Inflammation in alcoholic and nonalcoholic fatty liver disease: friend or foe? (original) (raw)

. Author manuscript; available in PMC: 2017 Jun 1.

Published in final edited form as: Gastroenterology. 2016 Jan 27;150(8):1704–1709. doi: 10.1053/j.gastro.2016.01.025

More than 90-95% people with excessive alcohol drinking or obesity develop fatty liver, but only some (5-40%) undergo steatohepatitis, which is characterized with steatosis, hepatocellular injury (i.e. ballooning, Mallory-Denk body etc), and inflammation (e.g., infiltration of inflammatory cells, and upregulation of inflammatory mediators).1 Emerging evidence suggests that inflammation plays a key role in promoting the progression of steatohepatitis to cirrhosis and cancer; however, inflammation is also crucial for host defense against pathogen infection, removal of dead cells, and liver regeneration. This commentary discusses the multifaceted functions of inflammation in the pathogenesis of early versus advanced stages of alcoholic liver disease (ALD) or nonalcoholic fatty liver disease (NAFLD) , as well as systemic inflammatory response in the diseases.

Detrimental and Beneficial effects of inflammation

Infiltration of inflammatory cells is the hallmark of steatohepatitis in ALD and NAFLD. In the present paper, we mainly discuss the harmful and favorable functions of neutrophils, macrophages, and T cells. Due to the space limitation, the functional significance of other immune cells is not covered and many inflammatory mediators implicated in ALD and NAFLD are briefly summarized in Table 1.

Table 1.

Inflammation in ASH and NASH: friend or foe

Inflammatorycells Detrimental effects Beneficial effects
Neutrophils Promote hepatocyte injury and liver fibrosisby producing ROS, proteases, andinflammatory mediators Suppress bacterial infectionRemove debris and dead cellsPromote liver regeneration
Macrophages Cause hepatocyte injury by producing ROSand inflammatory mediatorsPromote liver fibrogenesis Promote liver regenerationRemove debris and dead cellsStimulate liver fibrosis resolution
Th1, Th2, Th17 Promote liver injury and inflammationStimulate liver fibrosis Inhibit bacterial infectionPromote liver regeneration
T reg cells Exacerbate bacterial infection in cirrhosis viaits immunosuppressive effect Ameliorate steatohepatitis via the inhibitionof immune responses
NKT cells Promote liver inflammation and injury Attenuate bacterial infection
NK cells Cause hepatocyte injury Inhibit tumor growthInhibit liver fibrosis
Inflammatory mediators *
LPS Activates macrophages to produceinflammatory mediators and subsequentlyinduce hepatocyte injury
TNF-α Induces injury in sensitized hepatocytesPromotes steatosis Promotes liver regenerationInduces acute phase responseSuppresses bacterial infection
IL-1β Induces hepatocyte injuryPromotes inflammation Induces acute phase response
IL-6 Promotes inflammationPromotes liver cancer cell growth Protects against hepatocyte apoptosisInduces acute phase responsePromotes mitochondrial DNA repairPromotes liver regenerationAmeliorates steatosisSuppress bacterial infection
IL-22 Promotes liver cancer cell growth but doesnot initiate liver cancer development Protects against hepatocyte injuryAmeliorates steatosisSuppress bacterial infectionSuppresses liver fibrosis
IL-17 Promotes hepatic neutrophil infiltrationPromotes liver fibrosis Suppresses bacterial infection
IL-8 Promotes hepatic neutrophil infiltration Attenuates bacterial infection via theactivation of neutrophils
Adiponectin Inhibits inflammationAmeliorates steatosisProtects against liver injuryReduces liver fibrosis
OPN Promotes hepatic neutrophil infiltration andliver injury at the early stage of ASH Prevent hepatic neutrophil infiltration andliver injury at the late stage of ASH
C3, C5 Exacerbate steatohepatitis Stimulate liver regenerationDecrease bacterial infection
MIF Aggravates inflammation via the induction ofchemokines and macrophage infiltration Ameliorates hepatocyte injury
MCP-1 Exacerbates steatohepatitis
Leptin Exaggerates liver fibrosis and inflammation Reduces steatosis

Macrophages

Macrophages represent the first line of defense against infection and injury of the tissue. Kupffer cells, a largest population of tissue macrophages in the body (~80%), are liver resident macrophages which fulfill important roles of clearing pathogen-associated molecular patterns (PAMPs) and translocated gut bacteria present in portal blood. In early and chronic phases of ALD and NAFLD, which are not presented with obvious hepatocellular necrosis, macrophage infiltration along with lymphocytes is a prominent feature, and elimination of these macrophages prevents experimental ALD2 and NAFLD,3 suggesting their pathogenic role. The prevailing notion is that proinflammatory cytokines, oxidative and nitrosative stress elicited by activated macrophages, are damaging to hepatocytes that are sensitized by their organelle stress (ER, mitochondrial, lysosomal) in ALD and NAFLD. In fact, many experimental interventions targeted to macrophage-based mechanisms such as antagonism for LPS signaling, TNF-α, and NADPH oxidase, ameliorate fatty liver and inflammation. These findings stimulated translational efforts as exemplified by anti-TNF-α therapies for patients with alcoholic hepatitis (AH). However, these clinical trials have met disappointing outcome.4 The lesson learned from this experience is that the efficacious modality shown in early experimental ALD cannot be directly translatable to severe ALD such as AH where inflammation is more severe and has a different cell type and meaning.

In asymptomatic early alcoholic steatohepatitis (ASH) or non-alcoholic steatohepatitis (NASH), M1 proinflammatory macrophage activation is a dominant feature which may serve as a reasonable therapeutic target. M1 macrophages seen in the early phase of ASH are mostly infiltrating macrophages derived from blood monocytes,5, 6 whereas Kupffer cells may not exhibit M1 phenotype.5 Thus heterogeneous populations of hepatic macrophages (HM) may have different functional significance. In AH, neutrophilic infiltration is a salient feature and HM may be defective in their phagocytic or pinocytic activity, particularly in decompensated AH. This defective HM phenotype is also evident in NASH patients and experimental model.7 In addition to phagocytosis, HM may play a role in stimulating the proliferation of hepatocytes and progenitor cells in AH patients.8 In animal models, depletion or impairment of HM due to deficiency in complement C3a and/or C5a attenuates liver regeneration. The stimulatory effect of activated HM on liver regeneration is likely mediated by releasing co-mitogens (TNF-α, IL-6), ICAM-1, TNF-like weak inducer of apoptosis (TWEAK), which prime/promote hepatocytes and/or liver progenitor cells for regeneration.9 However, liver regeneration may be suppressed in AH and NASH due to defective macrophage activation, and we may need to consider restoring this macrophage function to stimulate regeneration for the treatment of these patients.

Another important consideration is inflammatory response of macrophages to gut bacterial translocation which is germane to the pathogenesis of ASH and NASH. Neutrophils are known to quickly transmigrate in response to infection; while HM may play an important role in promoting transmigration of neutrophils in ASH and NASH by releasing cytokines and chemokines, and assisting neutrophils’ bactericidal function by trapping bacteria via the binding of lectins and adhesion molecules expressed on their surface. Upon controlling infection, macrophages normally eliminate neutrophils to resolve inflammation. However, in AH, HM with defective phagocytic activity may not efficiently clear bacteria, necessitating intense neutrophil infiltration which in turn may persist due to inefficient clearance neutrophils by defective macrophages. If so, our therapeutic approach has to be directed to restore macrophage function rather than suppressing neutrophil inflammation.

Phenotypic regulation of macrophages is critical for wound healing response. Typically, M1 activation in response to hepatocellular injury is followed by M2 macrophages which promote scar formation. A regenerative response may require migration of monocyte-derived macrophages which is Notch-1 dependent5 and mediated by Kupffer cells.10 Thus proper and timely switch of macrophage cell fate regulation is key to uneventful wound healing, and the basic knowledge on molecular mechanisms underlying this regulation is essential for understanding dysregulated wound healing in ASH and NASH.

Neutrophils

It is generally believed that infiltrated neutrophils promote ALD progression by inducing hepatocyte injury via the generation of reactive oxygen species, release of proteases, and production of pro-inflammatory mediators.11 Several studies from experimental models have revealed that blockade of several inflammatory mediators implicated in neutrophil infiltration or deletion of neutrophils, ameliorates alcoholic liver injury in mouse models of early steatohepatitis, confirming neutrophils promote hepatocyte injury.12 In severe AH, hepatic expression of a wide variety of chemokines (e.g.: IL-8, CXCl1, CXCL5, CXCL6, CXCL10) and pro-inflammatory cytokines (e.g.: IL-1, IL-17) that promote neutrophil infiltration is markedly elevated and some of them correlate with AH disease severity, suggesting neutrophils may exacerbate AH.13 However, a recent study reported that the AH patients with more neutrophil infiltration had better outcome than those with less neutrophil infiltration.14 This association may be related to neutrophil suppression of bacterial infection and stimulation of liver regeneration. The worse outcome in some AH patients with a lower number of neutrophils may reflect poor immune defense system and increased susceptibility to bacterial infection in these patients as also discussed for defective macrophages above. Similarly, phagocytic functions of neutrophils against bacteria are also often impaired in AH patients, which may contribute to the increased susceptibility to bacterial infection despite elevated neutrophil counts. Indeed, septicemia is one of the most common complications of AH.

In human NAFLD, lobular inflammation (neutrophil infiltration), which is routinely assessed for the diagnosis of disease is believed to play an important role in promoting hepatocyte damage. However, how neutrophil infiltration affects NAFLD progression has not been characterized. Recently, several studies reported that different types of inflammatory cells including neutrophils accumulate within portal tracts and correlate with liver fibrosis and ductular reaction in human NAFLD.15 Production of IL-17 is probably one of mechanisms that neutrophils promote inflammation in NAFLD.15 More extensive future studies are required to define the functional significance of neutrophils in the pathogenesis of NAFLD.

T Lymphocytes

Accumulating evidence suggests that the oxidation of ethanol results in the formation of protein adducts that can serve as neo-antigens to induce clonal T cell expansions, thereby inducing ALD.16 Similarly, significant infiltration of T cells is also detected in the patients with NAFLD and correlates with the disease severity, suggesting that T cells promote the progression of NAFLD.15 The data from the study of experimental NASH models suggest that oxidative stress activates adaptive immune response and results in T cell activation and liver injury.17 Although the exact functions of T cells in the pathogenesis of ALD and NAFLD remain unknown, it is generally believed that activation of Th1, Th2, and Th17 cells contribute to steatohepatitis by producing pro-inflammatory mediators or directly killing hepatocytes; whereas activation of T regulatory cells ameliorates steatohepatitis via the inhibition of immune responses. Finally, activation of T cells is well known to play an important role in antibacterial adaptive immune responses; but this antibacterial function of T cells is impaired in patients with AH due to overexpression of immune inhibitory receptors, serving as another reason for the increased susceptibility to bacterial infection in these patients.18

Systemic inflammatory response in ALD and NAFLD

Besides hepatic inflammation discussed above, systemic inflammatory response syndrome (SIRS) is crucial clinical component of severe ALD (e.g. AH, cirrhosis) and NAFLD (e.g. cirrhosis), inducing disease progression, extrahepatic complications, and multiorgan failure.19 Many of these patients have bacterial infection, which is an important factor inducing SIRS. In the absence of bacterial infection, the damage-associated molecular pattern (DAMPs) released by hepatocyte necrosis and PAMPs derived from gut bacteria are likely responsible for the SIRS generation. SIRS not only plays a critical role in host defense response against bacterial infection but also aggravates liver injury and induces multiorgan failure. Thus, a new therapeutic approach needs to be developed to selectively target SIRS by augmenting its anti-bacterial defense but attenuating its harmful inflammatory functions for the treatment of severe forms ALD and NAFLD.

Inflammation in early versus late stages of diseases

As elaborated above and summarized in Table 1, multiple inflammatory cells and inflammatory mediators play both injurious and favorable roles in the pathogenesis of ALD and NAFLD. The injurious functions include induction of hepatocyte injury and liver fibrosis; whereas the beneficial functions include stimulation of liver regeneration and defense against bacterial infections. The partition between detrimental and beneficial functions is influenced by differential expression of individual inflammatory mediators or the type of inflammatory cells present, and most importantly the stage of disease. For example, IL-22 generally promotes liver repair whereas IL-17 mediates liver injury, and the expression profiles of these mutually antagonistic cytokines shift in favor of IL-17 in advanced stage.20 In addition, inflammation may also have opposed functional roles in early versus late stages of disease. In early ALD and NAFLD, where bacterial infection is minimal and liver regeneration is not essential because of mild injury, inflammation contributes to liver injury. In late stage where bacterial infection often ensues due to a combination of severely impaired gut barrier and defective inflammatory cells, inflammation becomes a key driver for both bacterial defense and liver regeneration.

Conclusions and Future Directions

In summary, inflammation plays pleiotropic roles in controlling the progression of steatohepatitis via its detrimental and beneficial effects (Table I and Figure 1). To understand an interplay of these opposed functions in evolution of ASH and NASH and to better define therapeutic approaches, the following points should be addressed in the future.

Figure 1.

Figure 1

Detrimental and beneficial effects of neutrophils and macrophages, two major types of inflammatory cells in ALD and NAFLD. Both cell types play dual roles in the pathogenesis of ALD and NAFLD. In general, the proinflammatory functions of macrophages and neutrophils are activated in ALD and NAFLD, while their phagocytic functions against bacterial infection are suppressed in severe ALD and NAFLD.

Supplementary Material

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Acknowledgments

The authors apologize to the colleagues whose work was not mentioned or cited in this paper because of space constraints.

Abbreviations

AH

alcoholic hepatitis

ALD

alcoholic liver disease

ASH

alcoholic steatohepatitis (ASH)

DAMPs

damage-associated molecular pattern

HM

hepatic macrophages

NAFLD

nonalcoholic fatty liver disease

NASH

non-alcoholic steatohepatitis

PAMPs

pathogen-associated molecular patterns

SIRS

systemic inflammatory response syndrome

Footnotes

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References

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Supplementary Materials

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