title: Divergent Neuroinflammatory Regulation of Microglial TREM Expression and Involvement of NF-κB.
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 conditionsin vitroandin vivo. Our data show that microglialTrem1andTrem2gene expression are regulated in an opposing manner by lipopolysaccharide (LPS)in vitroin both adult murine and human microglia. LPS caused a significant induction ofTrem1and a contrasting suppression ofTrem2expression. We also observed similar divergentTrem1andTrem2responsesin vivoin response to acute brain inflammation and acute cerebral ischaemia. Our data show that inhibition of NF-κB activation prevents the LPS-induced alterations in bothTrem1andTrem2expressionin vitroindicating NF-κB as a common signaling intermediate controlling these divergent responses. Distinct patterns of microglialTrem1induction andTrem2suppression to different Toll-like receptor (TLR) ligands were also evident, notably withTrem1induction 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.
authors.affiliation: The Royal (Dick) School of Veterinary Studies, University of Edinburgh Midlothian, UK.
authors.forename: Rosie
authors.initials: R
authors.lastname: Owens
authors.affiliation: The Royal (Dick) School of Veterinary Studies, University of Edinburgh Midlothian, UK.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Grabert
authors.affiliation: The Royal (Dick) School of Veterinary Studies, University of Edinburgh Midlothian, UK.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Davies
authors.affiliation: The Royal (Dick) School of Veterinary Studies, University of Edinburgh Midlothian, UK.
authors.forename: Alessio
authors.initials: A
authors.lastname: Alfieri
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University Montreal, QC, Canada.
authors.forename: Jack P
authors.initials: JP
authors.lastname: Antel
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University Montreal, QC, Canada.
authors.forename: Luke M
authors.initials: LM
authors.lastname: Healy
authors.affiliation: The Royal (Dick) School of Veterinary Studies, University of Edinburgh Midlothian, UK.
authors.forename: Barry W
authors.initials: BW
authors.lastname: McColl
keywords: NF-κB; TREM2; lipopolysaccharide (LPS); microglia; microglial activation; myeloid cells; neuroinflammation