Figure 2
From: DAMPs activating innate and adaptive immune responses in COPD
Ligation of pattern recognition receptors (PRRs) by damage-associated molecular patterns (DAMPs), relevant for chronic obstructive pulmonary disease (COPD), initiates the release of proinflammatory cytokines by multiple pathways. Toll-like receptor (TLR)-2/4 receptors can be activated upon binding of DAMPs, e.g., high-mobility group box-1 (HMGB1), heat shock proteins (HSPs), defensins, and hyaluronan, which can cause interferon regulatory factor 3 (IRF3)-mediated release of type I interferons by activation of the Trif/Traf3/IRF3 pathway and subsequent translocation of IRF3 to the nucleus where it initiates transcription of type I interferons. Ligation of TLR2/4 can also cause nuclear factor-κB (NF-κB)-mediated release of proinflammatory cytokines by activation of the MyD88/Traf6/NF-κB pathway and subsequent translocation of NF-κB to the nucleus where it induces transcription of proinflammatory genes, including tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8. TLR-7/9 ligation by DAMPs, e.g., double stranded DNA (dsDNA), RNA, and LL-37, can cause IRF7-mediated release of type I interferons and MyD88/NF-κB-mediated release of proinflammatory cytokines. Ligation of receptor for advanced glycation end-products (RAGE) by DAMPs, e.g., HMGB1, LL-37, and S100 proteins, causes mitogen-activated protein kinase (MAPK)/NF-κB pathway-mediated release of proinflammatory cytokines. Adenosine 5'-triphosphate (ATP) can ligate purine receptors (P2X and P2Y receptors) that cause K+ efflux and subsequent activation of the NLRP3 inflammasome that activates caspase-11 and caspase-1 that, in turn, can cleave Pro-IL-1β and Pro-IL-18, which are transcribed upon NF-κB activation, into their mature forms, after which they will be secreted. DAMPs and receptors underlined in the figure are shown to be upregulated in COPD patients.
