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Several scientific and clinical studies have shown an association between chronic alcohol consumption and the occurrence of cancer in humans. The mechanism for alcohol-induced carcinogenesis has not been fully understood, although plausible events include genotoxic effects of acetaldehyde, cytochrome P450 2E1 (CYP2E1)-mediated generation of reactive oxygen species, aberrant metabolism of folate and retinoids, increased estrogen, and genetic polymorphisms. Here, we summarize the impact of alcohol drinking on the risk of cancer development and potential underlying molecular mechanisms. The interactions between alcohol abuse, anti-tumor immune response, tumor growth, and metastasis are complex. However, multiple studies have linked the immunosuppressive effects of alcohol with tumor progression and metastasis. The influence of alcohol on the host immune system and the development of possible effective immunotherapy for cancer in alcoholics are also discussed here. The conclusive biological effects of alcohol on tumor progression and malignancy have not been investigated extensively using an animal model that mimics the human disease. This review provides insights into cancer pathogenesis in alcoholics, alcohol and immune interactions in different cancers, and scope and future of targeted immunotherapeutic modalities in patients with alcohol abuse.

Alcoholic liver disease occurs due to chronic, heavy drinking and is driven both by metabolic alterations and immune cell activation. Women are at a higher risk than men for developing alcohol induced liver injury and this dimorphism is reflected in animal models of alcoholic liver disease. The importance of adipose tissue in alcoholic liver disease is emerging. Chronic alcohol consumption causes adipose tissue inflammation, which can influence liver injury. Sex differences in body fat composition are well known. However, it is still unclear if alcohol-induced adipose tissue inflammation occurs in a sex-dependent manner. Here we have employed the clinically relevant NIAAA model of chronic-binge alcohol consumption to investigate this sexual dimorphism. We report that female mice have greater liver injury than male mice despite lower alcohol consumption. Chronic-binge alcohol induces adipose tissue inflammation in vivo in female mice, which is illustrated by increased expression of TNFα, IL-6, and CCL2, compared to only IL-6 induction in male adipose tissue. Further, macrophage activation markers such as CD68 as well as the pro-inflammatory activation markers CD11b and CD11c were higher in female adipose tissue. Interestingly, alcohol induced expression of TLR2, 3, 4, and 9 in female but not male adipose tissue, without affecting the TLR adaptor, MyD88. Higher trends of serum endotoxin in female mice may likely contribute to adipose tissue inflammation. In vitro chronic alcohol-mediated sensitization of macrophages to endotoxin is independent of sex. In summary, we demonstrate for the first time that there is a sexual dimorphism in alcohol-induced adipose tissue inflammation and female mice exhibit a higher degree of inflammation than male mice.

The Coronavirus Disease 2019 (COVID‐19) pandemic has exacted a heavy toll on patients with alcohol‐associated liver disease (ALD) and alcohol use disorder (AUD). The collective burden of ALD and AUD was large and growing, even before the COVID‐19 pandemic. There is accumulating evidence that this pandemic has had a large direct effect on these patients and is likely to produce indirect effects through delays in care, psychological strain, and increased alcohol use. Now a year into the pandemic, it is important that clinicians fully understand the effects of the COVID‐19 pandemic on patients with ALD and AUD. To fill existing gaps in knowledge, the scientific community must set research priorities for patients with ALD regarding their risk of COVID‐19, prevention/treatment of COVID‐19, changes in alcohol use during the pandemic, best use of AUD treatments in the COVID‐19 era, and downstream effects of this pandemic on ALD. Conclusion: The COVID‐19 pandemic has already inflicted disproportionate harms on patients with ALD, and ongoing, focused research efforts will be critical to better understand the direct and collateral effects of this pandemic on ALD. COVID‐19 has inflicted disproportionate direct and indirect harms on patients with alcohol‐associated liver disease. Ongoing research efforts will be critical to better understand the effects of this pandemic on patients with alcohol‐associated liver disease.

The review further describes the existence of multiple macrophage origins and phenotypes, their identification markers and roles in disease pathogenesis, and how this knowledge can be translated into future therapies.Oates et al.highlight the landscape of mechanisms underlying macrophage dynamics, macrophage interplay with other cells/tissues, and immunometabolism that collectively contribute to NAFLD progression. Since macrophage-driven inflammation is intricately linked to various metabolic pathways, the potential benefits to be gained from understanding the interplay between metabolic and inflammatory pathways in macrophages are immense. Besides efferocytosis, macrophages facilitate resolution of liver fibrosis [characterized by excessive accumulation of extracellular matrix (ECM) proteins] by producing matrix-degrading enzymes (matrix metalloproteinases, MMPs) that degrade fibrotic ECM. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Cellular stress–mediated chaperones are linked to liver macrophage activation and inflammation in alcohol‐associated liver disease (ALD). In this study, we investigate the role of endoplasmic reticulum (ER) resident stress chaperone GP96/HSP90B1/GRP94, paralog of the HSP90 family, in ALD pathogenesis. We hypothesize that ER resident chaperone, heat shock protein GP96, plays a crucial role in alcohol‐associated liver inflammation and contributes to liver injury. We show high expression of GP96/HSP90B1 and GRP78/HSPA5 in human alcohol‐associated hepatitis livers as well as in mouse ALD livers with induction of GP96 prominent in alcohol‐exposed macrophages. Myeloid‐specific GP96 deficient (M‐GP96KO) mice failed to induce alcohol‐associated liver injury. Alcohol‐fed M‐GP96KO mice exhibit significant reduction in steatosis, serum endotoxin, and pro‐inflammatory cytokines compared with wild‐type mice. Anti‐inflammatory cytokines interleukin‐10 and transforming growth factor β, as well as activating transcription factor 3 and triggering receptor expressed on myeloid cells 2, markers of restorative macrophages, were higher in alcohol‐fed M‐GP96KO livers. M‐GP96KO mice exhibit protection in a model of endotoxin‐mediated liver injury in vivo, which is in agreement with reduced inflammatory responses during ex vivo lipopolysaccharide/endotoxin– stimulated bone marrow–derived macrophages from M‐GP96KO mice. Furthermore, we show that liver macrophages from alcohol‐fed M‐GP96KO mice show compensatory induction of GRP78 messenger RNA, likely due to increased splicing of X‐box binding protein‐1. Finally, we show that inhibition of GP96 using a specific pharmacological agent, PU‐WS13 or small interfering RNA, alleviates inflammatory responses in primary macrophages. Conclusion: Myeloid ER resident GP96 promotes alcohol‐induced liver damage through activation of liver macrophage inflammatory responses, alteration in lipid homeostasis, and ER stress. These findings highlight a critical role for liver macrophage ER resident chaperone GP96/HSP90B1 in ALD, and its targeted inhibition represents a promising therapeutic approach in ALD. ER resident chaperone GP96/GRP94 is crucial in facilitating alcohol‐mediated liver inflammation and injury. Deletion of chaperone GP96 in myeloid cells confers protection from ALD and indicates GP96 as a target to modulate and restore macrophage function in ALD.

In the multifactorial pathophysiology of alcoholic liver disease (ALD), inflammatory cascade activation plays a central role. Recent studies demonstrated that Toll-like Receptors, the sensors of microbial and endogenous danger signals, are expressed and activated in innate immune cells as well as in parenchymal cells in the liver and thereby contribute to ALD. In this paper, we discuss the importance of gut-derived endotoxin and its recognition by TLR4. The significance of TLR-induced intracellular signaling pathways and cytokine production as well as the contribution of reactive oxygen radicals is evaluated. The contribution of TLR signaling to induction of liver fibrosis and hepatocellular cancer is reviewed in the context of alcohol-induced liver disease.

Liver fibrosis is an aberrant wound healing response that results from chronic injury and is mediated by hepatocellular death and activation of hepatic stellate cells (HSCs). While induction of oxidative stress is well established in fibrotic livers, there is limited information on stress‐mediated mechanisms of HSC activation. Cellular stress triggers an adaptive defense mechanism via master protein homeostasis regulator, heat shock factor 1 (HSF1), which induces heat shock proteins to respond to proteotoxic stress. Although the importance of HSF1 in restoring cellular homeostasis is well‐established, its potential role in liver fibrosis is unknown. Here, we show that HSF1 messenger RNA is induced in human cirrhotic and murine fibrotic livers. Hepatocytes exhibit nuclear HSF1, whereas stellate cells expressing alpha smooth muscle actin do not express nuclear HSF1 in human cirrhosis. Interestingly, despite nuclear HSF1, murine fibrotic livers did not show induction of HSF1 DNA binding activity compared with controls. HSF1‐deficient mice exhibit augmented HSC activation and fibrosis despite limited pro‐inflammatory cytokine response and display delayed fibrosis resolution. Stellate cell and hepatocyte‐specific HSF1 knockout mice exhibit higher induction of profibrogenic response, suggesting an important role for HSF1 in HSC activation and fibrosis. Stable expression of dominant negative HSF1 promotes fibrogenic activation of HSCs. Overactivation of HSF1 decreased phosphorylation of JNK and prevented HSC activation, supporting a protective role for HSF1. Our findings identify an unconventional role for HSF1 in liver fibrosis. Conclusion: Our results show that deficiency of HSF1 is associated with exacerbated HSC activation promoting liver fibrosis, whereas activation of HSF1 prevents profibrogenic HSC activation. Schematic representation depicting the role of master proteostasis regulator, heat shock factor 1 (HSF1) in hepatic stellate cell activation in liver fibrosis. Deficiency of HSF1 promotes fibrosis by facilitating hepatic stellate cell activation whereas activation of HSF1 reduces stellate cell activation and alleviates fibrosis.