Figure 2.

TLR4 in context of TREM1/2 and the NLRP3 inflammasome. Activation of TLR4 through hemoglobin causes expression of the NLRP3 inflammasome, which initiates the priming step. For activation, lysosomal damage (as one example of many potential activation mechanisms) induces activation of the NLRP3 inflammasome. Upon ligand binding, the TREM2-associated adaptor DAP12 undergoes tyrosine phosphorylation by the protein kinase SRC and recruits the tyrosine protein kinase SYK, which activates phosphatidylinositol 3-kinase. TREM2 limits inflammation by interfering with proinflammatory signals, which can be transmitted by TLR4. By contrast, the TREM1 signaling cascade reinforces the production of inflammatory mediators that are initiated by TLR4 and act synergistically. TREM1 acts here as an amplifier of TLR-induced inflammation and vice versa.