Portal de Periódicos da CAPES

Kupffer Cells

2020; Elsevier BV; Volume: 190; Issue: 11 Linguagem: Inglês

10.1016/j.ajpath.2020.08.014

1525-2191

Elise Slevin, Leonardo Baiocchi, Nan Wu, Burcin Ekser, Keisaku Sato, Emily Lin, Ludovica Ceci, Lixian Chen, Sugeily Ramos Lorenzo, Wenjuan Xu, Konstantina Kyritsi, Victoria E. Meadows, Tianhao Zhou, Debiyoti Kundu, Yuyan Han, Lindsey Kennedy, Shannon Glaser, Heather Francis, Gianfranco Alpini, Fanyin Meng,

Eicosanoids and Hypertension Pharmacology

Chronic alcohol consumption is linked to the development of alcohol-associated liver disease (ALD). This disease is characterized by a clinical spectrum ranging from steatosis to hepatocellular carcinoma. Several cell types are involved in ALD progression, including hepatic macrophages. Kupffer cells (KCs) are the resident macrophages of the liver involved in the progression of ALD by activating pathways that lead to the production of cytokines and chemokines. In addition, KCs are involved in the production of reactive oxygen species. Reactive oxygen species are linked to the induction of oxidative stress and inflammation in the liver. These events are activated by the bacterial endotoxin, lipopolysaccharide, that is released from the gastrointestinal tract through the portal vein to the liver. Lipopolysaccharide is recognized by receptors on KCs that are responsible for triggering several pathways that activate proinflammatory cytokines involved in alcohol-induced liver injury. In addition, KCs activate hepatic stellate cells that are involved in liver fibrosis. Novel strategies to treat ALD aim at targeting Kupffer cells. These interventions modulate Kupffer cell activation or macrophage polarization. Evidence from mouse models and early clinical studies in patients with ALD injury supports the notion that pathogenic macrophage subsets can be successfully translated into novel treatment options for patients with this disease. Chronic alcohol consumption is linked to the development of alcohol-associated liver disease (ALD). This disease is characterized by a clinical spectrum ranging from steatosis to hepatocellular carcinoma. Several cell types are involved in ALD progression, including hepatic macrophages. Kupffer cells (KCs) are the resident macrophages of the liver involved in the progression of ALD by activating pathways that lead to the production of cytokines and chemokines. In addition, KCs are involved in the production of reactive oxygen species. Reactive oxygen species are linked to the induction of oxidative stress and inflammation in the liver. These events are activated by the bacterial endotoxin, lipopolysaccharide, that is released from the gastrointestinal tract through the portal vein to the liver. Lipopolysaccharide is recognized by receptors on KCs that are responsible for triggering several pathways that activate proinflammatory cytokines involved in alcohol-induced liver injury. In addition, KCs activate hepatic stellate cells that are involved in liver fibrosis. Novel strategies to treat ALD aim at targeting Kupffer cells. These interventions modulate Kupffer cell activation or macrophage polarization. Evidence from mouse models and early clinical studies in patients with ALD injury supports the notion that pathogenic macrophage subsets can be successfully translated into novel treatment options for patients with this disease. Alcohol-associated liver disease (ALD) is a major cause of chronic liver injury,1Xu J. Liu X. Gao B. Karin M. Tsukamoto H. Brenner D. Kisseleva T. New approaches for studying alcoholic liver disease.Curr Pathobiol Rep. 2014; 2: 171-183Crossref PubMed Scopus (10) Google Scholar which has a wide clinical spectrum. This ranges from the accumulation of lipids in the liver (steatosis), steatosis with inflammation (steatohepatitis), fibrosis, cirrhosis, and an increased risk of hepatocellular carcinoma.2Ohashi K. Pimienta M. Seki E. Alcoholic liver disease: a current molecular and clinical perspective.Liver Res. 2018; 2: 161-172Crossref PubMed Scopus (52) Google Scholar Despite alcohol abuse, only 35% of heavy drinkers develop ALD.1Xu J. Liu X. Gao B. Karin M. Tsukamoto H. Brenner D. Kisseleva T. New approaches for studying alcoholic liver disease.Curr Pathobiol Rep. 2014; 2: 171-183Crossref PubMed Scopus (10) Google Scholar This suggests there are additional factors influencing ALD development, such as sex, weight, drinking patterns, as well as other genetic and metabolic factors.1Xu J. Liu X. Gao B. Karin M. Tsukamoto H. Brenner D. Kisseleva T. New approaches for studying alcoholic liver disease.Curr Pathobiol Rep. 2014; 2: 171-183Crossref PubMed Scopus (10) Google Scholar Women tend to drink less alcohol than men. However, they are more susceptible to the hepatotoxic effects of alcohol.3Ajakaiye M. Jacob A. Wu R. Nicastro J.M. Coppa G.F. Wang P. Alcohol and hepatocyte-Kupffer cell interaction (review).Mol Med Rep. 2011; 4: 597-602PubMed Google Scholar Binge drinking, defined as a pattern of drinking alcohol that brings blood alcohol concentration to ≥0.08%, or ≥0.08 g of alcohol per deciliter, which corresponds to consuming of five or more alcoholic drinks for males or four or more alcoholic drinks for females on the same occasion within about 2 hours on at least 1 day in the past month by the National Institute on Alcohol Abuse and Alcoholism, and heavy drinking (≥8 drinks a week for women and ≥15 drinks a week for men) are the particularly concerning drinking patterns. They exacerbate liver injury and increase immune system activation, intestinal permeability, and oxidative stress.3Ajakaiye M. Jacob A. Wu R. Nicastro J.M. Coppa G.F. Wang P. Alcohol and hepatocyte-Kupffer cell interaction (review).Mol Med Rep. 2011; 4: 597-602PubMed Google Scholar Alcohol-induced liver injury is mediated through several processes, including the generation of harmful metabolites and reactive oxygen species (ROS), increase of intestinal permeability, and an increase of endogenous mediators.4Nagy L.E. Ding W.X. Cresci G. Saikia P. Shah V.H. Linking pathogenic mechanisms of alcoholic liver disease with clinical phenotypes.Gastroenterology. 2016; 150: 1756-1768Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar There are multiple ethanol catabolic routes leading to toxic effect in ALD: i) the oxidation of ethanol to acetate, ii) the microsomal ethanol-oxidizing system, and iii) peroxisomal catalase. The oxidation of ethanol to acetate is a two-step process performed by the enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) that use NAD+ as a cofactor (Figure 1).5Yang L. Wu D. Wang X. Cederbaum A.I. Cytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver.Free Radic Biol Med. 2012; 53: 1170-1180Crossref PubMed Scopus (61) Google Scholar This process results in the accumulation of NADH lowering the ratio of NAD+/NADH in the mitochondria,5Yang L. Wu D. Wang X. Cederbaum A.I. Cytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver.Free Radic Biol Med. 2012; 53: 1170-1180Crossref PubMed Scopus (61) Google Scholar resulting in a reduction of β-oxidation.5Yang L. Wu D. Wang X. Cederbaum A.I. Cytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver.Free Radic Biol Med. 2012; 53: 1170-1180Crossref PubMed Scopus (61) Google Scholar The change in ratio results is the accumulation of lipids in the liver, resulting in fatty liver. This is the first stage of ALD, known as steatosis. Although this condition seems reversible after abstinence,2Ohashi K. Pimienta M. Seki E. Alcoholic liver disease: a current molecular and clinical perspective.Liver Res. 2018; 2: 161-172Crossref PubMed Scopus (52) Google Scholar if neglected it can progress to inflammation and liver fibrosis.5Yang L. Wu D. Wang X. Cederbaum A.I. Cytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver.Free Radic Biol Med. 2012; 53: 1170-1180Crossref PubMed Scopus (61) Google Scholar The microsomal ethanol-oxidizing system (Figure 2) is activated after high alcohol consumption, and cytochrome P450 (CYP2E1) converts alcohol to acetaldehyde.5Yang L. Wu D. Wang X. Cederbaum A.I. Cytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver.Free Radic Biol Med. 2012; 53: 1170-1180Crossref PubMed Scopus (61) Google Scholar,6Lautt W.W. Hepatic Circulation: Physiology and Pathophysiology. Morgan & Claypool Life Sciences, San Rafael, CA2009Crossref Google Scholar CYP2E1 plays a major role in oxidative stress, and ethanol-induced fatty liver7Louvet A. Mathurin P. Alcoholic liver disease: mechanisms of injury and targeted treatment.Nat Rev Gastroenterol Hepatol. 2015; 12: 231-242Crossref PubMed Scopus (533) Google Scholar and chronic alcohol exposure can lead to CYP2E1 activation in small intestine as well as in Kupffer cells (KCs)8Forsyth C.B. Voigt R.M. Shaikh M. Tang Y. Cederbaum A.I. Turek F.W. Keshavarzian A. Role for intestinal CYP2E1 in alcohol-induced circadian gene-mediated intestinal hyperpermeability.Am J Physiol Gastrointest Liver Physiol. 2013; 305: G185-G195Crossref PubMed Scopus (53) Google Scholar,9Jarvelainen H.A. Fang C. Ingelman-Sundberg M. Lukkari T.A. Sippel H. Lindros K.O. Kupffer cell inactivation alleviates ethanol-induced steatosis and CYP2E1 induction but not inflammatory responses in rat liver.J Hepatol. 2000; 32: 900-910Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar with production of significant amounts of ROS, which is exacerbated by hypoxia, bacterial translocation, and the release of proinflammatory cytokines.10Paik Y.-H. Kim J. Aoyama T. De Minicis S. Bataller R. Brenner D.A. Role of NADPH oxidases in liver fibrosis.Antioxid Redox Signaling. 2014; 20: 2854-2872Crossref PubMed Scopus (165) Google Scholar Several liver cell types then play a role in alcohol-induced liver injury, including hepatic stellate cells (HSCs), hepatocytes, hepatic dendritic cells, biliary epithelial cells (ie, cholangiocytes), and sinusoidal endothelial cells. However, Kupffer cells, the hepatic macrophages, play an important role in triggering the inflammatory and fibrotic processes leading to end-stage liver injury. In this review, we describe the specific contribution of KCs in the progression of injury during ALD. KCs, first described at the end of the 18th Century as cells of endothelial origin, were lately more correctly identified as liver resident macrophages.11Naito M. Hasegawa G. Takahashi K. Development, differentiation, and maturation of Kupffer cells.Microsc Res Tech. 1997; 39: 350-364Crossref PubMed Google Scholar KCs make up approximately 80% of the total macrophages of the body.12Choi W.-M. Kim M.-H. Jeong W.-I. Functions of hepatic non-parenchymal cells in alcoholic liver disease.Liver Res. 2019; 3: 80-87Crossref Scopus (3) Google Scholar Their strategic localization in sinusoidal spaces allows KCs to behave not only as an important immunologic barrier against pathologic components deriving from the gut but also to provide to senescent red cells removal and iron recovery. However, their activities may undergo relevant changes comparing healthy or diseased conditions. In fact, although KCs are immunologically regarded as cells maintaining a tolerogenic status during normal circumstances,13Thomson A.W. Knolle P.A. Antigen-presenting cell function in the tolerogenic liver environment.Nat Rev Immunol. 2010; 10: 753-766Crossref PubMed Scopus (551) Google Scholar their response may sometimes enhance liver injury, such as during ethanol abuse.14Nagy L.E. Recent insights into the role of the innate immune system in the development of alcoholic liver disease.Exp Biol Med (Maywood). 2003; 228: 882-890Crossref PubMed Scopus (198) Google Scholar This observation is not surprising as KCs mirror the characteristic functional plasticity shared by the components of the macrophage family.15Stout R.D. Suttles J. Functional plasticity of macrophages: reversible adaptation to changing microenvironments.J Leukoc Biol. 2004; 76: 509-513Crossref PubMed Scopus (546) Google Scholar Macrophages are in fact able to express several functional patterns, which may also change during time if the stimulating trigger is maintained. Finally, important changes occur according to the surrounding microenvironment so that KCs are largely different from alveolar macrophages or microglial cells.15Stout R.D. Suttles J. Functional plasticity of macrophages: reversible adaptation to changing microenvironments.J Leukoc Biol. 2004; 76: 509-513Crossref PubMed Scopus (546) Google Scholar In the immunologic human liver environment, at least two well distinct populations of resident macrophages were identified by using single-cell RNA sequencing.16MacParland S.A. Liu J.C. Ma X.Z. Innes B.T. Bartczak A.M. Gage B.K. Manuel J. Khuu N. Echeverri J. Linares I. Gupta R. Cheng M.L. Liu L.Y. Camat D. Chung S.W. Seliga R.K. Shao Z. Lee E. Ogawa S. Ogawa M. Wilson M.D. Fish J.E. Selzner M. Ghanekar A. Grant D. Greig P. Sapisochin G. Selzner N. Winegarden N. Adeyi O. Keller G. Bader G.D. McGilvray I.D. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations.Nat Commun. 2018; 9: 4383Crossref PubMed Scopus (538) Google Scholar One is supposed to participate in inflammatory response; the other has immune-modulatory properties. In a simplistic view, these two subsets give origin to a different M1 or M2 response. The details of this process, also with regard to ethanol injury, will be reviewed below (M1/M2 Kupffer Cells Unbalance during ALD). KC contribution to alcohol-induced liver injury was clearly demonstrated in research using the selective KC blocking agent, gadolinium chloride, in rat models.6Lautt W.W. Hepatic Circulation: Physiology and Pathophysiology. Morgan & Claypool Life Sciences, San Rafael, CA2009Crossref Google Scholar The inactivation of KCs prevented ethanol-induced liver damage, confirming the important KC involvement in tissue injury. KC-induced secretion of proinflammatory cytokines has been largely demonstrated after ethanol exposure.17Massey V.L. Arteel G.E. Acute alcohol-induced liver injury.Front Physiol. 2012; 3: 193Crossref PubMed Scopus (88) Google Scholar Tumor necrosis factor (TNF), for instance, is a major mediator of alcohol-induced damage in the liver,17Massey V.L. Arteel G.E. Acute alcohol-induced liver injury.Front Physiol. 2012; 3: 193Crossref PubMed Scopus (88) Google Scholar it interacts with TNF receptors on hepatocytes,18Roy S. Benz F. Luedde T. Roderburg C. The role of miRNAs in the regulation of inflammatory processes during hepatofibrogenesis.Hepatobiliary Surg Nutr. 2015; 4: 24-33PubMed Google Scholar it increases free fatty acid released from peripheral adipocytes and de novo lipogenesis, and it inhibits β-oxidation.19Mandrekar P. Szabo G. Signalling pathways in alcohol-induced liver inflammation.J Hepatol. 2009; 50: 1258-1266Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar In this respect, the lipid accumulation in hepatocytes is the liver's first response to alcohol abuse. However, several hits are needed for the progression from fatty liver toward chronic inflammation and fibrosis during ethanol abuse. The important role of KCs in this multistep process is discussed in detail in the following paragraphs. The liver is chronically exposed to gut-derived bacteria and bacterial components, such as lipopolysaccharide (LPS).20Zhou Z. Zhong W. Targeting the gut barrier for the treatment of alcoholic liver disease.Liver Res. 2017; 1: 197-207Crossref PubMed Scopus (59) Google Scholar In this way, a gut-liver axis is established. LPS is normally circulating in blood at a low concentration, peaking around 0.45 EU/mL without significant consequences.21Jayashree B. Bibin Y.S. Prabhu D. Shanthirani C.S. Gokulakrishnan K. Lakshmi B.S. Mohan V. Balasubramanyam M. Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes.Mol Cell Biochem. 2014; 388: 203-210Crossref PubMed Scopus (214) Google Scholar However, the total LPS content in the gut is 1000 times higher than its lethal dose in blood.22Wassenaar T.M. Zimmermann K. Lipopolysaccharides in food, food supplements, and probiotics: should we be worried?.Eur J Microbiol Immunol (Bp). 2018; 8: 63-69Crossref PubMed Google Scholar When excess LPS is presented to toll-like receptors (TLRs) on KCs, this results in the production of proinflammatory cytokines, including TNF-α, interleukins (IL-1β and IL-6), chemokines (IL-8 and CCL2), and ROS.18Roy S. Benz F. Luedde T. Roderburg C. The role of miRNAs in the regulation of inflammatory processes during hepatofibrogenesis.Hepatobiliary Surg Nutr. 2015; 4: 24-33PubMed Google Scholar TNF-α is the principal mediator of the inflammatory response in mammals, and has a role in the development of acute septic shock as well as a variety of inflammatory diseases, including ALD.23Ajakaiye M.A. Jacob A. Wu R. Zhou M. Ji Y. Dong W. Wang Z. Qiang X. Chaung W.W. Nicastro J. Coppa G.F. Wang P. Upregulation of Kupffer cell alpha2A-adrenoceptors and downregulation of MKP-1 mediate hepatic injury in chronic alcohol exposure.Biochem Biophys Res Commun. 2011; 409: 406-411Crossref PubMed Scopus (15) Google Scholar Activated KCs trigger signaling cascades that include CD14, MyD88, MD-2, mitogen-activated protein kinases [c-Jun N-terminal kinase (JNK)], and NF-κB.18Roy S. Benz F. Luedde T. Roderburg C. The role of miRNAs in the regulation of inflammatory processes during hepatofibrogenesis.Hepatobiliary Surg Nutr. 2015; 4: 24-33PubMed Google Scholar In addition, Kupffer cells produce nitric oxide (NO) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which further contributes to ALD. When the canonical cascade of events following the interaction between LPS and KCs is examined in detail, the first step is represented by the interaction of LPS with TLR4, and with its coreceptors, CD14 and MD-2. TLRs are involved in cytotoxicity and effector responses,19Mandrekar P. Szabo G. Signalling pathways in alcohol-induced liver inflammation.J Hepatol. 2009; 50: 1258-1266Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar which recognize signature motifs, often referred to as pathogen-associated molecular patterns.24Soares J.B. Pimentel-Nunes P. Roncon-Albuquerque R. Leite-Moreira A. The role of lipopolysaccharide/toll-like receptor 4 signaling in chronic liver diseases.Hepatol Int. 2010; 4: 659-672Crossref PubMed Scopus (198) Google Scholar CD14 facilitates the transfer of LPS to the TLR4/MD2 receptor complex and modulates LPS recognition25Seki E. Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut.J Physiol. 2012; 590: 447-458Crossref PubMed Scopus (306) Google Scholar (Figure 3). MD2 is noncovalently associated with TLR4 and binds LPS directly also in the absence of TLRs.25Seki E. Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut.J Physiol. 2012; 590: 447-458Crossref PubMed Scopus (306) Google Scholar LPS binding protein (LBP), in this system, facilitates the association between LPS and CD14.25Seki E. Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut.J Physiol. 2012; 590: 447-458Crossref PubMed Scopus (306) Google Scholar The TLR4/CD14 receptor complex recognition of LPS then originates the following molecular steps. The LPS/TLR4 transduction pathway may in general progress through a MyD88-dependent or MyD88-independent [TIR domain-containing adapter-inducing interferon-β (TRIF)–mediated] route.26Kawai T. Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.Nat Immunol. 2010; 11: 373-384Crossref PubMed Scopus (6189) Google Scholar Because reduction of inflammatory alcoholic damage was not observed in rodents after MyD88 disruption,27Hritz I. Mandrekar P. Velayudham A. Catalano D. Dolganiuc A. Kodys K. Kurt-Jones E. Szabo G. The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88.Hepatology. 2008; 48: 1224-1231Crossref PubMed Scopus (320) Google Scholar this type of liver injury is thought to mainly progress through the TRIF/MyD88-undependent pathway. The three, TRIF-regulated, downstream inflammatory activators are finally represented by NF-κB, MAPK, and IRF3,28Wang H.J. Gao B. Zakhari S. Nagy L.E. Inflammation in alcoholic liver disease.Annu Rev Nutr. 2012; 32: 343-368Crossref PubMed Scopus (209) Google Scholar responsible for the cascade of events characterizing the inflammatory immune response to alcoholic damage. However, the increased concentration of LPS in blood (so-called endotoxemia) is a crucial step in eliciting liver inflammation, during ethanol abuse.25Seki E. Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut.J Physiol. 2012; 590: 447-458Crossref PubMed Scopus (306) Google Scholar In fact, since the late 1980s, data on rats under alcoholic diet demonstrated that for progression from simple steatosis to liver inflammation, administration of LPS was required.29Bhagwandeen B.S. Apte M. Manwarring L. Dickeson J. Endotoxin induced hepatic necrosis in rats on an alcohol diet.J Pathol. 1987; 152: 47-53Crossref PubMed Scopus (146) Google Scholar Moreover, a linear relationship between plasma endotoxin levels and histologic liver necrosis and inflammation was also demonstrated in rats under ethanol administration.30Nanji A.A. Khettry U. Sadrzadeh S.M. Yamanaka T. Severity of liver injury in experimental alcoholic liver disease. Correlation with plasma endotoxin, prostaglandin E2, leukotriene B4, and thromboxane B2.Am J Pathol. 1993; 142: 367-373PubMed Google Scholar These observations recall our attention on the possible failure of the physiological mechanisms limiting or preventing endotoxemia in the course of chronic alcohol exposure. Conditions that have been linked to LPS blood increase in this setting include defective removal of gut-derived products by KCs31Fukui H. Kitano H. Okamoto Y. Kikuchi E. Matsumoto M. Kikukawa M. Morimura M. Tsujita S. Nagamoto I. Nakatani T. Tsujii T. Interaction of Kupffer cells to splenic macrophages and hepatocytes in endotoxin clearance: effect of alcohol.J Gastroenterol Hepatol. 1995; 10: S31-S34Crossref PubMed Scopus (11) Google Scholar and intestinal bacteria dysbiosis/overgrowth.32Hartmann P. Chu H. Duan Y. Schnabl B. Gut microbiota in liver disease: too much is harmful, nothing at all is not helpful either.Am J Physiol Gastrointest Liver Physiol. 2019; 316: G563-G573Crossref PubMed Scopus (34) Google Scholar However, the evidence of a so-called leaky gut in humans, affected by ALD, supports the important role of an impaired intestinal barrier at the base of endotoxemia during alcohol abuse.33Rao R.K. Seth A. Sheth P. Recent advances in alcoholic liver disease I: role of intestinal permeability and endotoxemia in alcoholic liver disease.Am J Physiol Gastrointest Liver Physiol. 2004; 286: G881-G884Crossref PubMed Scopus (286) Google Scholar,34Keshavarzian A. Holmes E.W. Patel M. Iber F. Fields J.Z. Pethkar S. Leaky gut in alcoholic cirrhosis: a possible mechanism for alcohol-induced liver damage.Am J Gastroenterol. 1999; 94: 200-207Crossref PubMed Scopus (294) Google Scholar Increased gut permeability in this setting is likely related to cellular adherens and tight junction damage by acetaldehyde.35Rao R. Endotoxemia and gut barrier dysfunction in alcoholic liver disease.Hepatology. 2009; 50: 638-644Crossref PubMed Scopus (337) Google Scholar Leaky gut may occur and support injury also in other liver and nonliver diseases; however, possible treatments for this condition have not been identified so far.36Odenwald M.A. Turner J.R. Intestinal permeability defects: is it time to treat?.Clin Gastroenterol Hepatol. 2013; 11: 1075-1083Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar Macrophages, including KCs, can widely modulate their phenotypic properties according to environmental immunologic signals.37Martinez F.O. Helming L. Gordon S. Alternative activation of macrophages: an immunologic functional perspective.Annu Rev Immunol. 2009; 27: 451-483Crossref PubMed Scopus (2051) Google Scholar In this perspective, a categorical classification of these cells denotes important limits as this pool may evolve in a continuum of phenotypes, switching one in the other according to environmental condition and stimuli.38Xu W. Zhao X. Daha M.R. van Kooten C. Reversible differentiation of pro- and anti-inflammatory macrophages.Mol Immunol. 2013; 53: 179-186Crossref PubMed Scopus (51) Google Scholar However, to enhance comprehension on the role of macrophages during inflammatory processes, a simplistic M1 or M2 functional classification has been adopted, and the possible switching between these two phenotypes has been described.39Chistiakov D.A. Myasoedova V.A. Revin V.V. Orekhov A.N. Bobryshev Y.V. The impact of interferon-regulatory factors to macrophage differentiation and polarization into M1 and M2.Immunobiology. 2018; 223: 101-111Crossref PubMed Scopus (151) Google Scholar M1 subtype expansion/activation (generally elicited by LPS/TLR interaction) is thought to be the first step in acute inflammatory response (Figure 4), enhancing phagocytic activities, type 1 helper T-cell (Th1) response, and release of proinflammatory cytokines, such as TNF-α, IL-6, and others.40Atri C. Guerfali F.Z. Laouini D. Role of human macrophage polarization in inflammation during infectious diseases.Int J Mol Sci. 2018; 19: 1801Crossref PubMed Scopus (566) Google Scholar On the other hand, M2 phenotype seems to be linked to Th2 response, showing modest phagocytic and proinflammatory activity and instead releasing TGF-β and IL-10. The latter are mainly considered as important anti-inflammatory cytokines, currently investigated as possible homeostatic/therapeutic factors for immunologic treatment of autoimmune diseases.41Komai T. Inoue M. Okamura T. Morita K. Iwasaki Y. Sumitomo S. Shoda H. Yamamoto K. Fujio K. Transforming growth factor-beta and interleukin-10 synergistically regulate humoral immunity via modulating metabolic signals.Front Immunol. 2018; 9: 1364Crossref PubMed Scopus (46) Google Scholar So, in this simplistic model, linking respectively M1 or M2 activation to Th1 or Th2 response, the M1 subtype would be involved in initiating and promoting the inflammatory process, whereas M2 would contribute to resolution of injury and tissue repair. Finally, in the presence of inflammation, the predominance of an M1 or M2 response would be dependent by the balance between STAT1 and STAT3/6.42Sica A. Mantovani A. Macrophage plasticity and polarization: in vivo veritas.J Clin Invest. 2012; 122: 787-795Crossref PubMed Scopus (3877) Google Scholar,43Wan J. Benkdane M. Teixeira-Clerc F. Bonnafous S. Louvet A. Lafdil F. Pecker F. Tran A. Gual P. Mallat A. Lotersztajn S. Pavoine C. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease.Hepatology. 2014; 59: 130-142Crossref PubMed Scopus (368) Google Scholar Because M1 depletion and/or M2 expansion may promote healing and tissue repair during significant inflammatory processes, modulation of the M1/M2 macrophage phenotype has recently gained more attention. In this perspective, a study conducted on human samples of patients with ALD and an animal model of ethanol-fed mice gave interesting results.43Wan J. Benkdane M. Teixeira-Clerc F. Bonnafous S. Louvet A. Lafdil F. Pecker F. Tran A. Gual P. Mallat A. Lotersztajn S. Pavoine C. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease.Hepatology. 2014; 59: 130-142Crossref PubMed Scopus (368) Google Scholar In a group of heavy alcohol drinkers, the hepatic expression of M2-associated genes [CD-206 (MRC1) and CD163] was reduced in subjects with significant liver damage compared with those with minimal tissue injury. In parallel with this finding, an increased M2/M1 ratio was associated with reduced damage and fatty infiltration of the liver in ethanol-fed C57BL6/J and BALB/c mice. Finally, in BALB/c mice strain (that showed a significant M2-mediated resistance to ethanol injury), a mechanism was identified that was characterized by M2 Kupffer cell induction of apoptosis on the M1 subset. This effect was determined by an enhanced IL-10 expression. In keeping with this study, a previous study observed increased ethanol-induced liver damage and LPS-stimulated inflammatory response in IL-10 (Il10−/−) knockout mice.44Hill D.B. D'Souza N.B. Lee E.Y. Burikhanov R. Deaciuc I.V. de Villiers W.J. A role for interleukin-10 in alcohol-induced liver sensitization to bacterial lipopolysaccharide.Alcohol Clin Exp Res. 2002; 26: 74-82Crossref PubMed Scopus (69) Google Scholar It has been demonstrated that knocking down an inflammation-associated miRNA, miR-21 (MIR21), can inhibit cytokine production and inflammatory responses during ALD injury.45Wu N. McDaniel K. Zhou T. Ramos-Lorenzo S. Wu C. Huang L. Chen D. Annable T. Francis H. Glaser S. Alpini G. Meng F. Knockout of microRNA-21 attenuates alcoholic hepatitis through the VHL/NF-kappaB signaling pathway in hepatic stellate cells.Am J Physiol Gastrointest Liver Physiol. 2018; 315: G385-G398Crossref PubMed Scopus (14) Google Scholar Taken all together, it becomes evident that strategies aiming to regulate, rather than delete, Kupffer cell response may be beneficial in the course of ALD, as in other human liver afflictions.46Sica A. Invernizzi P. Mantovani A. Macrophage plasticity and polarization in liver homeostasis and pathology.Hepatology. 2014; 59: 2034-2042Crossref PubMed Scopus (304) Google Scholar In this perspective, nanoparticle-driven delivery of drugs, immunomodulators, or siRNAs has been proposed and tested.47van der Heide D. Weiskirchen R. Bansal R. Therapeutic targeting of hepatic macrophages for the treatment of liver diseases.Front Immunol. 2019; 10: 2852Crossref PubMed Scopus (97) Google Scholar miRNAs act as the important regulator