Triggering Receptor Expressed on Myeloid Cells-1 in Neutrophil Inflammatory Responses: Differential Regulation of Activation and Survival

Radsak, Markus P.; Salih, Helmut R.; Rammensee, Hans‐Georg; Schild, Hansjörg

doi:10.4049/jimmunol.172.8.4956

Cited by 184 publications

(196 citation statements)

References 36 publications

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“…CD300e ligation induced a rapid intracellular calcium mobilization, as well as the production of ROS, supporting that this receptor may regulate the microbicidal activity of monocytes [33]. Similarly, and in line with the previous reports on the ability of both hOSCAR and TREM-1 to trigger the respiratory burst in granulocytes [27,34], we have observed that TREM-1 activates ROS production also in monocytes.…”

Section: Discussionsupporting

confidence: 91%

Functional analysis of the CD300e receptor in human monocytes and myeloid dendritic cells

et al. 2010

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The CD300e surface molecule, originally termed immune receptor expressed by myeloid cells (IREM)-2, was reported to associate with the DNAX-activating protein (DAP) 12 adaptor in co-transfected cells, and is capable of signaling. In the present report, we investigated in detail the function of CD300e in monocytes and myeloid DC (mDC) freshly isolated from peripheral blood of normal blood donors. Upon engagement by an agonistic mAb, CD300e triggered an intracellular calcium mobilization and superoxide anion O À 2 production in monocytes. Activation via CD300e provided survival signals that prevented monocyte and mDC apoptosis, triggered the production of pro-inflammatory cytokines and upregulated the expression of cell surface co-stimulatory molecules in both cell types. Moreover, CD300e activation of mDC enhanced the alloreactive response of naive T cells. Overall, our data formally support the notion that CD300e functions as an activating receptor capable of regulating the innate immune response in myeloid cells.Key words: Cell activation . Cell surface molecules . DC . Monocytes IntroductionA number of surface molecules expressed by myeloid cells are members of multigenic families that include both activating and inhibitory receptors [1,2], which contribute to establish a balance of opposite signals that control the initiation, amplitude and duration of the cell response. Activating receptors have a short cytoplasmic tail with a positively charged amino acid residue within their transmembrane region that allows their association with ITAM-bearing adaptors (e.g. DNAX-activating protein (DAP) 12, FceRIg or CD3z) [3]. Upon ligand recognition and receptor clustering, ITAM become tyrosine phosphorylated and serve as docking sites for Src homology type 2 domaincontaining protein tyrosine kinases such as ZAP-70 or Syk [4,5]. Recruitment and activation of protein tyrosine kinases and downstream effectors regulate calcium mobilization, transcriptional activation, cytokine production, migration, proliferation and/or differentiation [6]. In contrast, inhibitory receptors display a longer cytoplasmic tail characterized by the presence of ITIM. Ligand-induced clustering results in tyrosine phosphorylation of ITIM that act as docking sites for SHP-1, SHP-2 or SHIP. Upon recruitment, tyrosine phosphatases become activated and dephosphorylate key signaling mediators of activation pathways such as Syk, LAT, BLNK/SLP-76, Vav, PI3K and cytoskeletal structures, consequently downregulating the signaling cascade [6][7][8].Ã These authors share equal credit for senior authorship. 722The CD300 or immune receptor expressed by myeloid celsl (IREM) family of myeloid-associated receptors consists of at least five surface molecules that are encoded by genes located on human chromosome 17 (17q25) [9]. CD300c (CMRF-35) was the first identified but has been thus far poorly characterized [10,11]. CD300a (IRp60) was shown to associate with SHP-1 and SHP-2, delivering inhibitory signals in human NK cells, mast cells, eosinophils and granulocyt...

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Section: Discussionsupporting

confidence: 91%

Functional analysis of the CD300e receptor in human monocytes and myeloid dendritic cells

et al. 2010

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“…Activation of TREM-1 is associated with release of proinflammatory mediators and reactive oxygen and nitrogen intermediates by phagocytic leukocytes (Bouchon et al, 2000;Gibot et al, 2007;Radsak et al, 2004). These activities have been linked to hepatotoxicity (Jaeschke and Hasegawa, 2006;Laskin and Laskin, 2001;Laskin and Pendino, 1995).…”

Section: Discussionmentioning

confidence: 99%

Regulation of TREM expression in hepatic macrophages and endothelial cells during acute endotoxemia

Chen

Laskin²,

Gordon

et al. 2008

Experimental and Molecular Pathology

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Triggering receptor expressed on myeloid cells (TREM) regulates inflammatory responses to lipopolysaccharide (LPS). In these studies, we analyzed expression of TREM in hepatic macrophages and endothelial cells which play a central role in LPS clearance. LPS administration to C3H/OuJ mice resulted in a rapid induction of TREM-1 and TREM-3, but a decrease in TREM-2 in liver macrophages and endothelial cells. The observation that TREM family members are detectable in endothelial cells is novel and demonstrates that their expression is not limited to myeloid cells. LPSinduced alterations in TREM expression were not evident in cells from C3H/HeJ TLR-4 mutant mice, indicating that the response is dependent on TLR-4. IL-1β and TNFα upregulated TREM-1 and TREM-3 expression and suppressed TREM-2 expression in macrophages and endothelial cells. This activity involved PI3-kinase and p38 MAP kinase signaling. Interestingly, no significant differences were noted in TREM expression between wild-type and TNFR1−/− mice treated with LPS. Treatment of macrophages and endothelial cells with LPS upregulated expression of nitric oxide synthase-2 (NOS-2). This was blocked by TREM-1 Fc/fusion protein, indicating that TREM-1 mediates LPSinduced NOS-2 expression. These results suggest that TREM proteins are important in the inflammatory response of hepatic macrophages and endothelial cells to acute endotoxemia.

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“…5A) and also did not promote neutrophil activation as measured by upregulation of cell surface levels of the adhesion molecule CD66b (Supplemental Fig. 5B) (45). IDR-1002 also did not affect the in vitro viability of human neutrophils at concentrations up to 125 mg/ml (Supplemental Fig.…”

Section: Effects Of Idr-1002 On Microbicidal Activities Of Leukocytesmentioning

confidence: 99%

Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

Nijnik

Madera

et al. 2010

The Journal of Immunology

185

225

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With the rapid rise in the incidence of multidrug resistant infections, there is substantial interest in host defense peptides as templates for production of new antimicrobial therapeutics. Natural peptides are multifunctional mediators of the innate immune response, with some direct antimicrobial activity and diverse immunomodulatory properties. We have previously developed an innate defense regulator (IDR) 1, with protective activity against bacterial infection mediated entirely through its effects on the immunity of the host, as a novel approach to anti-infective therapy. In this study, an immunomodulatory peptide IDR-1002 was selected from a library of bactenecin derivatives based on its substantially more potent ability to induce chemokines in human PBMCs. The enhanced chemokine induction activity of the peptide in vitro correlated with stronger protective activity in vivo in the Staphylococcus aureus-invasive infection model, with a >5-fold reduction in the protective dose in direct comparison with IDR-1. IDR-1002 also afforded protection against the Gram-negative bacterial pathogen Escherichia coli. Chemokine induction by IDR-1002 was found to be mediated through a Gi-coupled receptor and the PI3K, NF-κB, and MAPK signaling pathways. The protective activity of the peptide was associated with in vivo augmentation of chemokine production and recruitment of neutrophils and monocytes to the site of infection. These results highlight the importance of the chemokine induction activity of host defense peptides and demonstrate that the optimization of the ex vivo chemokine-induction properties of peptides is a promising method for the rational development of immunomodulatory IDR peptides with enhanced anti-infective activity.

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Triggering Receptor Expressed on Myeloid Cells-1 in Neutrophil Inflammatory Responses: Differential Regulation of Activation and Survival

Cited by 184 publications

References 36 publications

Functional analysis of the CD300e receptor in human monocytes and myeloid dendritic cells

Functional analysis of the CD300e receptor in human monocytes and myeloid dendritic cells

Regulation of TREM expression in hepatic macrophages and endothelial cells during acute endotoxemia

Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

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