Fig. 2

Schematic illustration of DAMP/ TLR/ inflammasome interactions. Damage-induced release of damage associated molecular patterns (DAMPs) into the extracellular region can result in ligand binding to specific receptors or uptake in diverse target cells. TOLL-like receptor (TLR)-binding and recruitment of the adaptor protein MyD88 leads to subsequent activation of TNF receptor associated factor (TRAF) 6 in the cytosol. Activation of the IKK kinase complex or mitogen-activated protein kinase (MAPKs) result in the translocation of the transcription factors nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) into the nucleus respectively. In the nucleus they induce the expression of pro-inflammatory cytokines like pro-IL-1β/ IL-18. TLR4 internalization will induce a switch from MyD88 to TIR-domain-containing adapter-inducing interferon-β (TRIF) signaling [135, 288]. The recruitment of TRIF results in signaling cascades similar to the ones described for the MyD88 pathway. On the one hand, TRIF can either interact with TRAF6 resulting in NFκB-dependent or AP-1 dependent production of inflammatory cytokines. In addition, TRIF can also interact with TRAF3 leading to the induction of the transcription factors Interferon regulatory factor (IRF)3/7. Translocation of IRF3/7 into the nucleus then triggers the production of type 1 interferons [130,131,132,133,134]. Furthermore, reactive oxygen species (ROS) and DAMPs can induce the activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome complex and subsequent caspase-1 activation, capable of cleaving pro-IL-1β and pro-IL-18 into mature and secreted IL-1β and IL-18. Nucleotides like ATP, ADP, AMP and the nucleoside adenosine can bind to its purino-receptors like P2XR, P2YR and P1R, respectively, thereby triggering the activation of the NLRP3 inflammasome complex. Additionally, intracellular DAMP (e.g. uric acid) uptake into phagosomes, lysosomal damage or specific binding of e.g. hyaluronan to the CD44 receptor can further activate the NLRP3 inflammasome complex, promoting inflammation