Signaling pathways and intervention therapies in sepsis

Abstract

Sepsis is defined as life-threatening organ dysfunction caused by dysregulated host systemic inflammatory and immune response to infection. Over decades, advanced understanding of host-microorganism interaction has gradually unmasked the genuine nature of sepsis, guiding toward new definition and novel therapeutic approaches. Diverse clinical manifestations and outcomes among infectious patients have suggested the heterogeneity of immunopathology, while systemic inflammatory responses and deteriorating organ function observed in critically ill patients imply the extensively hyperactivated cascades by the host defense system. From focusing on microorganism pathogenicity, research interests have turned toward the molecular basis of host responses. Though progress has been made regarding recognition and management of clinical sepsis, incidence and mortality rate remain high. Furthermore, clinical trials of therapeutics have failed to obtain promising results. As far as we know, there was no systematic review addressing sepsis-related molecular signaling pathways and intervention therapy in literature. Increasing studies have succeeded to confirm novel functions of involved signaling pathways and comment on efficacy of intervention therapies amid sepsis. However, few of these studies attempt to elucidate the underlining mechanism in progression of sepsis, while other failed to integrate preliminary findings and describe in a broader view. This review focuses on the important signaling pathways, potential molecular mechanism, and pathway-associated therapy in sepsis. Host-derived molecules interacting with activated cells possess pivotal role for sepsis pathogenesis by dynamic regulation of signaling pathways. Cross-talk and functions of these molecules are also discussed in detail. Lastly, potential novel therapeutic strategies precisely targeting on signaling pathways and molecules are mentioned.

Fig. 1

Cross-talks of signaling pathway in innate immune cells. At initiation of sepsis, innate immune cells are generally activated at recognition of DAMPs and PAMPs. Membrane-bound and intracellular receptors sense danger signals, which converge with multiple pathways related to activation and regulation of innate immune responses. In general, these converge toward IRF3 and NF-κB signaling pathway that are required to initiate early phase inflammatory responses. Besides, TLR4 agonist (i.e., LPS or HMGB1) provide essential priming signal for the first step of inflammasome activation—upregulation of pro-inflammatory genes. Another substantial group of pathogenic products and endogenous alarmins were required to provide signal 2 for AIM2/NLRP3 inflammasome assembly, which subsequently cleave caspase, GSDMD, and pro-IL-1β/18 to drive canonical inflammasome activation and pyroptosis. Acting as late-phase alarmin, HMGB1 interact with RAGE for delivery of cytosolic LPS, which further trigger pyroptosis via caspase-11-dependent pathway (equivalent to caspase-4 and caspase-5 in human, non-canonical pathway). Intracellularly, cytosolic DNA derived from apoptotic cells or intracellular pathogen could be sensed by AIM2 and cGAS-STING to induce inflammasome assembly and IRF3 phosphorylation, leading to type I interferon responses and inflammasome activation. During sepsis, persisted stress stimuli result in mitochondria dysfunction, ROS production, and metabolism reprogramming that further enhance redox state modification and alarmin production (HMGB1). These cellular changes activate multiple signaling pathways that converge with NLRP3 inflammasome activation. Inflammasome plays a pivotal role in sepsis pathogenesis due to its cross-talk with stress signaling, immune cell activation, and cell homeostasis. Interaction between inflammatory and coagulation cascades serve as underlined mechanism for DIC pathogenesis. As a cytosolic LPS receptor, caspase-11 participated in initiation of coagulation by enhancing tissue factor (TF) activity, performed by GSDMD pore-mediated Ca²⁺ efflux that trigger PS externalization, while macrophage pyroptosis facilitate release of cellular contents including procoagulant products (TF) and alarmins to sustain systemic coagulation. ROS reactive oxygen species, DAMP damage-associated molecular pattern, PAMP pathogen-associated molecular pattern, cfDNA cell-free DNA, EC endothelial cells, ER endoplasmic reticulum, ASC apoptosis-associated speck-like protein, TRX thioredoxin, TXNIP thioredoxin-interacting protein, HMGB1 high mobility group box protein 1, RAGE receptor for advanced glycation end products, GPX4 glutathione peroxidase 4, PLCG phospholipase C gamma 1, PKM2 pyruvate kinase M2, PKR RNA-activated protein kinase, HDAC1 histone deacetylase 1, GLUT1 glucose transporter 1, HIF1a hypoxia-inducible factor-1, PS phosphatidylserine, GSDMD gasdermin D

Fig. 2

Stress signaling and cell homeostasis. Intracellularly, oxidative stress-mediated redox state is pivotal to maintain host cell survival and homeostasis via cross-talks with inflammasome, cell death pathways, and stress-responsive proteins. Mitochondria-derived ROS and mtDNA provide stimuli for upregulation of JAK-STAT pathway and inhibition of HDAC1, which is required for hyperacetylation and cytosolic translocation of HMBG1. In the presence of pathogenic stimuli, substantial release of all thiol-reduced HMGB1 by exosomes serve as inflammatory mediators that marked the prelude of sepsis. This redox form interacts with AIM2 and dsDNA to initiate inflammasome activation and caspase-1-mediated responses, which serve as pre-requisite for autophagy/mitophagy induction via beclin1-mediated pathways. Besides, prolonged oxidative stress oxidize HMGB1 into the disulfide form, which is potent to displace Bcl2 from its association with beclin1, allowing autophagy initiation and removal of hazardous oxidative stress stimulus. Interaction of beclin-1 with PINK/Parkin further facilitate mitochondria priming and autophagosome formation, which subsequently interact with lysosome to induce mitophagy. Autophagy and mitophagy are essential mechanisms to regulate innate immune response and prevent stress-induced injuries. During systemic inflammation context (sepsis), failure to initiate protective autophagy/mitophagy might result in profound cell stress signaling and deleterious pro-inflammatory cell deaths. HDAC1 histone deacetylase 1, Bcl-2 B cell lymphoma-2, GSDMD gasdermin D, SESN2 sestrin 2, PINK PTEN-induced putative kinase 1, LC3 microtubule-associated protein 1A/1B-light chain 3

Fig. 3

Endothelial barrier and coagulation cascades. Lined by membrane-binding proteoglycans and glycosaminoglycan side chains, dearrangement of endothelial glycocalyx result in loss of anti-thrombogenicity and exposure of adhesion molecules, which allow leukocyte adhesion, platelet recruitment, and thrombus formation. Increased vascular permeability trigger leukocyte extravasation, plasma protein leakage, and tissue edema. Under immunogenic stimuli, procoagulant tissue factors were substantially expressed in the form of microvesicles by macrophages and neutrophils, which triggered extrinsic coagulation cascade and cleavage of prothrombin. Neutrophils and platelets work reciprocally to regulate innate immune response and bacterial clearance via NETosis and platelet-mediated responses. During sepsis, NET-derived histones HMGB1 and cfDNA abundantly found serve as procoagulants that accelerate thrombus formation, while activated platelets and RBC recruitment result in thrombocytopenia and platelet-rich thrombus. In order to monitor coagulation dynamics, thrombin interacts with endothelial-bound TM to exhibit profound anti-coagulant and anti-inflammatory effects. In the presence of APC-EPCR, TM/thrombin interact with coagulation–fibrolysis system to act as negative feedback loop. APC–EPCR interaction also allow switching of PAR-1 signaling to anti-inflammatory pattern and strengthened endothelial integrity via activities mediated by S1P and Ang/Tie axis. Besides, TM/thrombin directly inactivate procoagulant alarmins to further restrict immunocoagulation. During severe infection, dysregulation of Ang/Tie axis were associated with weakened vascular stability, which include inhibition of junctional protein, destabilization of cortical actin, and increased vascular adhesion and permeability. Finally, extensive formation of inflammatory thrombus and activation of coagulation cascades result in microcirculatory dysfunction and organ injury. TM thrombomodulin, PAR-1 protease activated receptor 1, EPCR endothelial protein C receptor, S1P sphingosine-1 phosphate, TFPI tissue factor pathway inhibitor, AT antithrombin, TAFI thrombin-activatable fibrinolysis inhibitor, Rac RAS-related C3 botulinum toxin substrate, RhoA ras homolog family member A, Ang1 angiopoietin 1, Ang2 angiopoietin 2, VEGF vascular endothelial growth factor, VE-PTP vascular endothelial protein tyrosine phosphatase, WPB Weibel–Palade body, MLCK myosin light chain kinase, ROCK Rho-associated kinase, ADAM disintegrin and metalloproteinase domain-containing protein

Fig. 4

Schematic diagram of different types of extracorporeal blood-purification strategies (removal of mediators). Red line = arterial line, blue line = venous line, yellow line = ultrafiltrate, purple line = replacement fluid

Fig. 5

Novel intervention therapeutic strategies in sepsis. In terms of the signaling pathways or molecules targeted, potential therapeutic strategies for sepsis that have been proposed so far could be classified into six categories: (1) targeting DAMPs (including host cell stress), (2) targeting PAMPs, (3) targeting inflammatory mediators (anti-inflammatory), (4) immune checkpoint modulation, (5) endothelial barrier stabilization, and (6) restoration of vascular anticoagulant properties. Nanoparticles therapy is a promising novel strategy that have broad therapeutic effects in sepsis experimental studies. Titles in italic refer to the specific targeted mechanism (strategies). Dot-labeled subtitles refer to the specific therapeutic techniques or bioactive molecules proposed