Abstract: Inflammation In the absence of pathogens occurs in all tissues in response to a wide range of stimuli that cause tissue stress and injury. Such sterile inflammation (SI) is a key process in drug-induced liver injury, nonalcoholic steatohepatitis, and alcoholic steatohepatitis and is a major determinant of fibrosis and carcinogenesis. In SI, endogenous damage-associated molecular patterns (DAMPS), which are usually hidden from the extracellular environment, are released on tissue injury and activate receptors on immune cells. More than 20 such DAMPS have been identified and activate cellular pattern recognition receptors, which were originally identified as sensors of pathogen-associated molecular patterns. Activation of pattern recognition receptors by DAMPS results in a wide range of immune responses, including production of proinflammatory cytokines and localization of immune cells to the site of injury. DAMPS result in the assembly of a cytosolic protein complex termed the inflammasome, which activates the serine protease caspase-1, resulting in activation and secretion of interleukin-1β and other cytokines. SI-driven liver diseases are responsible for the majority of liver pathology in industrially developed countries and lack specific therapy. Identification of DAMPS, their receptors, signaling pathways, and cytokines now provides a wide range of therapeutic targets for which many antagonists are already available. Inflammation In the absence of pathogens occurs in all tissues in response to a wide range of stimuli that cause tissue stress and injury. Such sterile inflammation (SI) is a key process in drug-induced liver injury, nonalcoholic steatohepatitis, and alcoholic steatohepatitis and is a major determinant of fibrosis and carcinogenesis. In SI, endogenous damage-associated molecular patterns (DAMPS), which are usually hidden from the extracellular environment, are released on tissue injury and activate receptors on immune cells. More than 20 such DAMPS have been identified and activate cellular pattern recognition receptors, which were originally identified as sensors of pathogen-associated molecular patterns. Activation of pattern recognition receptors by DAMPS results in a wide range of immune responses, including production of proinflammatory cytokines and localization of immune cells to the site of injury. DAMPS result in the assembly of a cytosolic protein complex termed the inflammasome, which activates the serine protease caspase-1, resulting in activation and secretion of interleukin-1β and other cytokines. SI-driven liver diseases are responsible for the majority of liver pathology in industrially developed countries and lack specific therapy. Identification of DAMPS, their receptors, signaling pathways, and cytokines now provides a wide range of therapeutic targets for which many antagonists are already available. The liver is a target of pathogens that induce a rapid inflammatory response, and much has been discovered regarding the pathogen-associated molecular patterns (PAMPs) that initiate this.1Thompson M.R. Kaminski J.J. Kurt-Jones E.A. et al.Pattern recognition receptors and the innate immune response to viral infection.Viruses. 2011; 3: 920-940Crossref PubMed Scopus (453) Google Scholar It is much less intuitive that injury in the absence of pathogens would result in inflammation. Sterile inflammation (SI), however, occurs in all tissues after injury of varied etiologies. Examples are soft tissue crush injuries, myocardial infarction, and pancreatitis after aberrant zymogen activation.2Zhang Q. Raoof M. Chen Y. et al.Circulating mitochondrial DAMPs cause inflammatory responses to injury.Nature. 2010; 464: 104-107Crossref PubMed Scopus (2199) Google Scholar In the liver, SI is particularly important because it is a major component of the pathology of a wide range of diseases, such as alcoholic steatohepatitis (ASH), nonalcoholic steatohepatitis (NASH), drug-induced liver injury, and ischemia/reperfusion (I/R).3Gao B. Seki E. Brenner D.A. et al.Innate immunity in alcoholic liver disease.Am J Physiol Gastrointest Liver Physiol. 2011; 300: G516-G525Crossref PubMed Scopus (157) Google Scholar, 4Brenner D.A. Seki E. Taura K. et al.Non-alcoholic steatohepatitis-induced fibrosis: Toll-like receptors, reactive oxygen species and Jun N-terminal kinase.Hepatol Res. 2010; 41: 683-686Crossref Scopus (0) Google Scholar, 5Maher J.J. DAMPs ramp up drug toxicity.J Clin Invest. 2009; 119: 246-249PubMed Google Scholar Collectively, these diseases are responsible for the majority of liver pathology in the industrialized world and lack specific therapy.The field of SI has recently undergone advances in the understanding of how tissue injury results in inflammation. The theoretical basis for this originated in the inability of self-recognition and non–self-recognition to explain the selectivity of the adaptive immune system. This led to the proposal that danger is used as a criterion for immune activation, and molecules termed “damage-associated molecular patterns” (DAMPs) released from damaged cells are a molecular trigger for inflammation (Figure 1).6Matzinger P. Tolerance, danger, and the extended family.Annu Rev Immunol. 1994; 12: 991-1045Crossref PubMed Google Scholar This has been experimentally validated and explains many aspects of the sterile inflammatory response.7Rock K.L. Latz E. Ontiveros F. et al.The sterile inflammatory response.Annu Rev Immunol. 2010; 28: 321-342Crossref PubMed Scopus (564) Google Scholar Recent advances have occurred in identification of a number of DAMPs, their receptors, and the cellular machinery required for processing this into a full inflammatory response. Some general concepts have emerged. Firstly, SI is a bona fide inflammatory response, with features including redness, swelling, heat, neutrophilic infiltrate, cytokine production, and tissue damage. SI can initiate in minutes using innate immune pathways but is also present chronically, for example, in NASH and ASH. Conceptually pathogen-driven inflammation and SI are distinct, but functionally there are many areas of overlap. Many receptors and pathways initially identified as activated by PAMPs are also activated by DAMPs.8Poltorak A. He X. Smirnova I. et al.Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene.Science. 1998; 282: 2085-2088Crossref PubMed Scopus (6245) Google Scholar, 9Park J.S. Gamboni-Robertson F. He Q. et al.High mobility group box 1 protein interacts with multiple Toll-like receptors.Am J Physiol Cell Physiol. 2006; 290: C917-C924Crossref PubMed Scopus (749) Google Scholar An example is Toll-like receptor (TLR)4, which can be activated by the bacterial lipopolysaccharide (LPS) as well as cellular high-mobility group protein B1 (HMGB1). Due to the unique vascular supply of the liver, PAMPs of intestinal origin and DAMPs of hepatocyte origin collectively contribute to inflammation in a number of diseases. There is also direct interaction with PAMPs, such as LPS stimulating the release of HMGB1.10Kim J.H. Kim S.J. 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Signal 1 results in transcriptional up-regulation of procytokines and inflammasome components, and signal 2 results in assembly of the inflammasome, cleavage of caspase-1, and activation and secretion of cytokines.View Large Image Figure ViewerDownload Hi-res image Download (PPT)DAMPsThe term “DAMPs” is broadly applied to self-molecules that have the ability to activate inflammation.6Matzinger P. Tolerance, danger, and the extended family.Annu Rev Immunol. 1994; 12: 991-1045Crossref PubMed Google Scholar A large and varied number of DAMPs have been identified, and the list is growing (Table 1).15Kono H. Rock K.L. How dying cells alert the immune system to danger.Nat Rev Immunol. 2008; 8: 279-289Crossref PubMed Scopus (1215) Google Scholar It had been recognized for many years that the cytosol of apoptotic cells was able to activate dendritic cells and thus by definition contained DAMPs. Chromatographic separation identified uric acid as a major DAMP, and interestingly it needed to be in crystal form to induce SI.16Shi Y. Evans J.E. Rock K.L. Molecular identification of a danger signal that alerts the immune system to dying cells.Nature. 2003; 425: 516-521Crossref PubMed Scopus (1345) Google Scholar At one level, this was unsurprising because the role of uric acid crystals in gout was well established.17Liote F. Hyperuricemia and gout.Curr Rheumatol Rep. 2003; 5: 227-234Crossref PubMed Google Scholar However, it highlighted the importance of the degradative uric acid pathway, which contains metabolites such as adenosine triphosphate (ATP), adenosine, and uric acid in immunoregulation. A partial list of the DAMPs, their receptors, and the type of signal they provide appears in Table 1. Many DAMPs activate pattern recognition receptors (PRRs), of which TLRs are the best characterized. The function of these receptors is best studied on immune cells, but they are expressed very broadly in the liver with important functions on parenchymal cells.18Mencin A. Kluwe J. Schwabe R.F. Toll-like receptors as targets in chronic liver diseases.Gut. 2009; 58: 704-720Crossref PubMed Scopus (261) Google Scholar, 19Dapito D.H. Mencin A. Gwak G.Y. et al.Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4.Cancer Cell. 2012; 21: 504-516Abstract Full Text Full Text PDF PubMed Scopus (700) Google ScholarMitochondria originate from obligate intracellular parasites and retain molecules and structures that share many features with bacteria.55Yang D. Oyaizu Y. Oyaizu H. et al.Mitochondrial origins.Proc Natl Acad Sci U S A. 1985; 82: 4443-4447Crossref PubMed Scopus (0) Google Scholar Not surprisingly, mitochondrial components have proven to be a rich source of DAMPs, including mitochondrial DNA, formyl peptides, cytochrome c, and ATP. Such a concentration of DAMPs makes mitochondria very potent stimulators of inflammation.56Iyer S.S. Pulskens W.P. Sadler J.J. et al.Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome.Proc Natl Acad Sci U S A. 2009; 106: 20388-20393Crossref PubMed Scopus (496) Google Scholar, 57Krysko D.V. Agostinis P. Krysko O. et al.Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation.Trends Immunol. 2011; 32: 157-164Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar The diversity of mitochondrial DAMPs such as DNA and ATP further increases their ability to induce inflammation because they can provide the full range of signals required to initiate SI. The liver is well positioned to undergo mitochondrial-driven inflammation due to the very large number of mitochondria present in the metabolically active hepatocytes.DAMPs were proposed to explain immune responses to tissue injury, and as such release of DAMPs by cell death has been extensively investigated. Two contrasting types of cell death are (1) the programmed death termed “apoptosis,” in which there is nuclear degradation and sequestration of cellular contents within plasma membrane blebs, and (2) the unexpected and unregulated cell death termed “necrosis,” in which cellular contents are relatively intact and extravasate due to disruption of the plasma membrane.58Lotze M.T. Tracey K.J. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal.Nat Rev Immunol. 2005; 5: 331-342Crossref PubMed Scopus (1884) Google Scholar As expected from these morphological descriptions, a number of DAMPs have been detected after necrotic but not apoptotic cell death.59Zitvogel L. Kepp O. Kroemer G. Decoding cell death signals in inflammation and immunity.Cell. 2010; 140: 798-804Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar In addition to physical retention of DAMPs in apoptotic plasma membrane blebs, a number of active processes such as degradation of nucleic acids and inactivation of HMGB1 by oxidation limit DAMP activity during apoptosis. Immunologically silent cell death by apoptosis is dependent on the removal of apoptotic bodies by phagocytosis. In its absence, apoptotic bodies undergo secondary necrosis and lose their integrity with spillage of their contents, including DAMPs, into the extracellular environment.60Silva M.T. Secondary necrosis: the natural outcome of the complete apoptotic program.FEBS Lett. 2010; 584: 4491-4499Crossref PubMed Scopus (251) Google ScholarEntirely unregulated necrotic cell death occurs in response to various destructive stimuli such as thermal and mechanical injury; however, cell death with features of necrosis also occurs in response to specific stimuli such as tumor necrosis factor (TNF).61Vandenabeele P. Galluzzi L. Vanden Berghe T. et al.Molecular mechanisms of necroptosis: an ordered cellular explosion.Nat Rev Mol Cell Biol. 2010; 11: 700-714Crossref PubMed Scopus (1540) Google Scholar This is termed “necroptosis,” and although it shares features of necrotic cell death, including release of DAMPs, it is highly regulated at many levels, including initiators, modulators, and cell signaling pathways. The importance of necroptosis in relation to the production of DAMPs and SI is that it provides a pathway of regulated proinflammatory type of cell death. In addition to a necroptosis pathway of inflammatory cell death, pure apoptotic stimuli can result in a mixed type of cell death in vivo due to cell-specific responses and to secondary changes such as hemorrhage and ischemia. Finally, release of DAMP also occurs as a regulated event independent of apoptosis. HMGB1 can be secreted by activated macrophages in response to LPS, TNF, and transforming growth factor β.58Lotze M.T. Tracey K.J. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal.Nat Rev Immunol. 2005; 5: 331-342Crossref PubMed Scopus (1884) Google Scholar This confirms the functional proinflammatory actions of HMGB1 and further shows that it straddles the boundary between a DAMP and a cytokine.A number of DAMPs undergo modifications that significantly alter their function. HMGB1, for example, undergoes acetylation, which stops its reentry into the nucleus with subsequent migration into cytoplasmic secretory vesicles.62Bonaldi T. Talamo F. 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The development of a less oxidative extracellular environment by release of nonprotein thiols from necrotic cells could prolong the activity of DAMPs and contribute to sustained inflammation.Nucleic acidsNonmethylated bacterial CpG DNA is a potent activator of TLR9. Mammalian DNA can also activate TLR9 and induce a number of cellular immune responses, including antibody production, dendritic cell maturation, and release of inflammatory cytokines by macrophages.64Busconi L. Bauer J.W. Tumang J.R. et al.Functional outcome of B cell activation by chromatin immune complex engagement of the B cell receptor and TLR9.J Immunol. 2007; 179: 7397-7405Crossref PubMed Scopus (48) Google Scholar, 65Barrat F.J. Meeker T. 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Publication Year: 2012
Publication Date: 2012-09-13
Language: en
Type: review
Indexed In: ['crossref', 'pubmed']
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