TREM‐2 Promotes Macrophage‐Mediated Eradication of Pseudomonas aeruginosa via a PI3K/Akt Pathway

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM-2) is a cell surface receptor abundantly expressed on myeloid lineage cells such as macrophages and dendritic cells. It is reported that TREM-2 functions as an inflammatory inhibitor in macrophages and dendritic cells. However, the role of TREM-2 in bacterial killing remains unclear. This study explored the role of TREM-2 in bacterial eradication of Pseudomonas aeruginosa (PA), a Gram-negative bacterium which causes various opportunistic infections. Phagocytosis assay assessed by flow cytometry suggested that TREM-2 was not involved in the uptake of PA by macrophages, while bacterial plate count data showed that TREM-2 was required for macrophage-mediated intracellular killing of PA. Moreover, our results demonstrated that TREM-2 promoted macrophage killing by enhancing reactive oxygen species (ROS), but not nitric oxygen (NO) production. Treatment with N-acetylcysteine, a ROS scavenger, diminished the TREM-2-mediated intracellular killing of PA. To further investigate the underlined mechanisms of TREM-2-promoted bacterial killing, we examined the activation of downstream mitogen-activated protein kinases and PI3K/Akt pathway. Western blot data showed that silencing of TREM-2 inhibited phosphorylation of Akt, but not ERK, JNK or P38. In addition, pretreatment with PI3K active product PIP3 DiC16 reversed the elevation of intracellular bacterial load in TREM-2-silenced macrophages, while PI3K inhibitor wortmannin restored the decline of bacterial load in TREM-2-overexpressed macrophages. These data together suggested that the TREM-2-mediated bacterial killing is dependent on the activation of PI3K/Akt signalling, which may provide a better understanding of the host antibacterial immune defence.

Pseudomonas aeruginosa promotes autophagy to suppress macrophage-mediated bacterial eradication

“…After internalization, phagocytosed bacteria are intracellularly killed via oxygen-dependent or -independent mechanisms [7,16,17]. Studies have demonstrated that treatment with rapamycin decreased ROS generation, NO production and NF-κB activation in LPS-activated rat hepatocytes [36].…”

“…As a major type of phagocytes in the innate immune system, macrophages display potent microbicidal activity to ingest and destroy invading microorganisms [16,17]. After internalization, phagocytosed bacteria are intracellularly killed via oxygen-dependent or -independent mechanisms [7,16,17].…”

“…And engulf invading pathogens with the help of several phagocytic receptors on the cell surface [11], such as scavenger receptor (SR) [12], mannose receptor (MR) [13], Fc receptors for IgG (FcγR) [14], complement receptor (CR) [15], etc. After that, activated phagocytes produce a large amount of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [16,17], to kill the engulfed bacteria.…”

The role of TREM-2 in internalization and intracellular survival of Brucella abortus in murine macrophages

“…There are two main functions in macrophages: as a phagocytic and immune modulatory receptor. In regard to phagocytic receptor, previous studies have demonstrated that TREM-2 expression promotes macrophage-mediated bacterial killing (Charles et al, 2008;N'Diaye et al, 2009;Zhu et al, 2014). However, TREM-2 also attenuates TLR-induced macrophages activation (Turnbull et al, 2006).…”

Pseudomonas aeruginosa Triggers Macrophage Autophagy To Escape Intracellular Killing by Activation of the NLRP3 Inflammasome

“…Different types of inflammasomes can be activated in innate immunocytes during bacterial infection (26). Studies have demonstrated that P. aeruginosa infection mainly activates the IPAF inflammasome in murine macrophages (27)(28)(29).…”