A New Triggering Receptor Expressed on Myeloid Cells (Trem) Family Member, Trem-Like 4, Binds to Dead Cells and Is a DNAX Activation Protein 12-Linked Marker for Subsets of Mouse Macrophages and Dendritic Cells

Abstract

ϩ DCs are superior cells for the cross-presentation of Ags on MHC class I molecules (5-7). Molecular mechanisms for these distinct functions are starting to be identified, e.g., CD8␣ϩ DCs express higher levels of mRNA transcripts and proteins involved in the MHC class I processing pathway (7).Apoptotic cells are generated continually in mammals and other species, and cell death is increased further during embryo development, tissue remodeling, and inflammation. Potentially harmful cells that are eliminated by apoptosis include self-reactive T and B cells, tumor cells, and cells infected with viruses and some bacteria. Engulfment of apoptotic cells in some instances suppresses production of inflammatory cytokines from activated macrophages (8). When dying cells are engulfed by DCs in the steady state in the absence of infection or immunological adjuvants, Ag-specific tolerance to Ags in the dying cells can be induced (3). In contrast, if mice are given dying cells with adjuvants, Ag-specific T cell responses develop (3, 9). Analyses of genetically modified mice have shown that increased accumulation of apoptotic cells induces the development of autoimmune diseases (10 -12). Thus, accumulating evidence indicates that the uptake of apoptotic cells is not only a clearance mechanism, but is also capable of suppressing inflammation and modulating immune responses from Ag-specific tolerance to resistance (13).In vitro studies indicate that many receptors can be involved in the uptake of dying cells by macrophages, including scavenger receptors, the phosphatidylserine receptor, integrins, CD14, C1q, C1qR,. Recently, the T cell Ig and mucin domain-containing molecules, Tim-1 and Tim-4, The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 3 Abbreviations used in this paper: DC, dendritic cell; DAP10, DNAX activation protein 10 kDa; DAP12, DNAX activation protein 12 kDa; Flt3L, Fms-like tyrosine kinase 3 ligand; HEK, human embryonic kidney; Mertk, Mer tyrosine kinase; PI, propidium iodide; poly(I:C), polyinosine-polycytidylic acid; Trem, triggering receptor expressed on myeloid cells; Treml4, Trem-like 4; SIGN-R1, specific intracellular adhesion molecule-grabbing nonintegrin receptor 1.

Comparison of gene expression profiles between human and mouse monocyte subsets

“…Another cluster of functionally related genes that were upregulated in mouse Ly-6C lo monocytes were those previously described to be involved in the recognition or engulfment of apoptotic cells (Figure 6B), including CD36, 40 Tgm2, 41 Treml4, 31 and the ␣ v integrin (ITGAV, CD51). 40 This finding fits well with recent observations that this subset of monocytes preferentially engulfs dying cells administered intravenously.…”

Neuronal and nonneuronal cholinergic structures in the mouse gastrointestinal tract and spleen

“…This antibody was widely used in the past for flow sorting, imunohisto-chemistry, and western blot in the mouse (see manufacturer’s datasheet). This antibody detects one large band of approximately 160 kDa in samples of peritoneal macrophages, lymphoid tissues, and skin (Hemmi et al, 2009; Moore et al, 2000; Seitz et al, 2010). Among many examples, macrophages located in the gut lamina propria, Peyer’s patches, liver, and spleen are stained by this antibody (deSchoolmeester et al, 2009; Donaldson et al, 2012; Lloyd et al, 2008).…”

The expanding roles of ITAM adapters FcRγ and DAP12 in myeloid cells

“…Hsieh et al have expanded on this finding by showing that neurons express a ligand for TREM-2 that is increased during the induction of apoptosis, shown by staining cells with a fusion protein of TREM-2 and human IgG1 (53). In fact, several cell lines have increased staining with the TREM-2 Fc reagent after the induction of cell death (53, 56). When non-phagocytic CHO cells are transfected with a TREM-2/DAP12 chimera they can endocytose apoptotic neurons, showing TREM-2 is a bona fide phagocytic receptor for these dying cells (53).…”