Damage-Associated Molecular Patterns As Double-Edged Swords in Sepsis

Abstract

Significance: Sepsis is defined as a life-threatening organ dysfunction caused by dysregulated host response to infection. This leads to an uncontrolled inflammatory response at the onset of infection, followed by immunosuppression. The development of a specific treatment modality for sepsis is still challenging, reflecting our inadequate understanding of its pathophysiology. Understanding the mechanism and transition of the early hyperinflammation to late stage of immunosuppression in sepsis is critical for developing sepsis therapeutics. Recent Advances: Damage-associated molecular patterns (DAMPs) are intracellular molecules and released upon tissue injury and cell death in sepsis. DAMPs are recognized by pattern recognition receptors to initiate inflammatory cascades. DAMPs not only elicit an inflammatory response but also they subsequently induce immunosuppression, both are equally important for exacerbating sepsis. Recent advances on a new DAMP, extracellular cold-inducible RNA-binding protein for fueling inflammation and immunosuppression in sepsis, have added a new avenue into the dual functions of DAMPs in sepsis. Critical Issues: The molecular modification of DAMPs and their binding to pattern recognition receptors transit dynamically by the cellular environment in pathophysiologic conditions. Correlation between the dynamic changes of the impacts of DAMPs and the clinical outcomes in sepsis still lacks adequate understanding. Here, we focus on the impacts of DAMPs that cause inflammation as well as induce immunosuppression in sepsis. We further discuss the therapeutic potential by targeting DAMPs to attenuate inflammation and immunosuppression for mitigating sepsis. Future Directions: Uncovering pathways of the transition from inflammation to immunosuppression of DAMPs is a potential therapeutic avenue for mitigating sepsis.

Keywords: ATP; DAMP; HMGB1; eCIRP; histones; immunosuppression; inflammation.

FIG. 1.

HMGB1 in sepsis. HMGB1 is released into the extracellular space either by active or passive pathways after cellular injury or cell death. As a DAMP, extracellular HMGB1 induces inflammation. HMGB1 binds to several PRRs, including RAGE, TLR2, TLR4, and TREM-1, to trigger immune responses. The immune activities of extracellular HMGB1 are dependent on its redox states. A fully reduced form of HMGB1 forms a complex with CXCL12 and activates CXCR4 signaling to release chemokines. Disulfide HMGB1 is formed under mild oxidizing conditions. Disulfide HMGB1 triggers an inflammatory reaction through multiple signaling pathways, including RAGE and TLR2/4. Fully oxidized HMGB1 is formed when exposing to oxidative agents. Oxidized HMGB1 suppresses both the chemokine and cytokine activation. The immunosuppressive effect of oxidized HMGB1 acts in a TLR4- and RAGE-dependent manner, but the signaling pathways are still not fully understood. CXCR4, C–X–C chemokine receptor type 4; CXCL12, C–X–C motif chemokine 12; DAMP, damage-associated molecular pattern; HMGB1, high-mobility group box protein 1; PRR, pattern recognizing receptor; RAGE, receptor for advanced glycation end products; TLR2/4, toll-like receptor 2/4; TREM-1, triggering receptor expressed on myeloid cells-1. Color images are available online.

FIG. 2.

eCIRP in sepsis. eCIPR is released from injured or dead cells as a DAMP to initiate an immune response. The binding of eCIRP to TLR4-MD2 and TREM-1 activates NF-κB signaling pathway for proinflammatory response, including the production of proinflammatory cytokines and formation of NETs. The interaction of eCIRP with IL-6R results in STAT3 phosphorylation and promotes transcription of immunosuppressive genes for immune tolerance and suppression. eCIRP, extracellular cold-inducible RNA-binding protein; IL-6R, interleukin 6 receptor; MD2, myeloid differentiation factor 2; NET, neutrophil extracellular trap; NF-κB, nuclear factor-kappa-light-chain-enhancer of activated B cells; STAT3, signal transducer and activators of transcription 3. Color images are available online.

FIG. 3.

eHistones in sepsis. Histones are released into the extracellular space during cell death or NETosis and act as cytotoxic DAMP. eHistones induce proinflammatory cytokine and chemokine production through the TLR2/4 signaling pathway. Activation of TLR9 by eHistones links to ROS production and inflammasome activation. eHistones alter cell membrane permeability. Dysregulation of posttranscriptional alteration on citrullination, methylation, and lactylation of histones associates with a suppressive immune reaction. eHistones, extracellular histones; ROS, reactive oxygen species. Color images are available online.

FIG. 4.

eATP in sepsis. eATP released from injured or dead cells acts as a DAMP to initiate the immune response. eATP can be dephosphorylated into ADP, AMP, and adenosine by enzymes. eATP mediates an inflammatory response via the purinergic receptors, mainly P2 receptors, to activate NLRP3 inflammasome and produce proinflammatory cytokines and chemokines. Extracellular adenosine accumulates via the breakdown of ATP. The immune-suppressive effect of adenosine is regulated by adenosine A2 receptors. A2 adenosine receptors signal predominantly via the adenylate cyclase-cAMP-PKA canonical pathway to inhibit the expression of proinflammatory mediators through downregulating the NF-κB-dependent pathway. ATP, adenosine triphosphate; eATP, extracellular ATP; NLRP3, nucleotide-binding domain-like receptor (NLR) family pyrin domain containing 3, PKA, protein kinase A. Color images are available online.

FIG. 5.

Effects of DAMPs in nonimmune cells in sepsis. DAMPs are released from injured or dead cells after sepsis/injury. DAMPs play critical roles in nonimmune cells such as endothelial and epithelial cells in sepsis. HMGB1 and eCIRP increase endothelial and epithelial permeability, induce cytokine and chemokine release, and cell injury or pyroptosis. These actions are mediated through their receptors. eCIRP also induces cardiomyocyte malfunction by interaction with TREM-1 receptor. eHistones show cytotoxicity on endothelial and epithelial cells. eHistones bind on the phospholipid bilayer of cell membrane causing the increase of permeability and cell death. MCP-1, monocyte chemoattractant protein-1. Color images are available online.