Sterile inflammatory insults are known to activate innate immunity and propagate organ damage through the recognition of extracellular Damage Associated Molecular Pattern (DAMP) molecules. Although DAMPs, such as endogenous DNA and nuclear High Mobility Group Box 1, have been shown to be critical in sterile inflammation, the role of nuclear histone proteins has not yet been investigated. We report that endogenous histones function as DAMPs following ischemic injury through the pattern recognition receptor Toll-Like Receptor 9 (TLR9) to initiate inflammation. Using an in vivo model of hepatic ischemia/reperfusion (I/R) injury, we show that levels of circulating histones are significantly higher after I/R, and that histone neutralization significantly protects against injury. Injection of exogenous histones exacerbates I/R injury through cytotoxic effects mediated by TLR9 and MyD88. In addition, histone administration increases TLR9 activation, while neither TLR9 nor MyD88 mutant mice respond to exogenous histones. Furthermore, we demonstrate in vitro that extracellular histones enhance DNA-mediated TLR9 activation in immune cells through a direct interaction. Conclusions these novel findings reveal that histones represent a new class of DAMP molecules and they serve as a crucial link between initial damage and activation of innate immunity during sterile inflammation.
Cellular processes that drive sterile inflammatory injury after hepatic ischemia/reperfusion (I/R) injury are not completely understood. Activation of the inflammasome plays a key role in response to invading intracellular pathogens, but mounting evidence suggests it also plays a role in inflammation driven by endogenous danger-associate molecular pattern (DAMP) molecules released after ischemic injury. The nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3) inflammasome is one such process, and the mechanism by which its activation results in damage and inflammatory responses following liver I/R is unknown. Here we report that both NLRP3 and its downstream target Caspase-1 are activated I/R and are essential for hepatic I/R injury as both NLRP3 and Caspase-1 KO mice are protected from injury. Furthermore, inflammasome-mediated injury is dependent on Caspase-1 expression in liver non-parenchymal cells. While upstream signals that activate the inflammasome during ischemic injury are not well characterized, we show that endogenous extracellular histones activate the NLRP3 inflammasome during liver I/R through Toll-like Receptor-9 (TLR9). This occurs through TLR9-dependent generation of reactive oxygen species. This mechanism is operant in resident liver Kupffer cells, which drive innate immune responses after I/R injury by recruiting additional cell types, including neutrophils and inflammatory monocytes. These novel findings illustrate a new mechanism by which extracellular histones and activation of NLRP3 inflammasome contribute to liver damage and activation of innate immunity during sterile inflammation.
High-mobility group box 1 (HMGB1) is an abundant chromatin-associated nuclear protein and released into the extracellular milieu during liver ischemia-reperfusion (I/R), signaling activation of proinflammatory cascades. Because the intracellular function of HMGB1 during sterile inflammation of I/R is currently unknown, we sought to determine the role of intracellular HMGB1 in hepatocytes after liver I/R. When hepatocytespecific HMGB1 knockout (HMGB1-HC-KO) and control mice were subjected to a nonlethal warm liver I/R, it was found that HMGB1-HC-KO mice had significantly greater hepatocellular injury after I/R, compared to control mice. Additionally, there was significantly greater DNA damage and decreased chromatin accessibility to repair with lack of HMGB1. Furthermore, lack of hepatocyte HMGB1 led to excessive poly(ADP-ribose)polymerase 1 activation, exhausting nicotinamide adenine dinucleotide and adenosine triphosphate stores, exacerbating mitochondrial instability and damage, and, consequently, leading to increased cell death. We found that this was also associated with significantly more oxidative stress (OS) in HMGB1-HC-KO mice, compared to control. Increased nuclear instability led to a resultant increase in the release of histones with subsequently more inflammatory cytokine production and organ damage through activation of Toll-like receptor 9. Conclusion: The lack of HMGB1 within hepatocytes leads to increased susceptibility to cellular death after OS conditions.
Ischemia-reperfusion (I/R) injury is a process whereby an initial hypoxic insult and subsequent return of blood flow leads to the propagation of innate immune responses and organ injury. The necessity of the pattern recognition receptor, toll-like receptor (TLR)-4, for this innate immune response has been previously shown. However, TLR4 is present on various cell types of the liver, both immune and non-immune cells. Therefore, we sought to determine the role of TLR4 in individual cell populations, specifically parenchymal hepatocytes, myeloid cells including Kupffer cells, and dendritic cells following hepatic I/R. When hepatocyte specific (Alb-TLR4-/-) and myeloid cell specific (Lyz-TLR4-/-) TLR4 knockout mice were subjected to warm hepatic ischemia there was significant protection in these mice compared to wild-type (WT). However, the protection afforded in these two strains was significantly less than global TLR4 specific TLR4 knockout (TLR4-/-) mice. Dendritic cell specific TLR4-/- (CD11c-TLR4-/-) mice had significantly increased hepatocellular damage compared to WT mice. Circulating levels of high mobility group box-1 (HMGB1) were significantly reduced in the Alb-TLR4-/- mice compared to WT, Lyz-TLR4-/-, CD11c-TLR4-/- mice and equivalent to global TLR4-/- mice, suggesting that TLR4 mediated HMGB1 release from hepatocytes may be a source of HMGB1 after I/R. Hepatocytes exposed to hypoxia responded by rapidly phosphorylating the mitogen-activated protein kinases JNK and p38 in a TLR4-dependent manner; inhibition of JNK decreased the release of HMGB1 after both hypoxia in vitro and I/R in vivo. Conclusion These results provide insight into the individual cellular response of TLR4. It was found that the parenchymal hepatocyte is an active participant in the sterile inflammatory response after I/R through TLR4-mediated activation of pro-inflammatory signaling and release of danger signals such as HMGB1.
Dendritic cells (DCs) are potent antigen-presenting cells critical in regulating the adaptive immune response. The role of DCs is dichotomous; they may both present antigens and the appropriate stimulatory molecules to initiate an adaptive immune response, or they may induce tolerance and release anti-inflammatory signals. The activation of immature DCs, required for the expression of the necessary costimulatory T cell molecules, is dependent on pattern recognition receptors. In addition to the pathogen-derived ligands of pattern recognition receptors, several damage-associated molecular patterns (DAMPs) have recently been shown to interact with DCs and dramatically affect their ultimate function. The complex interplay of DAMPs on DCs is clinically important, with implications for transplantation, tumor immunity, autoimmunity, chronic inflammation and other conditions of sterile inflammation such as ischemia reperfusion injury. In this review, we will focus on the role of DAMPs in DC function.
BACKGROUND Pediatric firearm injury is a leading cause of death for U.S. children. We sought to further characterize children who die from these injuries using a validated national database. METHODS The National Trauma Data Bank 2010 to 2016 was queried for patients aged 0 to 19 years old. International Classification of Diseases external cause of injury codes were used to classify patients by intent. Differences between groups were analyzed using χ2 or Mann-Whitney U tests. Patterns over time were analyzed using nonparametric tests for trend. Multivariable logistic regression was used to investigate associations between the above factors and mortality. RESULTS There were a total of 45,288 children with firearm injuries, 12.0% (n = 5,412) of whom died. Those who died were younger and more often white than survivors. Mortality was associated with increased injury severity, shock on presentation, and polytrauma (p < 0.001 for all). There was an increasing trend in the proportion of self-inflicted injuries over the study period (p < 0.001), and mortality from these self-inflicted injuries increased concordantly (35.3% in 2010 to 47.8% in 2016, p = 0.001). Location of severe injuries had significant different mortality rates, ranging from 51.3% of head injuries to 3.9% in the extremities. In the multivariable model, treatment at a pediatric trauma center was protective against mortality, with odds ratios of 2.10 (confidence interval, 1.64–2.68) and 1.80 (confidence interval, 1.39–2.32) for death at adult and dual-designated trauma centers, respectively. This finding was confirmed in age-stratified cohorts. CONCLUSION Proportions of self-inflicted pediatric firearm injury in the National Trauma Data Bank increased from 2010 to 2016, as did mortality from self-inflicted injury. Because mortality is highest in this subpopulation, prevention and treatment efforts should be prioritized in this group of firearm-injured children. LEVEL OF EVIDENCE Epidemiological study, level V.
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