Prognostic Value and Therapeutic Potential of TREM-1 in <b><i>Streptococcus pyogenes-</i></b>Induced Sepsis

Abstract

TREM-1 (triggering receptor expressed on myeloid cells) is a surface molecule expressed on neutrophils and macrophages which has been implicated in the amplification of inflammatory responses triggered during infection. In the present study, we have investigated the clinical significance of TREM-1 in Streptococcus pyogenes-induced severe sepsis in both experimentally infected mice as well as in patients with streptococcal toxic shock. We found that S. pyogenes induced a dose-dependent upregulation of TREM-1 in in vitro cultured phagocytic cells and in the organs of S. pyogenes-infected mice. Furthermore, we reported a positive correlation between serum levels of soluble TREM-1 (sTREM-1) and disease severity in infected patients as well as in experimentally infected mice. Hence, sTREM-1 may represent a useful surrogate marker for streptococcal sepsis. We found that modulation of TREM-1 by administration of the TREM-1 decoy receptor rTREM-1/Fc substantially attenuated the synthesis of inflammatory cytokines. More importantly, treatment of S. pyogenes-infected septic mice with rTREM-1/Fc or the synthetically produced conserved extracellular domain LP17 significantly improved disease outcome. In summary, our data suggest that TREM-1 may not only represent a valuable marker for S. pyogenes infection severity but it may also be an attractive target for the treatment of streptococcal sepsis.

TREM-1 Signaling Promotes Host Defense during the Early Stage of Infection with Highly Pathogenic Streptococcus suis

“…However, blockage of TREM-1 signaling did not improve the survival of mice experiencing S. suis-induced septic shock in this study, which was inconsistent with the effects of TREM-1 blockage on sepsis or septic shock induced by other pathogens (33,34,45,(48)(49)(50). In contrast, activation of TREM-1 signaling with the agonistic antibody significantly improved the survival of mice infected with S. suis.…”

“…Because of the central function of TREM-1 in amplification of the inflammatory response, TREM-1 was identified as an essential regulator of innate immunity in sepsis syndrome (35) and was confirmed as an attractive target for the treatment of septic shock (45,48), sepsis (30,33,34,49,50), inflammatory bowel disease (51,52), etc. However, blockage of TREM-1 signaling did not improve the survival of mice experiencing S. suis-induced septic shock in this study, which was inconsistent with the effects of TREM-1 blockage on sepsis or septic shock induced by other pathogens (33,34,45,(48)(49)(50).…”

A novel ligand-independent peptide inhibitor of TREM-1 suppresses tumor growth in human lung cancer xenografts and prolongs survival of mice with lipopolysaccharide-induced septic shock

“…In contrast, blockade of TREM-1 modulates the inflammatory response and improves survival in this and other mouse models of sepsis including CLP, and E. coli -, S. pyogenes -, or P. aeruginosa -induced peritonitis models [13, 21–22, 41–42, 61]. In this study, we demonstrated for the first time that a novel and first-in-class ligand-independent TREM-1 inhibitory peptide GF9 can be used to silence the TREM signaling pathway and prolong survival in mice with LPS-induced septic shock.…”

RNA sequencing atopic dermatitis transcriptome profiling provides insights into novel disease mechanisms with potential therapeutic implications

“…20,21 TREM-1 activation was also shown to induce inflammatory mediators (CCL2, CCL3, IL6, TNF, Toll-like receptor [TLR] 2, and TLR4). [20][21][22] Soluble TREM-1 expression has recently been found to be a useful surrogate marker for sepsis. 23 The TREM-1 pathway has not been reported in patients with AD, despite the disease association with infection, 24,25 but increased TREM-1 expression has been recently reported in patients with psoriasis.…”