MYD88‐dependent and ‐independent activation of TREM‐1 via specific TLR ligands

Abstract

Triggering receptor expressed on myeloid cells (TREM)-1 plays an important role in myeloid cell-activated inflammatory responses. Although TLR ligands such as LPS and lipoteichoic acid have been shown to upregulate TREM-1 expression in macrophage and neutrophils, the role of specific TLR in inducing the expression of TREM-1 remains unclear. In this study, we investigated whether the presence of TLR is necessary for the expression of TREM-1. We show that BM-derived macrophages from TLR4 and TLR2 KO mice failed to induce expression of TREM-1 message and protein in response to their specific ligands. Interestingly, the expression of TREM-1 in response to LPS is not altered in myeloid differentiation factor 88 (MyD88) KO macrophages, suggesting that downstream of TLR a MyD88-independent pathway induces the expression of TREM-1. Inhibiting toll/IL-1R domain-containing adaptor-inducing IFN-b (TRIF) expression by siRNA decreased TREM-1 expression in response to LPS, suggesting that the expression of TREM-1 in response to LPS was mediated by the TRIF signaling pathway. On the other hand, the expression of TREM-1 in response to lipoteichoic acid is dependent on MyD88 expression. These data indicate that the expression of TREM-1 in response to TLR ligands occurs secondary to downstream signaling events and that the presence of TLR is necessary for the expression of TREM-1 in response to their specific ligands. However, the downstream signaling required for the expression of TREM-1 is dependent on the stimulus and the surface receptor through which the signaling is initiated.Key words: Innate immunity . TLR . TREM-1 IntroductionTriggering receptor expressed on myeloid cells 1 (TREM-1) belongs to the TREM super-family of receptors, which is expressed on monocytes and neutrophils [1][2][3][4][5]. These receptors activate downstream signaling pathways with the help of an adaptor molecule, DAP12 [2]. Although the natural ligands for TREM-1 have not been identified the engagement of TREM-1 synergizes with the effects of the TLR ligands and amplifies the synthesis of inflammatory cytokines [2][3][4]6]. Because blocking of TREM-1 improves the survival of mice with bacterial sepsis TREM-1 has been perceived to play an essential role in acute inflammatory responses in murine models of septic shock [2,[7][8][9][10][11][12][13].In the presence of infection, inflammation is triggered through the recognition of microorganism-by the pathogen associated molecules such as the TLR, which are expressed on the surface of innate immune cells such as monocytes, macrophages, and dendritic cells [14][15][16]. To date ten members of TLR have been identified in human, and 13 in mice, and a series of genetic series have revealed their respective ligands. On engagement with 162ligands, TLR recruit specific adapter molecules that propagate downstream signaling [17]. This interaction then leads to the activation of NF-kB and to the release of pro-inflammatory TNF-a, IL-12, IL-1, IL-6, IL-8, and anti-inflammatory (IL-10 and TGF-b) cytokines [18]. TLR ...

TREM-1 Amplifies Corneal Inflammation after Pseudomonas aeruginosa Infection by Modulating Toll-Like Receptor Signaling and Th1/Th2-Type Immune Responses

“…TREM-1 elevated the expression of TLR2, TLR4, and MyD88, while TLR5 and TLR9 expression was not affected (data not shown). Interestingly, other studies have demonstrated that TREM-1 expression is enhanced by activating TLR2 and TLR4 but not TLR3, TLR7/8, or TLR9 (23,43,44). Taken together, these findings suggested that TREM-1 may be associated with TLR2 and TLR4 but not other TLRs.…”

Triggering receptor expressed on myeloid cells -1 as a new therapeutic target during inflammatory diseases

“…5,[26][27][28] The regulation of TREM-1 by these Pattern recognition receptors (PRRs) is independent of MyD88 but TRIF-dependent, 29 and involves transcription factors NFκB (p65), PU.1 and AP1. 30 Co-engagement of PRRs and TREM-1 results in higher cytokines production than the sum of the responses of either TREM-1 or PRRs alone.…”

Cathelicidin Peptide LL-37 Modulates TREM-1 Expression and Inflammatory Responses to Microbial Compounds

“…Previous studies showed that LL-37 inhibits inflammatory cytokine production in response to LPS through the downregulation of p38 MAPK and NFκB signaling pathways [11,14,63,64]; similar mechanisms may be responsible for the antagonistic effects of LL-37 on TREM-1 expression in response to LPS or LTA. It was recently reported that upregulation of TREM-1 by LPS is mediated through a signaling pathway dependent on the adapter protein TIR-domain-containing adapterinducing interferon-β (TRIF) while its upregulation by LTA is mediated by MyD88 [65]. The ability of LL-37 to inhibit TREM-1 induction by both LPS and LTA therefore suggests that modulation of both MyD88 and TRIF-dependent TLR signaling responses is involved.…”