Abstract
The triggering receptor expressed on myeloid cells (TREM) family of proteins are cell surface receptors with important roles in regulation of myeloid cell inflammatory activity. In the central nervous system, TREM2 is implicated in further roles in microglial homeostasis, neuroinflammation and neurodegeneration. Different TREM receptors appear to have contrasting roles in controlling myeloid immune activity therefore the relative and co-ordinated regulation of their expression is important to understand but is currently poorly understood. We sought to determine how microglial TREM expression is affected under neuroinflammatory conditions in vitro and in vivo. Our data show that microglial Trem1 and Trem2 gene expression are regulated in an opposing manner by lipopolysaccharide (LPS) in vitro in both adult murine and human microglia. LPS caused a significant induction of Trem1 and a contrasting suppression of Trem2 expression. We also observed similar divergent Trem1 and Trem2 responses in vivo in response to acute brain inflammation and acute cerebral ischaemia. Our data show that inhibition of NF-κB activation prevents the LPS-induced alterations in both Trem1 and Trem2 expression in vitro indicating NF-κB as a common signaling intermediate controlling these divergent responses. Distinct patterns of microglial Trem1 induction and Trem2 suppression to different Toll-like receptor (TLR) ligands were also evident, notably with Trem1 induction restricted to those ligands activating TLRs signaling via TRIF. Our data show co-ordinated but divergent regulation of microglial TREM receptor expression with a central role for NF-κB. Neuroinflammatory conditions that alter the balance in TREM expression could therefore be an important influence on microglial inflammatory and homeostatic activity with implications for neuroinflammatory and neurodegenerative disease.
Highlights
The triggering receptor expressed on myeloid cells (TREM) family of proteins comprises a group of cell surface innate immune receptors of the immunoglobulin superfamily that are expressed on various myeloid cell populations throughout the body, including microglia in the brain (Colonna, 2003; Colonna and Wang, 2016)
We show that microglial TREM1 and TREM2 expression is regulated in an opposing manner in vitro and in vivo and that NF-κB activation is a common intermediate governing this divergent regulation
Trem2 expression was abundant in microglia from all forebrain regions examined and at markedly greater levels than Trem1 and Trem3, both of which were expressed at negligible levels (Figure 1A)
Summary
The triggering receptor expressed on myeloid cells (TREM) family of proteins comprises a group of cell surface innate immune receptors of the immunoglobulin superfamily that are expressed on various myeloid cell populations throughout the body, including microglia in the brain (Colonna, 2003; Colonna and Wang, 2016). The importance of TREM function in the CNS was first highlighted by the discovery of Nasu-Hakola disease, known as Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL) (Hakola, 1972; Nasu et al, 1973) This is a fatal presenile dementia, presenting with bone pathology, caused by homozygous loss of function mutations in TREM2 (or DAP12) affecting the microglial and ostecoclast myeloid lineages (Paloneva et al, 2000, 2001, 2002). Regulation of TREM gene and protein expression will influence the extent and balance of signaling through these receptors and may be important for their effects on inflammation and disease. We sought to determine the comparative regulation of TREM receptor expression in response to microglial activation and the signaling mechanisms involved. We show that microglial TREM1 and TREM2 expression is regulated in an opposing manner in vitro and in vivo and that NF-κB activation is a common intermediate governing this divergent regulation
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