Cytosolic nucleic acid sensing as driver of critical illness: mechanisms and advances in therapy

Abstract

Nucleic acids from both self- and non-self-sources act as vital danger signals that trigger immune responses. Critical illnesses such as acute respiratory distress syndrome, sepsis, trauma and ischemia lead to the aberrant cytosolic accumulation and massive release of nucleic acids that are detected by antiviral innate immune receptors in the endosome or cytosol. Activation of receptors for deoxyribonucleic acids and ribonucleic acids triggers inflammation, a major contributor to morbidity and mortality in critically ill patients. In the past decade, there has been growing recognition of the therapeutic potential of targeting nucleic acid sensing in critical care. This review summarizes current knowledge of nucleic acid sensing in acute respiratory distress syndrome, sepsis, trauma and ischemia. Given the extensive research on nucleic acid sensing in common pathological conditions like cancer, autoimmune disorders, metabolic disorders and aging, we provide a comprehensive summary of nucleic acid sensing beyond critical illness to offer insights that may inform its role in critical conditions. Additionally, we discuss potential therapeutic strategies that specifically target nucleic acid sensing. By examining nucleic acid sources, sensor activation and function, as well as the impact of regulating these pathways across various acute diseases, we highlight the driving role of nucleic acid sensing in critical illness.

Fig. 1

Timeline diagram of milestones in nucleic acid sensing research. Significant discoveries of fundamental DNA sensors (blue), RNA sensors (red) and key signaling proteins (purple) are demonstrated in chronological order. Figure created with BioRender.com

Fig. 2

DNA sensing pathways. Distinct sensing pathways are activated by DNA derived from exogenous and endogenous sources. TLR9 detects CpG-DNA and recruits MyD88 to induce IRF7-mediated type I IFN production, IRF1-mediated ISGs expression and NF-κB-mediated pro-inflammatory cytokine production. Upon recognition of dsDNA, cGAS catalyzes cGAMP synthesis to activate STING that initiates IRF3-mediated type I IFN response and NF-κB-mediated inflammatory response. Furthermore, dsDNA-bound AIM2 drives inflammasome assembly with ASC and caspase-1, triggering the release of IL-1β and IL-18 as well as pyroptosis. Figure created with BioRender.com. ATP adenosine triphosphate, GTP guanosine-5’-triphosphate, HIN hematopoietic interferon-inducible nuclear, ISGs interferon-stimulated genes, IκB inhibitor of nuclear factor kappa B, PYD pyrin domain

Fig. 3

RNA sensing pathways. RNA originating from exogenous and endogenous sources activates downstream RNA sensing pathways. In endosome, TLR3 detects dsRNA and initiates signaling through TRIF, TRAF3 and IRF3 to induce type I IFNs as well as via TRIF, TRAF6, MAPK and NF-κB to the production of proinflammatory cytokines. TLR7 and TLR8 detect ssRNA and induces the expression of type I IFN, chemokines and cytokines via MyD88 signaling and downstream activation of IRF5/7, MAPK and NF-κB. In cytoplasm, RIG-I and MDA5 senses 5’(p)pp dsRNA and long ssRNA, respectively. Activated RIG-I and MDA5 multimerize to enable MAVS to recruit kinases, activating NF-κB and IRF5/7 and inducing transcription of antiviral proteins, chemokines and cytokines. Figure created with BioRender.com. 5’(p)pp dsRNA 5’diphosphorylated or 5’triphosphorylated double-stranded RNA, AP-1 activator protein-1, IκB inhibitor of nuclear factor kappa B, NEMO nuclear factor κB essential modulator, RIP1 receptor-interacting protein 1

Fig. 4

Ligands for nucleic acid sensors. Mislocated nucleic acids are predominantly ascribed to pathogen infection, cell stress and damage, cell death and active release mechanisms such as NETosis and extracellular vesicles. Cell-free DNA could bind to proteins such as histones and HMGB1. In addition, the impairment of subcellular components including mitochondria, nuclei, micronuclei and lysosome causes cytosolic leakage of host nucleic acids. Figure created with BioRender.com. ROS reactive oxygen species

Fig. 5

Targeting ligands for nucleic acid sensors offers a potential treatment for critical illness management. Inhibition of nucleic acid release and clearance of nucleic acids ideally limit the activation of nucleic acid sensors at the source. Inhibition of nucleic acid release includes restraining the formation of neutrophil extracellular traps by Cl-amidine as well as suppressing mitochondrial DNA leakage by MSN-125, cyclosporin A and VBIT4. Clearance of nucleic acids includes reducing extracellular DNA and RNA by nucleases and nanomaterials, as well as deleting intracellular mitochondrial DNA by ethidium bromide and 2′,3′-dideoxycytidine. Figure created with BioRender.com

Fig. 6

Targeting DNA sensing as a potential therapeutic strategy for critical illness. Manipulation on DNA sensing protects against critical illness. Pharmacological inhibitors (red) or activators (blue) directly regulate key proteins in distinct DNA sensing pathways, including TLR9, cGAS, STING, TBK1/IKKε, AIM2, caspase-1 and IL-1β. Figure created with BioRender.com. Ac-YVAD-cmk N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone, cAIMP cyclic adenosine-inosine monophosphate, CMA 10-carboxymethyl-9-acridanone, G3-YSD G3-ended Y-form short DNA, IL-1Ra interleukin-1 receptor antagonist, TST-SSM thiostrepton encapsulated in phospholipid sterically stabilized micelles

Fig. 7

Targeting RNA sensing presents a promising clinical approach for critical illness treatment. Pharmacological inhibitors (red) or activators (blue) directly manipulating RNA sensors including TLR3, TLR7, TLR8, RIG-I and MDA5 offer therapeutic options in critical illness. Figure created with BioRender.com. 5’ppp RNA 5’triphosphorylated RNA, dbPNA double-stranded RNA-binding peptide nucleic acid, IRS661 immunoregulatory sequence 661, SLR stem-loop RNA, ssODN single-stranded oligonucleotide