The Triggering Receptors Expressed on Myeloid Cells (TREM) are expressed on a variety of innate immune cells including monocytes, macrophages, dendritic cells (DC), neutrophils, and osteoclasts. These receptors deliver signals to their host cells via association with the signaling chain, DAP12. DAP12 signaling is dependent on the presence of an immunoreceptor tyrosine-based activation motif (ITAM) within its cytoplasmic tail. Upon stimulation of a DAP12-coupled receptor, DAP12 is phosphorylated and recruits proteins critical to the propagation of downstream signals. Recent work has demonstrated that members of the TREM family, via DAP12, can deliver either activation or inhibitory signals to monocytes and macrophages. However, the biochemical nature of DAP12 signaling within myeloid cells is largely uncharacterized as is the overall immunological role of the TREM gene cluster. Thus, we have taken a bipartite approach to understand the immunobiology of the TREM cluster. Our second approach to understanding the role of TREM in regulation of innate immunity and cancer is dissection of the DAP12 signaling pathway in myeloid cells. Our studies have identified a shifting, developmentally regulated signaling cassette in macrophages and monocytes. Monocytes express two key intracellular adaptor proteins, the Linker for Activation of T cells (LAT) and the Linker for Activation of B cells (LAB, also known as the Non-T cell Adaptor, NTAL). We find that during maturation of DC or macrophages from monocytes in vitro, the levels of LAT fall whereas the levels of LAB increase. Our previous work had demonstrated the ability of LAB to regulate inflammatory cytokine production in macrophages. More recently, we have demonstrated that dendritic cells (DC) signal via LAB. A screen of multiple DC lignads suggested that the fungal particle zymosan (Zy) could elicit robust LAB phosphorylation whereas TLR stimulation does not. Fractionation and transfection studies demonstrated that LAB phosphorylation was caused by fungal-derived mannons signaling via Dectin-1 on the DC cell surface. Interestingly, we found that DC lacking LAB produced lower levels of inflammatory cytokine due to increased levels of nuclear beta catenin. Accordingly, T cell responses are reduced in LAB null mice and these mice are more susceptible to fungal infection. In addition to our signaling studies in the myeloid compartment of the innate immune system we study the role of the TREM in the inflammation associated with cancer. We find that tumor associated myeloid-derived suppressor cells express TREM1 and that mice harboring 4T1 breast cancers have elevated levels of soluble (s)TREM1 in their blood. In addition, we find high expression of TREM2 on tumor associated macrophages and we have demonstrated the involvement of TREM-2 on colitis and colon cancer associated with colitis. Most recently we have been involved in the characterization of TREM-like Transcript-4 (Treml4) in cardiovascular disease. This work has defined Treml4 as an unusual protein that is highly expressed in neutrophils. Polymorphisms within Treml4 are associated with expression and correlate with cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010300-16
Application #
8763066
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2013
Total Cost
$822,032
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
De Ravin, Suk See; Wu, Xiaolin; Moir, Susan et al. (2016) Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med 8:335ra57
Burg, Ashley R; Quigley, Laura; Jones, Adam V et al. (2016) Orally administered β-glucan attenuates the Th2 response in a model of airway hypersensitivity. Springerplus 5:815
Thomas, Douglas D; Heinecke, Julie L; Ridnour, Lisa A et al. (2015) Signaling and stress: The redox landscape in NOS2 biology. Free Radic Biol Med 87:204-25
Shanker, Anil; Pellom Jr, Samuel T; Dudimah, Duafalia F et al. (2015) Bortezomib Improves Adoptive T-cell Therapy by Sensitizing Cancer Cells to FasL Cytotoxicity. Cancer Res 75:5260-72
Sen, Shurjo K; Boelte, Kimberly C; Barb, Jennifer J et al. (2014) Integrative DNA, RNA, and protein evidence connects TREML4 to coronary artery calcification. Am J Hum Genet 95:66-76
Montalvo, Vanessa; Quigley, Laura; Vistica, Barbara P et al. (2013) Environmental Factors Determine DAP12 Deficiency To Either Enhance or Suppress Immunopathogenic Processes. Immunology :
Orr, Selinda J; Burg, Ashley R; Chan, Tim et al. (2013) LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing β-catenin activation in dendritic cells. PLoS Pathog 9:e1003357
Derive, Marc; Bouazza, Youcef; Sennoun, Nacira et al. (2012) Soluble TREM-like transcript-1 regulates leukocyte activation and controls microbial sepsis. J Immunol 188:5585-92
Orr, Selinda J; McVicar, Daniel W (2011) LAB/NTAL/Lat2: a force to be reckoned with in all leukocytes? J Leukoc Biol 89:11-9
Orr, Selinda J; Roessler, Stephen; Quigley, Laura et al. (2010) Implications for gene therapy-limiting expression of IL-2R gamma c delineate differences in signaling thresholds required for lymphocyte development and maintenance. J Immunol 185:1393-403

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