Table 2. Organ-specific effects of extracellular histone in various models of sterile organ injury.
| Organ | Animal model of AOI | Effects of histone/anti-histone therapy |
|---|---|---|
| Brain | I/R53 | Chromatin released post I/R injury |
| Exogenous histone infusion | ||
| Increases infarct volume | ||
| Worsens neurological scores. | ||
| Improve neurological scores | ||
| Anti-H2A/H4 antibodies | ||
| Reduce infarct volume | ||
| Histone-induced toxicity54 | Dose-dependent, H1 neurotoxicity | |
| H1-mediated microglial | ||
| Survival | ||
| Increased reactivity | ||
| MHC class II receptor expression | ||
| Chemoattractant activity | ||
| Heart | I/R55, 56 | Accumulation of eHistones within myocardium |
| eHistone-mediated myocytoxicity | ||
| PAD4 KO mice are protected from MI injury | ||
| DNase1 treatment | ||
| Improves ventricular remodelling | ||
| Prolongs local cardiomyocyte survival | ||
| Reduces MI volume | ||
| Improves cardiac function | ||
| Reduces nucleosome release and neutrophil infiltration | ||
| No effect on mortality, infarct size or inflammation | ||
| Lungs | TRALI57 | Activated platelets promote NET formation in TRALI |
| NETs increase permeability of LPS primed endothelial cells | ||
| Anti-H2A/H4 antibodies attenuate | ||
| Histone-mediated lung oedema | ||
| Vascular permeability | ||
| Mortality | ||
| Prevent further NET formation | ||
| NET induced35 | NETs and eHistones induce cell death | |
| Epithelial | ||
| HUVECs | ||
| DNase | ||
| Does not decrease NET-mediated cytotoxicity | ||
| Anti-H1/2A/2B/4 antibodies, PSA and APC are protective | ||
| IgG and Complement induced36 | eHistone | |
| Released into BALF of ALI patients | ||
| Dependent on complement (C5aR and C5L2) activation | ||
| Exhibits alveolar epithelial cytotoxicity | ||
| C5aR and C5L2 activation induces neutrophil-dependent ALI (?NETs) | ||
| Anti-H4 IgG antibody attenuates ALI severity | ||
| Trauma19 | Serum histone reaches toxic levels post-trauma | |
| Release correlates with | ||
| Lung injury severity | ||
| Endothelial damage | ||
| Coagulation | ||
| eHistone actions | ||
| Direct toxicity to endothelial cells | ||
| Stimulate cytokine and NET release | ||
| Phospholipid-histone complexes result in direct cellular toxicity through membrane disruption and calcium influx | ||
| Liver | ConA and APAP induced2 | eHistones stimulate a “cytokine storm” |
| Potentiate TLR2 and TLR4 signal transduction | ||
| No activity at TLR3/5/7/8/9 | ||
| Cytokine release is abolished in TLR4 KO mice | ||
| H3 histone is released in ConA and APAP induced liver injury | ||
| Anti-H3 antibody | ||
| Reduces mortality and cytokine release | ||
| Does not prevent histone release or improve liver injury markers | ||
| I/R17, 58, 59, 60 | Histones released from hepatocytes post-I/R injury | |
| Histone infusion | ||
| Worsens markers of acute liver injury | ||
| Activates non-parenchymal KC TLR9-MyD88 pathways | ||
| Enhances DNA-TLR9 signalling | ||
| TLR9-mediates mitochondrial ROS production | ||
| ROS activates NLRP3 Inflammasome | ||
| Effects attenuated in TLR9 and NLRP3 KO mice | ||
| DAMPs (eHistone and HMGB1) stimulate NET formation post I/R injury by activating TLR4 and TLR9 | ||
| NETs | ||
| Hepatocytotoxic | ||
| Stimulate KC-cytokine release | ||
| Formation is inhibited by PAD4i and DNase1 | ||
| Anti-H3/H4 histone antibody | ||
| Attenuates TLR9 signalling | ||
| Improves markers of acute liver injury | ||
| Kidney | I/R16 | Necrotic TECs release histone |
| eHistone actions | ||
| Direct toxicity to renal endothelial and TECs | ||
| Leukocyte recruitment | ||
| Microvascular vascular leakage | ||
| Renal inflammation | ||
| Activates TLR2/TLR4 and potentiates NFkB, MyD88, MAPK signalling | ||
| Anti-histone IgG is protective | ||
| Pancreas | Gallstone and CCK61 | Histone released from necrotic acinar cells. |
| eHistone concentration correlates well with severity of tissue injury |
Abbreviations: APC, activated Protein C; ALF, acute liver failure; ALI, acute lung injury; APAP, Paracetemol/Acetominophen; BALF, bronchoalveolar lavage fluid; C5aR, component 5a receptor; C5L2, anaphylatoxin chemotactic receptor; citH3, citrullinated H3; ConA, Concanavalin A; DNA, deoxyribonucleic acid; DNase, deoxyribonuclease; EC, endothelial cells; eHistones, extracellular histones; ELISA, enzyme linked immunosorbent assay; H1/H2A/H2AX/H2B/H3/H4/H5, histone subtypes; HMGB1, high-mobility group box 1; HUVEC, human vascular endothelial cells; IgG, immunogloblin G; KC, kupffer cells; KO, knockout; I/R, ischaemia reperfusion; LPS, lipopolysaccharide; mAb, monoclonal antibody; MAPK, mitogen-activated protein kinases; MCA, middle cerebral artery; MHC, major histocompatibility complex; MI, myocardial Infarction; MPO, myeloperoxidase; MyD88, myeloid differentiation primary response gene 88; NET, neutrophil extracellular traps; NFkB, nuclear factor kappa B; NLRP3, nucleotide-binding domain leucine-rich repeat containing protein 3; NS, non-significant result; PAD4i, peptidyl-arginine-deiminase-4; PSA, polysialic acid; ROS, reactive oxygen species; S, significant result; TECs, tubular epithelial cells; TLR, Toll-like receptor; TRALI, transfusion-associated lung injury