Triggering receptor expressed on myeloid cells 1 and NLR family pyrin domain containing 3 signaling axis (TREM-1/NLRP3 axis)

The Triggering receptor expressed on myeloid cells 1 (TREM-1) and NLR family pyrin domain containing 3 (NLRP3) signaling axis in macrophages is a critical pro-inflammatory pathway that amplifies innate immune responses [1, 5]. TREM-1, a cell-surface receptor, signals through the adaptor protein DAP12 to activate the PI3K/AKT/mTOR pathway, which promotes HIF-1α-mediated metabolic reprogramming toward glycolysis [1, 4]. This metabolic shift is essential for the activation of the NLRP3 inflammasome, a cytosolic multiprotein complex that processes pro-inflammatory cytokines like IL-1β and IL-18 and induces pyroptotic cell death [3, 11]. Furthermore, a positive feedback loop exists where NLRP3 activation can upregulate TREM-1 expression via the release of HMGB1 and IL-18 [5]. Dysregulation of this axis is implicated in various inflammatory conditions, including acute lung injury, sepsis, and neurodegenerative diseases [6, 12]. Therapeutic strategies targeting this pathway include TREM-1 inhibitors like nangibotide and NLRP3-specific inhibitors like MCC950, aiming to dampen the hyper-inflammatory response and prevent tissue damage [2, 9].

Other names

TREM-1-NLRP3 axisTREM-1-governed NLRP3 activationTREM-1/NLRP3/pyroptosis pathwayTREM-1 and NLRP3 inflammasome signaling

The axis is targeted through the inhibition of the TREM-1 receptor (blocking ligand binding or DAP12 signaling), direct blockade of the NLRP3 inflammasome assembly and ATPase activity, or suppression of the mTOR/HIF-1α/glycolysis metabolic link that bridges TREM-1 activation to NLRP3 assembly [1, 2, 9].