Triggering receptor expressed on myeloid cells‐2 fine‐tunes inflammatory responses in murine Gram‐negative sepsis

Abstract

During infections, TLR-mediated responses require tight regulation to allow for pathogen removal, while preventing overwhelming inflammation and immunopathology. The triggering receptor expressed on myeloid cells (TREM)-2 negatively regulates inflammation by macrophages and impacts on phagocytosis, but the function of endogenous TREM-2 during infections is poorly understood. We investigated TREM-2's role in regulating TLR4-mediated inflammation by studying wild-type and TREM-2 2/2 mice challenged with LPS and found TREM-2 to dampen early inflammation. Augmented early inflammation in TREM-2 2/2 animals was followed by an accelerated resolution and ultimately improved survival, associated with the induction of the negative regulator A20. Upon infection with Escherichia coli, the otherwise beneficial effect of an exaggerated early immune response in TREM-2 2/2 animals was counteracted by a 50% reduction in bacterial phagocytosis. In line with this, TREM-2 2/2 peritoneal macrophages (PMs) exhibited augmented inflammation following TLR4 stimulation, demonstrating the presence and negative regulatory functionality of TREM-2 on primary PMs. Significantly, we identified a high turnover rate because TREM-2 RNA is 25-fold downregulated and the protein proteasomally degraded upon LPS encounter, thus ensuring a tightly regulated and versatile system that modulates inflammation. Our results illustrate TREM-2's effects on infection-triggered inflammation and identify TREM-2 as a potential target to prevent overwhelming inflammation while preserving antibacterial-effector functions.-Gawish, R., Martins, R., Böhm, B., Wimberger, T., Sharif, O., Lakovits, K., Schmidt, M., Knapp, S. Triggering receptor expressed on myeloid cells-2 fine-tunes inflammatory responses in murine Gram-negative sepsis.

TREM2, Microglia, and Neurodegenerative Diseases

“…Microglia and macrophage TREM2 expression in vivo and in vitro sharply decline in response to acute proinflammatory stimuli such as lipopolysaccharide (LPS) or tumor necrosis factor (TNF) [51,91,[96][97][98]. One mechanism by which the downregulation of TREM2 mRNA is proposed to occur is through the NF-kB pathway.…”

The Emerging Role of Curcumin in the Modulation of TLR-4 Signaling Pathway: Focus on Neuroprotective and Anti-Rheumatic Properties

“…Recent studies have shown that Triggering Receptor Expressed on Myeloid cells 2, also known as (TREM2), is an efficient negative regulator of TLR-4 signaling [145][146][147]. TREM2 is a membrane receptor that mediates critical functions of microglia, such as suppression of pro-inflammatory cytokines and promotion of phagocytosis of apoptotic neurons and cell debris [148].…”

TREM2 inhibits inflammatory responses in mouse microglia by suppressing the PI3K/NF‐κB signaling

“…TREM2 is highly expressed in microglia with approximately 300-fold higher than that in the neuron and other glial cells (Luo et al, 2014;Wu et al, 2015), and acts as a key regulator of inflammatory response (Torika et al, 2016;Choi et al, 2017;Zhong et al, 2017). TLR4 is activated by bacteria to modulate the innate immune responses, which releases pro-and antiinflammatory cytokines to promote robust inflammatory responses (Gawish et al, 2015). TLR4 is activated by bacteria to modulate the innate immune responses, which releases pro-and antiinflammatory cytokines to promote robust inflammatory responses (Gawish et al, 2015).…”

“…TREM-2 down-regulates TLR4-mediated cytokine responses, TNF-a production and the NF-kB activation (Peng et al, 2010;Sharif et al, 2014). TLR4 is activated by bacteria to modulate the innate immune responses, which releases pro-and antiinflammatory cytokines to promote robust inflammatory responses (Gawish et al, 2015). The PI3K is an upstream event of the NF-kB pathway, which is the most important downstream pathway mediated by TLR4.…”