DAMPs and NETs in Sepsis

Abstract

Sepsis is a deadly inflammatory syndrome caused by an exaggerated immune response to infection. Much has been focused on host response to pathogens mediated through the interaction of pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs). PRRs are also activated by host nuclear, mitochondrial, and cytosolic proteins, known as damage-associated molecular patterns (DAMPs) that are released from cells during sepsis. Some well described members of the DAMP family are extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1), histones, and adenosine triphosphate (ATP). DAMPs are released from the cell through inflammasome activation or passively following cell death. Similarly, neutrophil extracellular traps (NETs) are released from neutrophils during inflammation. NETs are webs of extracellular DNA decorated with histones, myeloperoxidase, and elastase. Although NETs contribute to pathogen clearance, excessive NET formation promotes inflammation and tissue damage in sepsis. Here, we review DAMPs and NETs and their crosstalk in sepsis with respect to their sources, activation, release, and function. A clear grasp of DAMPs, NETs and their interaction is crucial for the understanding of the pathophysiology of sepsis and for the development of novel sepsis therapeutics.

Keywords: CIRP; DAMPs (damage-associated molecular patterns); HMGB1 (high-mobility group box 1); NETs (neutrophil extracellular traps); cold-inducible RNA-binding protein; histone; neutrophils; sepsis.

Figure 1

Cross talks between DAMPs and NETs in sepsis. Sepsis or hypoxia activates immune reactive cells, including macrophages, and neutrophils. In bacterial sepsis, PAMPs interact with PRR on macrophages to activate NF-κB, leading to increased expression of DAMPs (HMGB1, CIRP, H3) at transcriptional and translational levels. These intracellular DAMPs are then released extracellularly through different mechanisms, such as inflammasome-mediated GSDMD activation, which causes increased membrane pore formation to release intracellular DAMPs, or pyroptosis-, necroptosis-, or exosome-mediated pathways. These DAMPs can in turn recognize PRR on surrounding neutrophils and activate PAD4, GSDMD to promote NET formation. NETs components such as H3, MPO, or DNA can further activate immune cells and endothelial cells to release increased levels of DAMPs to augment the inflammatory cascade. In epithelial cells, extracellular histones derived from NETs promote cell/tissue injury, resulting in increased severity of ALI. DAMPs, damage-associated molecular patterns (DAMPs); NETs, neutrophil extracellular traps; PAMPs, pathogen-associated molecular patterns; PRR, pattern recognizing receptors; GSDMD, gasdermin D; HMGB1, high mobility group box 1; CIRP, cold-inducible RNA-binding protein; PAD4, peptidoglycan arginine deiminase 4; ALI, acute lung injury.

Figure 2

DAMPs or not DAMPs? In sepsis, extracellular motifs of several receptors like TREM-1, ST2 are cleaved by matrix metalloproteinases, leading to increased accumulation of truncated receptors in the blood. These soluble receptors serve as decoy molecules to recognize their ligands, thereby modulating respective intracellular signal transduction. During sepsis, cells release miRNA or cfDNA through exosomes or passively. Extracellular miRNAs can enter into adjacent cells and recognize endosomal TLR7 to induce inflammation. cfDNA can recognize HMGB1, and this protein-DNA complex is then recognized by the RAGE receptor and become internalized. Intracellular cfDNA then can activates endosomal TLR9 or STING to activate the production of pro-inflammatory mediators. DAMPs, damage-associated molecular patterns (DAMPs); TREM-1, triggering receptor expressed on myeloid cells-1; HMGB1, high mobility group box 1; cfDNA, cell-free DNA; STING, stimulator of interferon genes.