TREM2 signaling pathway in sepsis-induced acute lung injury: physiology, pathology, and therapeutic applications

Abstract

Sepsis emerges as a formidable and life-threatening condition, born from an unregulated immune response to infection, presenting a significant challenge to global health. A notable complication of sepsis is acute lung injury (ALI), marked by profound hypoxia, rampant inflammation, and the accumulation of fluid within the pulmonary system. ALI harbors the potential to escalate into acute respiratory distress syndrome (ARDS), thereby exacerbating the severity of sepsis. The triggering receptor expressed on myeloid cells 2 (TREM2), predominantly situated within various myeloid cell types, plays a pivotal role in the modulation of neurodegeneration, inflammation, neoplasms, and other pathologies. Recent investigations have illuminated TREM2's considerable involvement in septic lung injury; however, the precise mechanisms and therapeutic implications within this context demand further scrutiny. This article endeavors to elucidate the intricate interplay between sepsis, lung injury, and TREM2's role in immune modulation. It will furnish an overview of the TREM2 signaling pathway's functions and mechanisms in both physiological and septic lung injury scenarios, while also evaluating the current status and advancements in TREM2-targeted therapies.

Keywords: ALI; TREM2; immunomodulation; sepsis; therapeutic application.

Figure 1

Genomic location and molecular structure of TREM-2 receptor. (a) Human TREM gene clusters located on human chromosome 6p21 locus, including TREM1, TREM2, TREML1, TREML2, and TREML4 genes. Also, this locus contains the NCR2 gene encoding NKp44, a typical cell-surface receptor of Natural killer (NK) cells and group 3 innate lymphoid cells. (b) A three-dimensional structure of the full-length TREM-2 protein, which is predicted by AlphaFold. Herein, the extracellular structure of TREM-2 contains a V-like Ig domain linked with a long stock followed by a TM domain. Also, the N-terminus leader sequence and C-terminus along with cytoplasmic domains are depicted in the predicted TREM-2 protein model (12).

Figure 2

TREM2 signaling pathway (by Figdraw). TREM-2 orchestrates the activation of signaling cascades within myeloid cells through the engagement of DAP12, DAP10, and an array of other receptors upon the detection of ligands. Notably, DAP12 is endowed with an immunoreceptor tyrosine-based activation motif (ITAM), facilitating downstream signaling, whereas DAP10 is devoid of such a motif. The formation of heterodimers between TREM-2 and either DAP12 or DAP10 catalyzes the phosphorylation of adaptor proteins, thereby igniting a cascade of downstream pathways subsequent to ligand binding. (a) In the intricate signaling network of TREM-2/DAP12, the Src kinase activates DAP12, which in turn recruits the Sos1/2 and GRB2 junction proteins, leading to the inhibition of the RAS/MEK/ERK (or MAPK) pathway, a process that curtails the release of proinflammatory cytokines. (b) TREM-2 further establishes a complex with DAP12 or DAP10, engaging in crosslinking with receptors such as CSF1R, which modulates TREM-2/DAP12 signaling through the phosphorylation of DAP12/ITAM by Src kinase. This interaction recruits spleen tyrosine kinase (SYK), setting in motion downstream signaling pathways that involve guanine nucleotide exchange factors Vav2/3, Pyk2, and PI3K, with the assistance of DAP10. (c) Conversely, the interplay between DAP12 and DOK3 facilitates the recruitment of SHIP1, an inositol phosphatase characterized by a Src homology 2 (SH2) domain, which catalyzes the conversion of PIP3 to PIP2. This pivotal process governs the involvement and activation of intracellular signaling proteins associated with the membrane through PIP3. (d) The regulatory mechanisms of transcription are mediated by β-catenin and mTORC1. The activation of AKT and mTORC2 by PIP2/3 underpins metabolic homeostasis, while the RAS/MEK/ERK pathway modulates proinflammatory gene expression, with Ca2+ modulation facilitating actin remodeling. (e) TREM2 plays a crucial role in the dual responses of immune cells—both pro-inflammatory and anti-inflammatory—triggered by TLR4. In the nascent stages of bacterial infection, various antigenic substances can directly activate the TLR4 receptor, instigating the NF-κB signaling pathway that augments the expression of inflammatory factors. Concurrently, the TREM2-DAP12-SYK pathway activates the IKK complex, promoting the degradation of IκBα and enabling NF-κB to translocate into the nucleus, thereby driving the inflammatory response. Upon activation, TREM2 recruits SHP-1, a protein that dephosphorylates critical molecules within the NF-κB pathway, such as IKKβ and p65, thereby obstructing their nuclear translocation. This mechanism effectively inhibits the excessive activation of NF-κB instigated by TLR4, leading to a reduction in the release of pro-inflammatory factors such as TNF-α and IL-6. Furthermore, it curtails glycolysis in macrophages via the AKT/mTOR pathway, diminishing the production of pro-inflammatory factors reliant on NF-κB.