Molecular mechanisms of phagocytosis and immune activation by TREM receptors

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Macrophages, along with other phagocytes, have the inherent ability to engulf or “eat” foreign material, in a process termed phagocytosis. Phagocytosis is a highly complex process that involves a myriad of signaling events that ultimately results in the engulfment of microbial pathogens, or the clearance of dying cells and debris within multicellular organisms. As such, phagocytosis plays a key role in both cellular immunity and tissue homeostasis. Macrophages can recognize and distinguish specific particles due the presence of a variety of cell surface receptors that can initiate the phagocytosis process. The identification and characterization of such receptors remains critical for a comprehensive understanding of phagocytosis. Since their discovery almost 20 years ago, multiple studies have demonstrated that the Triggering Receptor Expressed on Myeloid cells (TREM) family of receptors play an important role in regulating inflammation. In particular, TREM1 and TREM2 have been well characterized in immune regulation and neurodegenerative diseases, but their role in phagocytosis remains unclear. There are conflicting reports on whether TREM2 functions to phagocytose bacteria. As such, there remains a major knowledge gap in whether and how TREM2 controls phagocytosis. We have recently discovered that TREM2 can directly bind to Mycobacterium tuberculosis (Mtb), the pathogenic bacteria responsible for tuberculosis. Preliminary studies also show that genetic deletion of TREM2 in macrophages dramatically impairs their ability to phagocytose Mtb. We therefore hypothesize that TREM2 can recognize and facilitate the uptake of mycobacteria, which can then impact the differential activation of antibacterial and inflammatory responses. To address this knowledge gap, we aim to: (1) identify the bacterial ligand recognized by TREM2, (2) examine the spatial-temporal regulation of TREM2 in response to bacterial stimuli as a means to elucidate the intracellular signaling pathways mediated through ligation of TREM2, and (3) determine the immunological effects of TREM2-mediated phagocytosis, including the activation of antimicrobial pathways, cytokine production, and ultimately bacterial survival. The long-term goal of this research program is to understand the molecular basis of how TREM-like receptors, many of which are uncharacterized, controls phagocytosis in all myeloid cell types. Given that phagocytic receptors are essential for host defense, nutrient acquisition, inflammation, and tissue homeostasis, the advancement of knowledge on these receptors will contribute answers to many important biological questions relevant for all organisms.