Alcoholic cirrhosis-associated immune dysfunction: What does it imply for us?

1

Introduction

With increasing affluence in densely populated regions and a rising trend in alcohol consumption, global per capita alcohol consumption is projected to reach 7.6 liters by 2030, driven by accelerated economic development [1]. Women exhibit heightened susceptibility to alcohol-induced liver injury at all consumption levels compared to men [2,3]. Even at lower consumption levels, specifically between 12 and 24 grams per day, an elevated risk of developing cirrhosis has been observed compared to those who abstain from alcohol [4]. Globally, alcohol consumption is the third leading cause of liver cirrhosis, following chronic hepatitis infection and non-alcoholic fatty liver disease (NAFLD), and it is the primary cause of chronic liver disease in approximately 45% of patients at risk for acute-on-chronic liver failure (ACLF) [5].

Alcohol is primarily metabolized in the liver, where chronic consumption promotes inflammation and negatively impact immune cell function. Alcoholic liver disease develops through several stages, beginning with hepatic steatosis, and, in some individuals, gradually progressing through alcoholic hepatitis, culminating in alcoholic cirrhosis [6]. Alcoholic cirrhosis is characterized by end-stage fibrotic restructuring of the liver parenchyma, which originates from chronic and persistent alcohol-induced injury that activates hepatic stellate cells and disrupts extracellular matrix homeostasis. Cirrhosis-associated immune dysfunction (CAID) is a multifactorial condition characterized by systemic immune dysfunction, marked by impaired clearance of circulatory cytokines, bacteria, and endotoxins [7,8]. This pathological process is highly dynamic and considerably progressive which includes two key pathways, that is, systemic inflammation and immunodeficiency, whose magnitude depends on the stage of cirrhosis and the presence of detrimental conditions and perturbations such as bacterial infections [9]. CAID originates from the compensated cirrhosis, deteriorates across the decompensated stage and reaches its peak in the context of ACLF [9,10]. Alcohol abstinence alone fails to fully reverse intestinal barrier damage or completely arrest cirrhosis progression. Therefore, it is imperative to elucidate the mechanisms underlying immune dysfunction among patients with alcoholic cirrhosis and to develop effective strategies concerning its management. This narrative review focuses on versatile aspects concerning the immune dysfunction in the scenario of alcoholic cirrhosis.

2

Alcoholic cirrhosis and systemic inflammation

Alcohol abuse has been linked to small intestine bacterial overgrowth, shifts in the composition of gut microbial and fungal communities (referred to intestinal microbial dysbiosis) [11], increased microbial translocation, and obvious damage to the gut barrier. These alterations, mediated via the liver-gut axis, drive the pathogenesis of liver damage, cirrhosis, and systemic inflammation, while demonstrating significant associations with the severity of psychiatric manifestations, including anxiety and depression [11]. The colon harbors the most abundant microbial community [12]. Alcohol abuse induces an increase in intestinal permeability to macromolecules [13], while elevated IgA levels exacerbate endotoxin translocation through compromised gut barrier integrity [14,15]. In this regard, the increased systemic translocation of bacterial products, such as lipopolysaccharide (LPS) and peptidoglycan (PGN), has been correlated with elevated levels of inflammatory markers in the plasma. These bacterial products enter the liver via the portal vein, in consequence, activate Kupffer cells and exacerbate or boost the inflammatory cascade. Serum levels of anti-Saccharomyces cerevisiae immunoglobulin G antibodies, a biomarker suggestive of systemic immune response against fungi and fungal products, are elevated in patients with alcoholic cirrhosis [16]. Additionally, alterations in fungal and viral populations are recognized as important contributors to the progression of alcoholic cirrhosis.

Endotoxemia manifests more severely in alcoholic cirrhosis than in cirrhosis of other etiologies [17]. Alcohol binge resulted in a rapid increase in serum endotoxin and 16S rDNA, a marker of bacterial translocation from the gut [3]. The molecular features of alcohol-induced Toll-like receptors (TLR) tolerance and sensitization are well characterized, evident by downstream components of TLR-induced signaling cascades. These include the activation of IRAK-M, IRAK1/4, Bcl-3, and nuclear factor-kappa B (NF-κB), all of which are responsible for proinflammatory cytokine production, resulting in chronic low-grade systemic inflammation [11]. Pathogen-associated molecular patterns (PAMPs) from the gut and damage-associated molecular patterns (DAMPs) from the injurious hepatocytes orchestrate a proinflammatory milieu by activating inflammasome formation [18], significantly increasing NLRP3 and IL-1β protein levels in addition to caspase-1 activity. Studies have shown that, inhibition of spleen tyrosine kinase in mice significantly reduces serum IL-1β levels and caspase-1 activation in the liver [19]. NLRP6 and NLRP12, which are associated with enhanced NF-κB activation, reduce alcohol-induced CCL20 expression and hepatic stellate cell (HSC) activation [20]. sCD137, known for its inflammatory properties, has been reported at higher levels in both obese individuals [21,22] and patients with alcoholic liver disease [23].

Liver inflammation is triggered and sustained by the secretion of cytokines and chemokines from innate immune cells, which express diverse pattern recognition receptors (PRRs), including cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signaling pathway [24,25]. Endoplasmic reticulum (ER) stress in response to alcohol stimulation initiates STING activation and interferon regulatory factor 3 (IRF3) phosphorylation, transmitted through gap junctions between hepatocytes, which in turn leads to intense inflammatory response [26,27]. cGAS is a critical cytosolic DNA sensor catalyzing the synthesis of cGAMP from ATP and GTP and activating type I interferons (IFNs) via the ER-resident adaptor protein STING [28,29], which subsequently instigates the transcription factors NF-kB and IRF3 via the TANK-binding kinase 1 (TBK1) [28,29] to harness inflammation activities (Figure 1). In summary, the cGAS-STING pathway is a fundamental mechanism for detecting cellular infections and damage, leading to innate immune activation and an effective defense against various pathogens.

Figure 1.

cGAS-STING signaling pathway. cGAS catalyzes the synthesis of cGAMP from ATP and GTP and activates IFNs via the ER-resident adaptor protein STING, which subsequently instigates the transcription factors NF-kB and IRF3 via the TBK1 to harness inflammation activities.TBK1: TANK-binding kinase 1; IRF3: Interferon regulatory factor 3; NF-κB: Nuclear factor kappa-B; TNF: Tumor necrosis factor; IFN: Interferon.

A significant imbalance exists between proinflammatory and anti-inflammatory responses in patients with alcoholic cirrhosis. Excessive proinflammatory responses, such as the release of tumor necrosis factor-α (TNF-α) and IL-6, along with an immunosuppressive status characterized by increased expression of IL-10, contribute to persistent inflammation and immunosuppression responsible for the risk of infections. Studies have shown that serum IL-6 levels correlate positively with the severity of alcoholic cirrhosis, although IL-6 plays a protective role in animal models [30]. In this regard, IL-6 and IL-22 activate signal transducer and activator of transcription 3 (STAT3) dimers to upregulate the translation concerning multiple anti-apoptotic, antioxidant, and mitochondrial DNA repair genes. Moreover, inhibition of lipid metabolism genes like SREBP-1c [31,32] improves steatosis, protects the liver from ethanol-induced damage, and facilitates liver regeneration [33]. However, IL-10 has also been reported to suppress innate immune activation and hepatoprotective cytokines [34], whose deficiency in mice enhances liver regeneration. Collectively, the pathophysiological consequence is defined by the balance and homeostasis between proinflammatory and hepatoprotective cytokines (Figure 2).

Figure 2.

Alcohol and systemic inflammation. Alcohol causes excessive growth of intestinal microbiota, secreting SCFAs and tryptophan metabolites. LPS and PGN are activated by the intestinal mucus layer through M cells and type 3 natural lymphocytes to eventually produce IL-22 acting on antibacterial molecules. At the same time, plasma cells bind pathogenic bacteria through IgA. DCs: Dendritic cells; LPS: Lipopolysaccharides; PGN: Peptidoglycan; SCFAs: Short-chain fatty acids; 3-ILA: (3-Indolyl) Lactic Acid; 3-IAC: 3-Indoleacrylic acid; PIgR: Polymeric immunoglobulin receptor.

3

Alcoholic cirrhosis and immune deficiency

Despite the chronic inflammatory response commonly observed in alcoholic cirrhosis, the immune system of affected patients also exhibits a state of immunosuppression. Alcohol’s direct toxicity and the inflammatory milieu collectively impair immune cell function, evident by significant suppression of phagocytes, T cells, and natural killer (NK) cell activities. This immunosuppressive state increases the patient's susceptibility to exogenous pathogens. A standard definition of immunodeficiency is currently lacking, but it can be arbitrarily identified as the presence of cellular abnormalities regarding immune system that impair its effector function and lead to immune paralysis. The immunodeficiency in cirrhosis is secondary to two main factors: structural distortion of the hepatic parenchyma, and functional impairment of circulating immune cells.

Within the hepatic sinusoidal system, endothelial cells form fenestration lacking a continuous basement membrane [35], and the blood flow velocity is notably curtailed, fostering an environment abundant in antigens [36]. These endothelial cells encounter antigen-presenting cells and lymphocytes, therefore a cascade of highly complex immune reactions is triggered, which plays a crucial role in modulating immune balance and determining processes associated with liver cirrhosis [37,38] (Table 1).

Table 1.

Cells involved in the immune response.

Cell type	Alcoholic cirrhosis
Innate immune system
Neutrophils		Released IL-1β and recruited NKT cells; Adhered to the vascular endothelium;
Monocytes/macrophages		Reduced monocyte HLA-DR expression and declined TNF-α production; Increased ROS; Assembled inflammasomes and released proinflammatory cytokines;
DCs		Impaired antigen presentation;
NKs		Promoted the production of interferon-gamma and IL-4;
MCs		Increased numbers promote fibrosis formation;
Adaptive immune system
T cells		Increased the proportion of Tregs; Halted the function of CD4+ and CD8+ T cells;
B cells		Reduced B cell populations;
MALT cells		Reduced and hyperactivated MALT cell populations;

CD4+, Cluster of Differentiation 4 positive; CD8+, Cluster of Differentiation 8 positive; DCs, Dendritic cells; HLA-DR, Human leukocyte antigen DR isotype; IL-1β, Interleukin-1 beta; IL-4, Interleukin-4; MALT, Mucosa-associated lymphoid tissue; MCs, Mast cells; NKT, Natural killer T cells; NKs, Natural killer cells; ROS, Reactive oxygen species; Tregs, Regulatory T cells; TNF-α, Tumor necrosis factor alpha.

3.1

Neutrophils

Neutrophils have served as the primary immune cell type in the early stage of the inflammatory responses [39]. Patients with alcoholic cirrhosis exhibit reduced neutrophil counts and impaired formation of neutrophil extracellular traps [40], a dysfunction characterized by higher susceptibility to bacterial infections [41]. Alcohol consumption and endotoxin aggravate the interaction between neutrophils and liver sinusoidal endothelial cells via the CD11b/ICAM-1 pathway [25]. This reciprocal effect further activates Kupffer cells (KCs), giving rise to the release of IL-1β and the recruitment of invariant NKT cells, which promotes neutrophil accumulation and contributes to the progression of alcoholic cirrhosis.

Cytokines can also harness the adhesion of neutrophils to the vascular endothelium, allowing the neutrophils to move along the vessel walls and migrate towards the infection site with the purpose of engulfing pathogen [42]. The initiation of this process depends on the binding of activated platelets to P-selectin glycoprotein ligand-1, a protein mimicking an antenna on the surface of neutrophils in the bloodstream [43,44]. It has been shown that neutrophil phagocytic capacity and ROS burst may predict the development of infection, organ dysfunction, and 90-day survival in decompensated cirrhosis [45,46].

3.2

Monocytes/macrophages

Monocyte dysfunction is a prominent hallmark of immune paralysis. Monocyte dysfunction has been defined as reduced monocyte HLA-DR expression [47] and declined ex-vivo endotoxin (LPS)-induced TNF-α production [48–52]. PGE2, via its EP4 receptor, downregulates monocyte TNF and IL-6 production in decompensated cirrhosis and represses monocyte HLA-DR expression. There is an opportunity to address alcohol dependence by reducing inflammatory cytokines.

Impaired phagocytic capacity pertaining to resident macrophage has been identified in patients with cirrhosis (primarily attributable to alcoholism) compared to healthy controls, which is positively correlated with liver disease severity, accounting for the development of infection and mortality [43,44]. A study demonstrated that TGF-β, an M2-associated profibrotic factor, is highly expressed in the livers of patients with alcoholic hepatitis, involving various M2 macrophage subtypes (M2a, M2b, and M2c) [53]. In patients undergoing alcohol withdrawal, macrophage infiltration is reduced, while M2 macrophage polarization increases in the subcutaneous adipose tissue. Additionally, studies have unveiled that inhibiting TLR2 expression and promoting TLR3 expression in Kupffer cells can activate STAT3 and induce IL-10 production, fostering the polarization of M1 to M2 macrophages. Macrophage polarization is regulated by the activation of multiple interconnected cellular signaling pathways. In this regard, key pathways involved in inflammation-related polarization comprise the Janus kinase (JAK)/STAT pathway, the NF-κB pathway, and the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB)/Akt pathway [48]. Consequently, the development of pharmacological treatments targeting specific signaling pathways offers significant potential as therapeutic avenues in the future.

Neutrophil-derived ROS instigate the transition from inflammatory to reparative macrophages. Activation of TLR-3 can induce KCs and HSCs to produce IL-10, whereas TLR4 enhances the transmission of inflammatory signals via calcium-dependent signaling pathways [54,55]. The inflammatory activation of macrophages contributes to the assembly of inflammasomes and the subsequent release of proinflammatory cytokines, thereby partially responsible for the pathogenesis of alcoholic cirrhosis [56,57]. Fas is an apoptosis-related receptor to favor early ethanol-induced M1 macrophage polarization and inflammation. Moreover, inhibition of M2 polarization reduces TGF-β production and in consequence, inhibits relevant profibrotic alterations and actions [58].

3.3

DCs

Dendritic cells (DCs) constitute two distinct subsets, conventional DCs and plasmacytoid DCs. Conventional type 1 DCs have been proved to mitigate alcohol-induced liver damage in the murine models by maintaining the local abundance of probiotic Lactobacillus mucosus [59]. In addition, chronic alcohol consumption is associated with the distribution, immunophenotype, and secretion of inflammatory mediators [60]. Alcohol consumption triggers DCs dysfunction, impairs antigen presentation, and disrupts the initiation of adaptive immune response. However, no studies have investigated the effects of long-term alcohol consumption on DCs in mice or human beings experiencing alcoholic cirrhosis.

3.4

NKs

Patients with alcoholic cirrhosis exhibit reduced NK cell activity alongside decreased NK cell numbers, weakening the body's antiviral defenses. This constructs a conducive environment suitable for the development of viral hepatitis in combination with alcoholic cirrhosis. Alcohol activates Type I NKT cells through direct recognition of specific lipids or TLR ligands, as well as by indirect stimulation via cytokines. This process in turn promotes the production of IFN-gamma (IFN-γ) and IL-4, all-trans retinoic acid through the retinoic acid receptor γ signaling [61]. In contrast, Type 2 T cell receptor lineage NKT cells exhibit immunomodulatory properties in the murine models challenged by chronic alcohol consumption. Sulfatide-mediated activation of Type II NKT cells can be considered to effectively halt alcoholic liver disease progression [61].

3.5

MCs

The presence of mast cells (MCs) expressing tryptase and chymase is strongly linked to the magnitude of fibrosis [62]. The number of MCs in the liver increase in the circumstance of alcoholic cirrhosis. These cells may contribute to the development of hepatic fibrosis indirectly via the release of substances facilitating cirrhosis or directly by secreting proteins to form the extracellular matrix [63]. In the liver, MCs can exhibit immunomodulatory effects on other immune cells, thereby enhancing or suppressing the initiation, magnitude, and/or duration of immune activities within the liver, preventing diminished hepatobiliary functions during disease progression, or by acting as a first effector cell in an innate response to encounter antigens [64,65] (Figure 3).

Figure 3.

Innate immune system. Including reduced neutrophil counts and impaired formation of neutrophil extracellular traps, monocyte dysfunction, the assembly of inflammasomes, reduced NK cells activity alongside decreased NK cell numbers, and an increase in the number of MCs. NKs: natural killer cells; MCs: mast cells; KCs: Kupffer cells; HLA-DR: human leukocyte antigen.

3.6

T Cells

During alcohol-induced liver injury, T cell proliferation and activation are considerably impaired, particularly with an increase in the proportion of regulatory T cells (Tregs), which weakens the anti-inflammatory response. Concurrently, the function of CD4+ and CD8+ T cells is to some extent compromised, diminishing the liver's ability to eliminate infections. Unlike the innate immune response, which can be triggered by any antigen, adaptive immunity is specific to certain antigen. Tregs limit and suppress immune responses to prevent excessive immune activation and autoimmune reactions [66,67]. T helper cells (CD4+) regulate the activity of other immune cells by generating and secreting various cytokines. Th1 cells activate macrophages or CD8+ cells to instigate a cell-mediated immune response against intracellular pathogens, primarily exerting their influences through the release of IFN-γ [68]. Th2 cells, on the other hand, are responsible for a humoral immune response against extracellular pathogens through proteins produced by B cells, primarily mediated by a range of interleukins, some of which have anti-inflammatory properties [69]. Additionally, Th17 cells, a subset of T helper cells, are characterized by their production of interleukin-17 and primarily functioning to defend against pathogens at epithelial and mucosal barriers [70].

3.7

B Cells

In patients with alcoholic cirrhosis, B cell dysfunction gives rise to insufficient antibody production, negatively impacting the body's defense against bacterial and viral infections, thereby increasing the risk of spontaneous bacterial peritonitis (SBP). The B cell populations are significantly reduced in the context of alcoholic cirrhosis [71–74], resulting in diminished antigen-specific antibody responses [60], although total levels of IgA, IgG, and IgM are elevated overall [75,76].

3.8

MALT cells

In cirrhosis, the gut-associated lymphoid tissue is highly active due to sustained bacterial translocation from the gut on account of increased intestinal permeability [77]. Local inflammation alters intestinal tight junction protein expression and barrier function [78–80]. Intestinal microbial dysbiosis and bacterial translocation are also expanded by depressed expression of antimicrobial peptides, including regenerating islet-derived 3 beta and gamma [81–84]. Mucosa-associated lymphoid tissue (MALT) cells are reduced in number, hyperactivated, and exhibit functional defects concerning antimicrobial cytokine and cytotoxic responses [17,85]. These alterations are exacerbated in patients experiencing alcoholic cirrhosis, which is in alignment with the dynamic course of CAID.

Immune system imbalance in alcoholic cirrhosis impairs the ability of organ to clear harmful metabolic byproducts, such as ammonia, leading to its accumulation in the bloodstream and subsequent effects on the central nervous system, triggering hepatic encephalopathy [86]. Ammonia impairs neutrophil function by reducing chemotaxis and phagocytosis while increasing spontaneous oxidative burst, which has been linked to 3-month and 1-year mortality among patients with cirrhosis [85,87]. Alcoholic cirrhosis is connected with reduced neutrophil counts, elevated CD8+ T cell levels, reduced steatosis, and impaired NK cell function. Additionally, an increase in LOX-1+ myeloid-derived suppressor cells, which exhibit immunosuppressive characteristics, has been observed in Child-Pugh C patients with alcoholic cirrhosis [88]. Several studies have reported a slight increase in PD-1 and/or TIM-3 lymphocyte expression in the circumstance of acute alcoholic hepatitis/cirrhosis, leading to the inhibition of the second signal required for T cell activation [89–92].

Furthermore, decompensated liver cirrhosis gives rise to a state of functional immunosuppression, and often presents with hypergammaglobulinemia (HGG) [92–94]. The inability of patients with advanced cirrhosis to mount protective antibody responses despite concurrent HGG is based on dysregulation of Tfh cells response [95]. Importantly, systemic C3c and IgG1 levels seem to be remarkable biomarkers indicative of CAID [8]. Concordantly, Massonnet et al. suggested that the upregulation of IgA production in cirrhosis is related to activation of TLR pathways [73]. The prognostic value of IL-6 and IgG1 likely underline the clinical significance of a proinflammatory state [96]. The finding of increased IgG-4 levels which is considered as a mediator of anti-inflammatory effects or even of immunotolerance in other context [97] support the concept that both inflammation and immunocompromise are intimate features of CAID [8,66]. Alpha-2-macroglobulin (A2M) functions as a protease inhibitor and may scavenge cytokines and other proinflammatory mediators [98]. The mechanistic implications caused by dysregulation of A2M may further contribute to immune dysfunction [98].

4

Potential treatment opportunity

Patients with alcoholic cirrhosis often present with a spectrum of immune-related complications, the most common being spontaneous bacterial peritonitis (SBP), hepatic encephalopathy, and hepatocellular carcinoma. The immune dysfunction associated with alcoholic cirrhosis leverages significant challenges on clinical practice. Targeting systemic inflammation increases the risk of infections, while stimulating the inflammatory response may exacerbate detrimental immune reactions and associated injuries. Mounting evidence suggests that certain interventions, which have recently gained increasing attention, may be beneficial.

4.1

Gut microbiota modulation

Probiotics and prebiotics reduce LPS and TNF-α levels, decrease bacterial overgrowth, and accelerate the repair of alcohol-induced cirrhosis, thereby lowering the incidence of bacterial infections. Obeticholic acid, a farnesoid X receptor agonist, contributes to restore the intestinal homeostasis and prevent intestinal vascular barrier dysfunction [51,99]. Additionally, fecal microbiota transplantation capsules have exhibited therapeutic potentials in enhancing microbial diversity with respect to the duodenal mucosa and intestines, increasing antimicrobial peptide expression, and reducing LPS-binding protein levels, representing a promising non-antibiotic therapeutic strategy [100].

4.2

Anti-infection therapy

Rifaximin-α can promote the intestinal microenvironment rich in TNF-α and interleukin-25, enhance the antibacterial response to invading pathogens, and promote the repair of intestinal barrier [86,99]. In a multicenter double-blind randomized trial conducted in 291 patients with advanced cirrhosis, Norfloxacin decreased 6-month mortality in patients with ascites fluid protein concentrations of less than 15 g/L [101]. A beneficial effect of norfloxacin could be related to a decrease in systemic inflammation through direct “off-label” anti-inflammatory effects of the antibiotic in immune cells [102]. It can not only reduce the recurrence of overt hepatic encephalopathy, but also favorably manage the intestinal microbiota [103,104]. However, long-term use of antibiotics in patients with liver cirrhosis can reduce the diversity of intestinal bacteria [105].

Nonantibiotic strategies should be implemented to prevent infections in the context of cirrhosis. Beta-blockers and long-term use of albumin were proved to decrease intestinal permeability, bacterial translocation, and magnitude of released inflammatory cytokines [106]. Statins exhibits anti-inflammatory and antifibrotic effects, and are shown to decrease the portal pressure in patients with cirrhosis, as well as improving survival in those with variceal hemorrhage [23]. A non-antibiotic gut decontaminating product CARBALIVE, known as a novel engineered orally ingested macroporus carbon bead, is capable of binding toxins [107]. This has the potential to ameliorate systemic and gut inflammation.

4.3

Immune enhancement therapy

There are few publications with respect to emerging immunotherapeutic approaches. G-CSF induces the mobilization of hematopoietic stem cells into the peripheral blood in response to neutrophil activation. This is thought to overcome functional immune paresis in patients with advanced cirrhosis and CAID [108]. Probiotics, metformin and their combination can promote M2 polarization and inhibit M1 polarization, partially contributing to the amelioration concerning alcoholic liver injury [109]. Branched-chain amino acid (BCAA) granules have been addressed as potential novel therapeutic agents for patients with cirrhosis experiencing CAID along with effectiveness [110]. BCAAs are integrated by immune cells. Studies have shown that BCAA granules significantly restore phagocytic activity across various stages of cirrhosis [108]. They activate the mTOR pathway, a central signaling pathway of the immune microenvironment [111,112]. A translational study demonstrated that BCAAs reduce bacterial translocation, lipopolysaccharide-binding protein expression, TLR-4 activation [81], and significantly improve neutrophil phagocytic capacity [94]. Activation of TLRs induces a significant impairment of neutrophil function (phagocytosis and oxidative rupture) [93], a decrease in the ability of T cells to produce IFN-γ, and an increase in serum levels of immunosuppressive receptors such as PD1 and TIM3 [89]. Endotoxin removal blocks TLR and restores the antimicrobial activity of neutrophils and T cell [89].

Both steroids and TNF-α inhibitors suppress inflammation, but they also repress liver regeneration and increase bacterial infection rates, indicative of the main reason regarding poor efficacy of current treatments. IL-22 has antibacterial effect and promotes liver regeneration [113]. It is feasible to administer IL-22 to treat alcoholic cirrhosis absence of liver cancer, but it cannot be used in patients with precancerous cirrhosis or liver cancer [113]. It has also been demonstrated that visceral sympathectomy causes an increase in E. coli phagocytosis [114]. A recent study has reported that microRNA (miR)-223 inhibits IL-6 expression within neutrophils, and mitigates ROS production [115,116]. However, the presence of a hepatic mitochondrial deoxyribonucleic acid/TLR-9/miR-223 axis mediates negative feedback loop bringing susceptibility to progressive liver injury [115,116].

5

Conclusions

Immune dysfunction in alcoholic cirrhosis is a key mechanism underlying disease progression and the development of complications, involving both the innate and adaptive immune systems. By exploring the molecular mechanisms of alcoholic cirrhosis and developing targeted interventions, this narrative review summarizes the primary research directions and therapeutic advances related to immune dysfunction in alcoholic cirrhosis. Therapeutic strategies targeting immune dysregulation, including cytokine modulation and macrophage polarization, hold promise for improving outcomes in these patients. Various cell types comprising the intestinal barrier contribute to mucosal dysfunction associated with the severity of liver disease. Therefore, multi-targeted and personalized therapies appear to be the most viable approach to effectively manage these patients. These approaches may offer promising strategies for patients with alcoholic cirrhosis in hopes of improving their prognosis and quality of life.

Author contributions

Mingyu Sun and Ziyang Yang – Writing – original draft; Fei Tang, Fenghui Li and Qing Ye – Data curation; Jing Liang and Chao Sun – Writing – review & editing; all authors read and approved the final manuscript.

Funding

This work was supported by the Natural Science Foundation of Tianjin Science and Technology Bureau, China, No. 23KPHDRC00350.