Innate immunity in alcoholic liver disease Gao, Bin; Seki, Ekihiro; Brenner, David A ...
American journal of physiology: Gastrointestinal and liver physiology,
04/2011, Letnik:
300, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Excessive alcohol consumption is a leading cause of chronic liver disease in the Western world. Alcohol-induced hepatotoxicity and oxidative stress are important mechanisms contributing to the ...pathogenesis of alcoholic liver disease. However, emerging evidence suggests that activation of innate immunity involving TLR4 and complement also plays an important role in initiating alcoholic steatohepatitis and fibrosis, but the role of adaptive immunity in the pathogenesis of alcoholic liver disease remains obscure. Activation of a TLR4-mediated MyD88-independent (TRIF/IRF-3) signaling pathway in Kupffer cells contributes to alcoholic steatohepatitis, whereas activation of TLR4 signaling in hepatic stellate cells promotes liver fibrosis. Alcohol consumption activates the complement system in the liver by yet unidentified mechanisms, leading to alcoholic steatohepatitis. In contrast to activation of TLR4 and complement, alcohol consumption can inhibit natural killer cells, another important innate immunity component, contributing to alcohol-mediated acceleration of viral infection and liver fibrosis in patients with chronic viral hepatitis. Understanding of the role of innate immunity in the pathogenesis of alcoholic liver disease may help us identify novel therapeutic targets to treat this disease.
Background & Aims Complement is involved in the development of alcoholic liver disease in mice; however, the mechanisms for complement activation during ethanol exposure have not been identified. ...C1q, the recognition subunit of the first complement component, binds to apoptotic cells, thereby activating the classical complement pathway. Because ethanol exposure increases hepatocellular apoptosis, we hypothesized that ethanol-induced apoptosis would lead to activation of complement via the classical pathway. Methods Wild-type and C1qa −/− mice were allowed free access to ethanol-containing diets or pair-fed control diets for 4 or 25 days. Results Ethanol feeding for 4 days increased apoptosis of Kupffer cells in both wild-type and C1qa −/− mice. Ethanol-induced deposition of C1q and C3b/iC3b/C3c was colocalized with apoptotic Kupffer cells in wild-type, but not C1qa −/− , mice. Furthermore, ethanol-induced increases in tumor necrosis factor–α and interleukin-6 expression at this early time point were suppressed in C1q-deficient mice. Chronic ethanol feeding (25 days) increased steatosis, hepatocyte apoptosis, and activity of serum alanine and aspartate aminotransferases in wild-type mice. These markers of hepatocyte injury were attenuated in C1qa −/− mice. In contrast, chronic ethanol (25 days)-induced increases in cytochrome P450 2E1 expression and oxidative stress did not differ between wild-type and C1qa −/− mice. Conclusions For the first time, these data indicate that ethanol activates the classical complement pathway via C1q binding to apoptotic cells in the liver and that C1q contributes to the pathogenesis of ethanol-induced liver injury.
Abstract Adiposity is associated with chronic low-grade systemic inflammation and increased inflammation in the hypothalamus, a key structure in feeding behavior. It remains unknown whether ...inflammation impacts other brain structures that regulate feeding behavior. We studied 44 overweight/obese and 19 lean individuals with MRI and plasma fibrinogen levels (marker of inflammation). We performed MRI-based segmentations of the medial and lateral orbitofrontal cortex (OFC) and hippocampal volumes. Gray matter (GM) volumes were adjusted for head size variability. We conducted logistic and hierarchical regressions to assess the association between fibrinogen levels and brain volumetric data. Using diffusion tensor imaging (DTI), we created apparent diffusion coefficient (ADC) maps and conducted voxelwise correlational analyses. Fibrinogen concentrations were higher among the overweight/obese (t61 =−2.33, P = 0.023). Lateral OFC associated together with fibrinogen correctly classified those with excess of weight (accuracy = 76.2%, sensitivity = 95.5%, and specificity = 31.6%). The lateral OFC volumes of overweight/obese were negatively associated with fibrinogen (r =−0.37, P = 0.016) and after accounting for age, hypertension, waist/hip ratio and lipid and sugar levels, fibrinogen significantly explained an additional 9% of the variance in the lateral OFC volume (β =−0.348, ΔR2 = 0.093, ΔF P = 0.046). Among overweight/obese the associations between GM ADC and fibrinogen were significantly positive (P < 0.001) in the left and right amygdala and the right parietal region. Among lean individuals these associations were negative and located in the left prefrontal, the right parietal and the left occipital lobes. This is the first study to report that adiposity-related inflammation may reduce the integrity of some of the brain structures involved in reward and feeding behaviors.
The development of alcoholic liver disease (ALD) is a complex process involving both parenchymal and nonparenchymal cells resident in the liver. Although the mechanisms for ALD are not completely ...understood, it is clear that increased oxidative stress, and activation of the innate immune system are essential elements in the pathophysiology of ALD. Oxidative stress from ethanol exposure results from increased generation of reactive oxygen species and decreased hepatocellular antioxidant activity, including changes in the thioredoxin/peroxiredoxin family of proteins. Both cellular and circulating components of the innate immune system are activated by exposure to ethanol. For example, ethanol exposure enhances toll-like receptor-4 (TLR-4)-dependent cytokine expression by Kupffer cells, likely due, at least in part, to dysregulation of redox signaling. Similarly, complement activation in response to ethanol leads to increased production of the anaphylatoxins, C3a and C5a, and activation C3a receptor and C5a receptor. Complement activation thus contributes to increased inflammatory cytokine production and can influence redox signaling. Here we will review recent progress in understanding the interactions between oxidative stress and innate immunity in ALD. These data illustrate that ethanol-induced oxidative stress and activation of the innate immune system interact dynamically during ethanol exposure, exacerbating ethanol-induced liver injury.
Ethanol‐induced liver injury is characterized by increased formation of reactive oxygen species (ROS) and inflammatory cytokines, resulting in the development of hepatic steatosis, injury, and cell ...death by necrosis and apoptosis. Thioredoxin (Trx), a potent antioxidant and antiinflammatory molecule with antiapoptotic properties, protects animals from a number of inflammatory diseases. However, the effects of ethanol on Trx or its role in ethanol‐induced liver injury are not known. Female C57BL/6 mice were allowed ad libitum access to a Lieber‐deCarli ethanol diet with 5.4% of calories as ethanol for 2 days to acclimate them to the diet, followed by 2 days with 32.4% of calories as ethanol or pair‐fed control diet. Hepatic Trx‐1 was decreased by ethanol feeding; daily supplementation with recombinant human Trx (rhTrx) prevented this ethanol‐induced decrease. Therefore, we tested the hypothesis that administration of rhTrx during ethanol exposure would attenuate ethanol‐induced oxidative stress, inflammatory cytokine production, and apoptosis. Mice were treated with a daily intraperitoneal injection of either 5 g/kg of rhTrx or phosphate‐buffered saline (PBS). Conclusion: Ethanol feeding increased accumulation of hepatic 4‐hydroxynonenal protein adducts, expression of hepatic tumor necrosis factor α, and resulted in hepatic steatosis and increased plasma aspartate aminotransferase and alanine aminotransferase. In ethanol‐fed mice, treatment with rhTrx reduced 4‐hydroxynonenal adduct accumulation, inflammatory cytokine expression, decreased hepatic triglyceride, and improved liver enzyme profiles. Ethanol feeding also increased transferase‐mediated dUTP‐biotin nick‐end labeling‐positive cells, caspase‐3 activity, and cytokeratin‐18 staining in the liver. rhTrx treatment prevented these increases. In summary, rhTrx attenuated ethanol‐induced increases in markers of oxidative stress, inflammatory cytokine expression, and apoptosis. (HEPATOLOGY 2009.)
The development of alcoholic liver disease (ALD) is a complex process involving both the parenchymal and non‐parenchymal cells in the liver. The impact of ethanol on hepatocytes can be characterized ...as a condition of organelle stress with multifactorial changes in hepatocellular function accumulating during ethanol exposure. These changes include oxidative stress, mitochondrial dysfunction, decreased methylation capacity, endoplasmic reticulum stress, impaired vesicular trafficking and altered proteasome function. Injury to hepatocytes is attributed, in part, to ethanol metabolism by the hepatocytes. Changes in the structural integrity of hepatic sinusoidal endothelial cells, as well as enhanced inflammation in the liver during ethanol exposure are also important contributors to injury. Activation of hepatic stellate cells initiates the deposition of extracellular matrix proteins characteristic of fibrosis. Kupffer cells, the resident macrophages in the liver, are particularly critical to the onset of ethanol‐induced liver injury. Chronic ethanol exposure sensitizes Kupffer cells to activation by lipopolysaccharides via toll‐like receptor 4. This sensitization enhances the production of inflammatory mediators, such as tumor necrosis factor‐α and reactive oxygen species that contribute to hepatocyte dysfunction, necrosis and apoptosis of hepatocytes and the generation of extracellular matrix proteins leading to fibrosis. In this review we provide an overview of the complex interactions between parenchymal and non‐parenchymal cells in the liver during the progression of ethanol‐induced liver injury.
Background & Aims Inflammatory gene expression plays a pathological role in acute and chronic hepatic inflammation, yet, inflammation also promotes liver repair by inducing protective mechanisms to ...limit collateral tissue damage by priming hepatocytes for proliferation. Early growth response (Egr)-1, a transcription factor that regulates inflammatory gene expression, plays a pathological role in many animal models of acute and chronic inflammatory disease. Here, we tested the hypothesis that Egr-1 is beneficial after toxic liver injury. Methods Acute liver injury was induced in wild-type and egr-1−/− mice by a single injection of carbon tetrachloride (CCl4 ). Liver injury, inflammatory, and hepatoprotective gene expression and signaling events were measured 18, 48, and 72 h after CCl4 administration. Results Peak liver injury was greater in egr-1−/− mice compared to wild-type mice. Enhanced injury in egr-1−/− mice was associated with reduced tumor necrosis factor (TNF)α mRNA and protein expression, reduced Akt phosphorylation and nuclear localization of NFκB-p65 in nuclei of cells in the hepatic sinusoid. Expression of inducible nitric oxide synthase and cyclooxygenase-2, TNFα-regulated genes that have hepatoprotective function, was attenuated in egr-1−/− mice compared to wild-type mice. Although plasma interleukin (IL)-6 protein and hepatic accumulation of IL-6, glycoprotein 130, and IL-6 receptor α mRNA in wild-type and egr-1−/− mice were equivalent, signal transducer and activator of transcription 3 phosphorylation was attenuated in egr-1−/− mice and associated with reduced oncostatin M expression. Conclusions In contrast to its role in inflammation-mediated tissue injury in other models, Egr-1 expression promotes protection in the liver after CCl4 exposure.
Background:
Correlative evidence indicates that apoptosis is associated with the progression of alcoholic liver disease. If apoptosis contributes to ethanol (EtOH)‐induced steatohepatitis and/or ...fibrosis, then mice deficient in Bid, a key pro‐apoptotic Bcl‐2 family member, or mice treated with a pan‐caspase inhibitor (VX166) should be resistant to EtOH‐induced liver injury.
Methods:
This hypothesis was tested in mice using a model of chronic, heavy EtOH‐induced liver injury, as well as in a model in which moderate EtOH feeding accelerated the appearance of early markers of hepatic fibrosis in response to acute carbon tetrachloride (CCl4) exposure.
Results:
Chronic EtOH feeding to mice increased TUNEL‐ and cytokeratin‐18‐positive cells in the liver, as well as the expression of receptor‐interacting protein kinase 3 (RIP3), a marker of necroptosis. In this model, Bid−/− mice or wild‐type mice treated with VX166 were protected from EtOH‐induced apoptosis, but not EtOH‐induced RIP3 expression. Bid deficiency or inhibition of caspase activity did not protect mice from EtOH‐induced increases in plasma alanine and aspartate amino transferase activity, steatosis, or mRNA expression of some inflammatory cytokines. Moderate EtOH feeding to mice enhanced the response of mice to acute CCl4 exposure, resulting in increased expression of α‐smooth muscle actin and accumulation of extracellular matrix protein. VX166‐treatment attenuated EtOH‐mediated acceleration of these early indicators of CCl4‐induced hepatic fibrosis, decreasing the expression of α‐smooth muscle actin, and the accumulation of extracellular matrix protein.
Conclusions:
EtOH‐induced apoptosis of hepatocytes was mediated by Bid. Apoptosis played a critical role in the accelerating the appearance of early markers of CCl4‐induced fibrosis by moderate EtOH but did not contribute to EtOH‐induced hepatocyte injury, steatosis, or expression of mRNA for some inflammatory cytokines.
ObjectivesObesity is on the rise in the US and is linked to the development of type 2 diabetes and cardiovascular disease. Emerging evidence over the last decade suggests that obesity may also ...adversely affect executive function and brain structure. Although a great deal of research focuses on how diet affects the brain and cognitive performance, no study focuses on how food choice may be associated with brain integrity. Here we investigated how lean and overweight/obese (o/o) adults differed in their food choices and how brain structure and cognition may be associated with those choices.DesignAs part of an ongoing study on diabetes and the brain, participants had routine blood work and a research MRI, received a battery of neurocognitive tests, and were instructed to keep a 3-day food diary.Results and conclusionsThe lean group ate more high quality foods and less low quality foods compared to the o/o group. In the o/o group, high quality food choices were associated with orbitofrontal cortex volume. The lean group performed better than the o/o group on neurocognitive measures of executive function, such as the Stroop Interference Test, the Wisconsin Card Sort Test and the Trail Making Test B-A, and on attention and concentration tasks such as the Digit Symbol Substitution Test. Taken together, these preliminary data suggest that in obesity poor food choices may be associated with frontal cognitive impairments that may be the result of, or contribute to, decreases in orbitofrontal cortex volume. Therefore, longitudinal studies are warranted to investigate a causal link between food choice and executive functioning.
Background & Aims: The complement pathway is an important component of the innate and adaptive immune response. Here we tested the hypothesis that activation of complement is required for development ...of ethanol-induced fatty liver. Methods: Wild-type mice and mice lacking the third (C3) or fifth (C5) components of the complement activation pathway, as well as mice lacking decay-accelerating factor (CD55/DAF), a complement regulatory protein, were fed Lieber–DeCarli ethanol-containing diets for 6 weeks or pair-fed control diets. Results: Ethanol feeding to wild-type mice increased C3a in plasma. Wild-type and C5−/− mice fed the ethanol diet developed hepatic steatosis characterized by microvesicular and macrovesicular lipid accumulation and increased triglyceride content. C3−/− mice did not develop steatosis, while CD55/DAF−/− mice accumulated even more hepatic triglyceride after ethanol feeding than wild-type mice. Levels of serum alanine aminotransferase and hepatic tumor necrosis factor α, indicators of hepatocyte injury and inflammation, respectively, were increased in wild-type and CD55/DAF−/− mice but not in C5−/− mice after ethanol feeding. In contrast to the protective effect of C3−/− against ethanol-induced steatosis, levels of both alanine aminotransferase and tumor necrosis factor α were increased in C3−/− mice after ethanol feeding. Conclusions: Here we have identified several elements of the complement system as important contributors to ethanol-induced fatty liver. C3 contributed primarily to the accumulation of triglyceride in the liver, whereas C5 was involved in inflammation and injury to hepatocytes. Further, the absence of CD55/DAF exacerbated these responses, suggesting that CD55/DAF serves as a barrier to ethanol-induced fatty liver.
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