Triggering Receptor Expressed on Myeloid Cells-2 Protects against Polymicrobial Sepsis by Enhancing Bacterial Clearance

Chen, Qixing; Zhang, Kai; Jin, Yue; Zhu, Tao; Cheng, Baoli; Shu, Qiang; Fang, Xiangming

doi:10.1164/rccm.201211-1967oc

Cited by 73 publications

(68 citation statements)

References 39 publications

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“…Expression of TREM2 in liver macrophages is in line with reports of its expression in resident macrophages in other tissues (21). TREM2 signaling was initially associated with negative regulation of macrophage activation (26), but multiple independent observations of TREM2 proinflammatory effects on macrophage activation in bacterial infections have been reported (27,28). This suggests that cellular functions of TREM2 may be context-dependent.…”

Section: Discussionsupporting

confidence: 81%

TREM2 governs Kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection

Gonçalves

Rodrigues-Duarte

Rodo

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Plasmodium liver stage infection is a target of interest for the treatment of and vaccination against malaria. Here we used forward genetics to search for mechanisms underlying natural host resistance to infection and identified triggering receptor expressed on myeloid cells 2 (TREM2) and MHC class II molecules as determinants of Plasmodium berghei liver stage infection in mice. Locus belr1 confers resistance to malaria liver stage infection. The use of newly derived subcongenic mouse lines allowed to map belr1 to a 4-Mb interval on mouse chromosome 17 that contains the Trem2 gene. We show that Trem2 expression in the nonparenchymal liver cells closely correlates with resistance to liver stage infection, implicating TREM2 as a mediator of the belr1 genetic effect. Trem2-deficient mice are more susceptible to liver stage infection than their WT counterparts. We found that Kupffer cells are the principle cells expressing TREM2 in the liver, and that Trem2 −/− Kupffer cells display altered functional activation on exposure to P. berghei sporozoites. TREM2 expression in Kupffer cells contributes to the limitation of parasite expansion in isolated hepatocytes in vitro, potentially explaining the increased susceptibility of Trem2 −/− mice to liver stage infection. The MHC locus was also found to control liver parasite burden, possibly owing to the expression of MHC class II molecules in hepatocytes. Our findings implicate unexpected Kupfferhepatocyte cross-talk in the control Plasmodium liver stage infection and demonstrate that TREM2 is involved in host responses against the malaria parasite. M alaria liver stage infection is asymptomatic but is absolutely required in the progression of Plasmodium infection in the vertebrate host, preceding propagation of parasites in the blood and clinical manifestations of malaria (1, 2). Current efforts in therapy and vaccine development include strategies aimed at deterring infection at the liver stage, preventing subsequent clinical complications and malaria transmission (3, 4). During liver stage infection, one Plasmodium sporozoite develops into thousands of merozoites inside each infected hepatocyte (5). Identification of host genetic factors that control liver parasite expansion may help elucidate response mechanisms operating during liver stage infection.Gene deficiency models and gene expression studies focusing on hepatocyte infection have highlighted genes that control hepatocyte invasion and intrahepatocyte parasite expansion [e.g., CD81 (6), SR-B1 (7, 8)], but the mechanisms of host response to liver stage infection remain elusive. It has been proposed that sporozoites' ability to traverse liver macrophages (9) and/or hepatocytes (10) in the course of liver stage infection may favor the release of proinflammatory factors at liver sites of sporozoite expansion (11,12). Innate immune mechanisms might be involved in sensing Plasmodium sporozoites and in controlling liver stage infection (13).Mouse models of liver stage infection suggest that sporozoites induce a innate in...

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Section: Discussionsupporting

confidence: 81%

TREM2 governs Kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection

Gonçalves

Rodrigues-Duarte

Rodo

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Soluble TREM-2 (sTREM-2) interferes with activation of membrane-bound TREM-2, analogous to the relationship between sTREM-1 and surface TREM-1 (63). In vivo administration of recombinant murine TREM-2 in mice worsened their survival in the cecal ligation and puncture model of polymicrobial sepsis, owing to impaired bacterial clearance (63).…”

Section: Trem-2 Functions and Therapeutic Applicationsmentioning

confidence: 99%

“…In vivo administration of recombinant murine TREM-2 in mice worsened their survival in the cecal ligation and puncture model of polymicrobial sepsis, owing to impaired bacterial clearance (63). More specifically, surface TREM-2 can be antagonized by soluble portions of the extracellular domain spanning human TREM-2 (amino acids 13 to 167) or murine TREM-2 (amino acids 19 to 171, or 18 to 164) (2, 64).…”

Section: Trem-2 Functions and Therapeutic Applicationsmentioning

confidence: 99%

Triggering receptor expressed on myeloid cells receptor family modulators: a patent review

Pelham

Pandya

Agrawal

2014

Expert Opinion on Therapeutic Patents

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Introduction Triggering receptor expressed on myeloid cells (TREM) receptors and TREM-like transcript (TLT; or TREML) receptors of the immunoglobulin superfamily are known as key modulators of host immune responses. TREM-1 (CD354) and TREM-2 share the transmembrane adaptor DNAX-activation protein of 12 kDa (DAP12), but they possess separate stimulatory and inhibitory functional roles, especially in myeloid cells. Areas covered This review covers findings related to TREMs and TLTs published in patent applications from their discovery in 2000 to the present. New roles for TREM-1, TREM-2, TLT-1 and TLT-2 in maladies ranging from acute and chronic inflammatory disorders to cardiovascular diseases and cancers are discussed. Putative endogenous ligands and novel synthetic peptide blockers are also discussed. Expert opinion So far, therapeutic use of activators/blockers specific for TREMs and TLTs has been limited to pre-clinical animal models. TREM-1 is an immediate therapeutic target for acute and chronic inflammatory conditions, especially sepsis. Certain mutations in DAP12 and TREM-2 manifest into a disorder named polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), and newly identified TREM-2 variants confer a significant increase in risk of developing Alzheimer’s disease. This makes TREM-2 an attractive therapeutic target for neurodegenerative diseases.

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“…Triggering receptor expressed on myeloid cells-2 (TREM-2) has recently emerged as important immune regulator (Chen et al, 2013;Hamerman et al, 2006;Turnbull et al, 2006). There are two main functions in macrophages: as a phagocytic and immune modulatory receptor.…”

Section: Introductionmentioning

confidence: 99%

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

Pan

Lü

Cui

et al. 2015

Veterinary Immunology and Immunopathology

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Triggering Receptor Expressed on Myeloid Cells-2 Protects against Polymicrobial Sepsis by Enhancing Bacterial Clearance

Abstract: TREM-2 plays an important role in the host defense response to sepsis by enhancing bacterial clearance.

Cited by 73 publications

References 39 publications

TREM2 governs Kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection

TREM2 governs Kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection

Triggering receptor expressed on myeloid cells receptor family modulators: a patent review

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

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