Mini review
Shaping macrophages function and innate immunity by bile acids: Mechanisms and implication in cholestatic liver diseases

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Summary

The liver is selectively enriched in innate immune cells, macrophages (Kupffer cells), natural killer, and natural killer T cells. These cells release an array of mediators with cytotoxic, pro- and anti-inflammatory, angiogenic, fibrogenic, and mitogenic activity that function to fight infections, limit tissue injury, and promote wound healing. The diverse activity of macrophages is mediated by distinct subpopulations that develop in response to signals within their microenvironment. Understanding the mechanisms and role of the microenvironment contributing to modulation of macrophage populations is crucial for comprehension of the pathophysiology of liver injury in diverse conditions. Several studies initiated in the 1990s have shown that bile acids modulate innate and adaptive immunity. In the last decade, bile acids turned into hormones and signalling molecules involved in many metabolic and inflammatory processes. Biological properties of bile acids are thought to be mediated mainly through activation of the nuclear receptor FXR, the membrane receptor TGR5, as well as PK, ERK, MAP kinases signalling pathways. FXR and TGR5 agonists are currently under development for clinical purpose. This review analyses the mechanisms involved in the immunomodulatory effects of bile acids on the macrophage and discuss their implications in the pathophysiology of cholestasis, primary biliary cirrhosis and primary sclerosing cholangitis.

Introduction

The liver is selectively enriched in innate immune cells, macrophages (Küpffer cells), natural killer, and natural killer T cells. These cells release an array of mediators with cytotoxic, pro- and anti-inflammatory, angiogenic, fibrogenic, and mitogenic activity that function to fight infections, limit tissue injury, and promote wound healing. The diverse activity of macrophages is mediated by distinct subpopulations that develop in response to signals within their microenvironment. Understanding the mechanisms and role of the microenvironment contributing to modulation of macrophage populations is crucial for comprehension of the pathophysiology of liver injury in diverse conditions. Several studies initiated in the 1990s have shown that bile acids modulate innate and adaptive immunity [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. In the last decade, bile acids turned into hormones and signalling molecules involved in many metabolic and inflammatory processes. Biological properties of bile acids are thought to be mediated mainly through activation of the nuclear receptor FXR, the membrane receptor TGR5, as well as PK, ERK, MAP kinases signalling pathways. FXR and TGR5 agonists are currently under development for clinical purpose.

This review analyses the mechanisms involved in the immunomodulatory effects of bile acids on the macrophage and discuss their implications in the pathophysiology of primary biliary cirrhosis.

Section snippets

Macrophages diversity and plasticity

Macrophages are professional phagocytic cells that play crucial roles in host defense, regulation of the inflammatory response and maintenance of tissue homeostasis [12], [13]. Macrophages present striking heterogeneity in their functions. Some functions are pro-inflammatory, such as the release of reactive toxic species or cytokine and chemokine production. These functions are crucial for efficient elimination of pathogens and communication with other components of the immune system. In

Macrophages recognize the presence of pathogens through Pattern Recognition Receptors (PRRs)

PRRs detect conserved molecular structures of pathogens, the Pathogen Associated Molecular Patterns (PAMPs). Recognition of PAMPs by PRRs activates signaling cascades that initiate innate immunity, which constitutes the first line of defense against microorganisms and represents an important interface with adaptive immunity [19]. The best-known family of PRRs is the Toll-like Receptor (TLR) family, comprising 10 members of membrane-bound receptors in humans. TLR4 recognizes lipopolysaccharide

Bile acids PKA-dependently reduce pro-inflammatory capability of human macrophages

In a recent study, Haselow et al. [20], afford new data on the mechanisms involved in the immunoregulatory effects of bile acids in human macrophages. Whereas IL-4 robustly induced alternative activation of human macrophages, with a clear switch toward M2-type macrophages, stimulation with taurolithocholate (TLC) did not result in an M2-like expression pattern in terms of cytometry. Basal and LPS-stimulated phagocytic activity was significantly decreased in the presence of TLC. The LPS-induced

Bile acids PKA-dependently induce a switch of the IL-10/IL-12 ratio in human macrophages

Evidence indicates that cAMP-mediated activation of C-AMP Response Element-binding element (CREB) interferes with the transcriptional activation of NF-κB-driven genes by competing with the p65 NF-κB subunit for the transcriptional cofactor CREB binding protein. Expression of CREB-dependent genes is up-regulated upon binding of activated CREB toward respective target sequences. In line with these considerations, bile acids PKA-dependently induced phosphorylated (activated) CREB in primary human

TGR5 mediates human macrophage function and plasticity

Hydrophobic bile acids such as TCDC inhibit proliferation of lymphocytes, production of inflammatory cytokines such as interleukin-1, IL-6 and tumour necrosis factor-alpha (TNF-alpha), humoral response and interferon signalling pathway [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. The identification of the TGR5 receptor, as a cell membrane G-protein-coupled receptor specific for bile acids [23], has improved our knowledge on the cellular pathways involved in these findings. TGR5

TGR5-independent immune-mediated effects of bile acids

All the effects of bile acids on the immune response are probably not only mediated by the activation of TGR5. Indeed, TGR5 is not expressed on lymphocytes. The effects could be in addition mediated by the activation of nuclear receptors in lymphocytes. Most nuclear receptors, including FXR, PPARalpha/beta/delta, PXR, GR, TR2, TR4 and TLX are expressed in highly purified CD4, CD8, CD19, and CD14 cells [29]. FXR−/− mice spontaneously develop hepatic damage associated with a marked increase in

Implications of macrophage function deficiency in cholestasis, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)

The ingestion of opsonized bacteria or pathogens is impaired in severe cholestasis whatever its cause. This failure account for the sepsis and further aggravation of cholestasis in this setting.

In PBC and PSC, PAMPS accumulate in the bile ducts, interact with TLRs and further aggravate inflammation [34]. The high expression of TGR5 in biliary epithelial cells and the anti-inflammatory property of the receptor suggested that TGR5 may play a role in the pathogenesis of these biliary diseases.

Conclusion

Hydrophobic bile acids and TGR5 activation are thus expected to exhibit two opposed effects in vivo. First, they could impair the removal of bacteria and pathogens accounting for their elimination into bile and, as in the case of severe cholestasis, promote sepsis. Second, by impairing clearance of apoptotic BEC they could promote autoimmune and humoral immunity (Fig. 3). Third, by blunting macrophages activation they could reduce the intense inflammatory cytokine production in the presence of

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

Glossary

Bile acids (or bile salts)
a family of steroids synthesized from cholesterol in the liver and in the gut by the micobiota. Bile acids have pleiomorphic properties mediated by microenvironment chemical-physical interactions, signalling pathways and sensing membrane (TGR5 receptor) and nuclear (FXR receptor) molecules.
CREB
cAMP response element-binding protein is a cellular transcription factor. After being phosphorylated upon the action of active PKA, it binds to DNA sequences called cAMP response

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