play a vital role in inflammation-associated liver diseases (Dou et al., 2019; Wen et al., 2021; Li W. et al., 2022).

Studies over the last few decades have introduced the concept of the gut-liver axis, which emphasizes the importance of crosstalk between gut-derived microbial agents and hepatic cells such as macrophages (Wu and Tian, 2017; Tripathi et al., 2018; De Muynck et al., 2021). Hepatic macrophages can trigger liver inflammation when stimulated by gut-derived signals such as pathogen-associated molecular patterns (PAMPs) (Thevaranjan et al., 2017; Toubal et al., 2020; Zhang et al., 2021b). In contrast, many microbial factors, such as short-chain fatty acids (SCFAs), can suppress or regulate hepatic macrophage activation (Bao et al., 2020; Wang Z. et al., 2020; Xia et al., 2022). This gut microbiota-macrophage-liver inflammation axis is highly significant in inflammation-related liver conditions.

The present review focuses on the crosstalk between hepatic macrophages and gut microbiota, as well as the association between specific microbes and inflammation-related liver conditions. Targeting hepatic macrophages as well as gut microbiota may have therapeutic potential in the treatment of inflammatory liver diseases.

Hepatic macrophages consist primarily of two subsets, resident KCs and circulating MoMφs, which differ in origin and characteristics. Generally, tissue-resident KCs are seeded into the fetal liver during embryogenesis. One hypothesis states that KCs originate from CSF1R⁺ erythromyeloid progenitors (EMPs) present in the fetal liver during embryogenesis (Gomez Perdiguero et al., 2015). These EMPs develop in the yolk sac on embryonic day 8.5 (E8.5), subsequently developing into monocytes after colonizing the fetal liver. KCs are thought to originate from fetal liver monocytes as early as E12.5 (Hoeffel et al., 2015). A second hypothesis states that KCs originate from circulating CD45⁺, Kit⁻, and Lin⁻ macrophage precursors (pMac) derived from EMPs, which colonize the fetal liver beginning on E9.5 and dependent on CX3CR1, giving rise to tissue-resident macrophages as early as E12.5 (Mass et al., 2016). Similar to other tissue-resident macrophages, KCs possess self-renewing ability and are mostly independent from bone marrow (BM)-derived progenitors (Schulz et al., 2012; Yona et al., 2013; Gomez Perdiguero et al., 2015). In an unsteady state, circulating monocytes can replenish KC populations (Hettinger et al., 2013; Scott et al., 2016).

Mature KCs share a series of common macrophage surface markers, such as CD11 and F4/80, whereas KCs in mice express the unique marker, C-type lectin domain family 4 member F (CLEC4F) (Krenkel and Tacke, 2017; Li W. et al., 2022). These KCs usually inhabit liver sinusoids, where they continuously engage with and process senescent cells and various gut-derived particles. Generally, KCs in the liver have three primary activities: clearance of pathogens and cells that have undergone apoptosis (Toth and Thomas, 1992; Shi et al., 1996; Horst et al., 2019; Deppermann et al., 2021); antigen presentation and the induction/regulation of inflammation (Liu et al., 2015; Yu et al., 2019; Zhang et al., 2021a; Ni et al., 2021; Li W. et al., 2022); and iron, bilirubin, and lipid metabolism (Scott and Guilliams, 2018; Diehl et al., 2020; Bleriot et al., 2021). KCs are essential for both maintaining liver homeostasis and responding to liver injury.

MoMφs originate from CX3CR1⁺, CD117⁺, and Lin^–progenitors, also called common monocyte progenitors (cMoP), in bone marrow (Fogg et al., 2006; Hettinger et al., 2013). In addition to common macrophage markers, MoMφs express unique CX3CR1 and CCR2 markers. Mouse MoMφs can be differentiated into two subsets according to their levels of expression of Ly6C. Ly6C⁺ cells can be recruited by chemokines and infiltrate the liver, where they have proinflammatory activity, whereas many Ly6C⁻ cells act as scavengers and regulators of inflammation (Carlin et al., 2013; Morias et al., 2015; Krenkel et al., 2018; Ambade et al., 2019). Another subset of CX3CR1⁺ Ly6C⁻ resident macrophages has been identified in liver capsules as liver capsular macrophages (LCMs), which can directly take up both particulate antigens such as LPS and bacteria in capsule with extended dendrites. They are replenished by circulative monocytes and can recruit neutrophil infiltration (Sierro et al., 2017).

Classically, the observation of the macrophage polarization under interferon gamma (IFN-γ) or interleukin 4 (IL-4) stimulation identified the distinct biologic profile between pro-inflammatory M1 (mainly secreting TNF-α and IL-1β) and anti-inflammatory M2 macrophages (mainly secreting IL-10), respectively. (Murray and Wynn, 2011; Murray, 2017). With the increasing understanding in recent years, the role of inflammation or resolution in hepatic macrophages were found to be interwoven and rapidly transformed (Ramachandran et al., 2012; Beattie et al., 2016; Mossanen et al., 2016). Some scholars have suggested that a more specific and dynamic method to clarify polarization of hepatic macrophages is needed under complex pathologic conditions (Xue et al., 2014; Tacke, 2017; Locati et al., 2020). However, the evidence of microbial regulation on hepatic macrophage polarization has not gone that far yet. The classic concept of macrophages polarization indicates a general view of functional heterogeneity, which is still helpful to describe the characteristics of hepatic macrophages here.

As members of the innate immune system, hepatic macrophages are crucial initiators of and participants in liver inflammation. They are mainly responsible for triggering inflammatory responses to various insults but may also cause severe tissue injury and dysfunction (Koyama and Brenner, 2017; Tacke, 2017; Locati et al., 2020).

In general, liver inflammation is initiated by the engagement between KCs and innate molecular patterns (IMPs), including PAMPs and damage-associated molecular patterns (DAMPs) (Dou et al., 2019; Li W. et al., 2022). PRRs such as TLRs play an important role in recognizing DAMPs, including free DNA and high-mobility group box 1 (HMGB1) from damaged hepatocytes, and in recognizing PAMPs, such as lipopolysaccharides (LPS), lipoproteins, and peptidoglycan (PGN) (Takeda et al., 2003; Takeuchi and Akira, 2010; Kumar et al., 2011). Upon recognizing IMPs, KCs can secrete proinflammatory agents (e.g., IL-1β, CCL2) through inflammatory signaling pathways (e.g., NF-κB, PI3K/AKT) to recruit or activate downstream cells (e.g., MoMφs, T cells, and vascular endothelial cells) (Janeway and Medzhitov, 2002; Taylor et al., 2005; Wynn et al., 2013).

MoMφs usually take part in the second stage of liver inflammation. Ly6C⁺ MoMφs can be recruited by KC-secreted chemokines such as CCL2 and massively infiltrate into injured liver to replenish hepatic macrophages and participate in further inflammation. In many inflammation-related liver diseases, Ly6C⁺ MoMφs act as potent proinflammatory cells, secreting a large number of cytokines and inducing tissue injury (Krenkel et al., 2018; Ambade et al., 2019; Dai et al., 2020; Kolodziejczyk et al., 2020). Inhibition of CCL2/CCR2 signaling, which blocks the recruitment of Ly6C⁺ MoMφs, is a potential therapeutic target in liver inflammation (Krenkel et al., 2018; Ambade et al., 2019). In addition, a subset of resident Ly6C⁻ MoMφs is responsible for sensing pathogens and recruiting neutrophils (Sierro et al., 2017).

Hepatic macrophages are also essential in the resolution of liver inflammation and the repair of liver injury. Reductions in the numbers of macrophages can decrease the proliferation of hepatocytes and the restoration of tissue homeostasis (Tacke, 2017). Hepatic macrophages with an anti-inflammatory phenotype, including Ly6C⁻ MoMφs, can promote the clearance of proinflammatory agents, such as cleaved IL-1β, and release cytokines with anti-inflammatory and wound-healing effects, such as IL-4 (Mosser and Edwards, 2008; Kim and Nair, 2019; Starkey Lewis et al., 2020). In addition, KCs are crucial components in the establishment of hepatic immune tolerance (Knolle et al., 1995; Chou et al., 2015; Doherty, 2016). KCs can both be activated or secret IL-10 to maintain an immunosuppressive environment in liver cancer and acute liver injury (ALI) (Erhardt et al., 2007; Wu et al., 2009). Meanwhile, KCs are capable to down-regulate own TLR4-signaling pathways under the long-term exposure to gut-derived LPS (low dose) partly due to the induction of interleukin-1 receptor-associated kinase M. This LPS tolerance may be necessary to maintain the homeostasis of the gut-liver axis (Liu et al., 2008). A recent study also identified that KCs treated with polymeric nanoparticles which contain disease-relevant antigens are sufficient to mediate immune tolerance in experimental autoimmune encephalomyelitis (EAE) (Casey et al., 2022). Figure 1 outlines the roles of hepatic macrophages in liver inflammation.

The human gut contains numerous commensal and external micro-organisms that play important roles in host physiology (Garrett, 2017; Zmora et al., 2019). Microbial components and metabolites can translocate into distant organs, especially the liver, through the portal vein system (Cani, 2018; Albillos et al., 2020; Jones and Neish, 2020). Under conditions of eubiosis or dysbiosis, gut-derived microbial signals exert various effects on the liver, with hepatic macrophages acting as crucial players in the gut-liver axis (Bruneau et al., 2021; De Muynck et al., 2021).

Among the various microbial components that can stimulate hepatic macrophages, the most typical agent is probably LPS. Gut bacteria constitute an abundant pool of LPS, which continuously stimulates hepatic macrophages through the portal vein system. LPS/TLR4 signaling on KCs can sense endotoxin translocation and initiate the activation of various inflammatory responses (Janeway and Medzhitov, 2002; Krenkel and Tacke, 2017; Tripathi et al., 2018; Gu et al., 2021). Receptor interacting protein kinase 3 (RIP3) signaling, which is regulated by gut microbiota and endotoxin translocation, is also key to macrophage secretion proinflammatory agents (Zhang et al., 2020; Zhang et al., 2021b). Although physiologic doses of LPS are essential for the development of both immunity and tolerance (Chou et al., 2015; Zhou W. et al., 2022), excessive endotoxin translocation due to gut dysbiosis can induce the pathogenic activation of hepatic macrophages. Such aberrant activation is believed to induce deleterious inflammatory processes in many liver diseases, such as nonalcoholic fatty liver disease (NAFLD) (Liu et al., 2015; Wesolowski et al., 2017; Hegazy et al., 2020) and alcoholic liver disease (ALD) (Inokuchi et al., 2011; Szabo, 2015; Bajaj, 2019). In addition, the translocation of microbial DNA contributes to liver inflammation. Some subsets of hepatic macrophages are essential barriers to clear the enrichment of microbial DNA, whereas obesity can reduce and weaken this barrier (Luo et al., 2021; Luo et al., 2022).

Some microbial metabolites produced by probiotics also possess the ability to regulate the inflammatory activation of macrophages. Generally, metabolites with anti-inflammatory properties, such as SCFAs and indole derivatives, can improve gut dysbiosis and intestinal barriers, thus inhibiting endotoxin translocation-induced activation of hepatic macrophages (Bao et al., 2020; Wang Y. et al., 2021; Xia et al., 2022). Specifically, indole treatment can inhibit proinflammatory activation of hepatic macrophages in a manner dependent on 6-phosphofructo-2-kinase/fructose-2 and 6-biphosphatase3 (PFKFB3) (Ma et al., 2020). Treatment with SCFA was found to alter macrophage phagocytosis in other tissues, such as the lungs and brain, leading to the regulation of inflammation (Trompette et al., 2014; Erny et al., 2021).

The microbial interventions which can exert influence on hepatic macrophage and inflammation-associated liver diseases are concluded in Table 1. Subsequent sections of this review will concretely describe the crosstalk between gut microbiota and liver macrophages in various inflammation-related liver diseases. Findings have suggested that targeting hepatic macrophages may have therapeutic potential in the treatment of microbial diseases.

Evaluation of the gut-liver axis has shown that inflammatory responses in the liver are a common but troublesome health problem due to various external chemical agents, such as alcohol, lipids, and drugs, as well as invasion by gut micro-organisms. Hepatic macrophages are a key player in liver homeostasis and responses to inflammation, as well as having close relationships with gut microbiota. Hepatic macrophages can regulate gut-derived inflammatory signals and maintain immune tolerance under physiologic conditions. However, disruption of the intestinal barrier due to dysbiosis aggravates the translocation from gut-derived inflammatory signals. This aberrant exposure induces an excessive proinflammatory phenotype in macrophages, thereby contributing to inflammation-related liver diseases. Thus, microbial interventions, such as reducing bacteria load with antibiotics or improving intestinal barrier with pre/probiotics, can indirectly alleviate the activation and infiltration of hepatic macrophages. Nevertheless, the clinical ability of microbial interventions to regulate endotoxin translocation remains unclear in some cases. Additional clinical trials of microbial interventions in patients with established liver inflammation are needed. In addition, several microbial metabolites have exhibited the potential to directly suppress inflammatory signaling or induce macrophage polarization toward the anti-inflammatory phenotype (e.g., M2 cells). Regulation of the inflammatory phenotype of macrophages is a potent target for microbial intervention, especially in chronic inflammatory responses. Figure 2 concludes the main pathways.

In conclusion, recent studies have indicated the importance of gut microbiota signals on the inflammatory phenotype in hepatic macrophages. Crosstalk between hepatic macrophages and gut microbiota is a promising target to regulate inflammatory responses and alleviate related liver diseases.