LILRB2 transduces negative signals by its association with SHP-1 phosphatase via the ITIM motifs. Leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), an inhibitory receptor bearing three immunoreceptor tyrosine-based inhibitory motifs (ITIM), was found to be expressed selectively in monocytes, macrophages, and dendritic cells. As a result, TREM2 promotes cell survival and counteracting inflammatory activation. TREM2 signaling significantly affects microglia cellular phenotypes and functions, including phagocytosis, lipid metabolism, metabolic shift. Further, this phosphorylation induces cell activation by initiating signal cascades involving Ca 2+ mobilization, cytoskeleton rearrangement, MAPK signaling, and activation of energetic metabolism. Upon cross-linking by ligands, phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAM) within DAP12 recruits and activates kinases. The transmembrane region of TREM2 is associated with adaptor protein DNAX-activation protein 12 (DAP12). TREM2, a single-pass transmembrane receptor expressed in microglia, binds to a variety of ligands, e.g., lipoproteins, phospholipids, and oligomeric Aβ (oAβ). TREM2 affects AD by its regulation of microglia functions. Among the microglia genes, polymorphisms of TREM2, a transmembrane protein selectively expressed in microglia, have been associated with an increased risk of developing AD. Microglia genetic variants, including genes CR1, CD33, and TREM2, contribute to the pathogenesis of late-onset AD (LOAD). Microglia, brain-resident myeloid cells, play pivotal roles in AD development by regulating brain homeostasis and neuroinflammation, promoting Aβ plaque phagocytic clearance, and clustering and limiting diffusion of Aβ plaques and tau tangles. Key pathological features of AD include progressive memory loss, cognitive deficits, synapse loss, neuronal death, β-amyloid (Aβ) plaque deposition, and hyperphosphorylated tau protein forming neurofibrillary tangles. Translationally, a LILRB2 antagonist antibody completely rescued the inhibition of TREM2 signaling by LILRB2, suggesting a novel therapeutic strategy for improving microglial functions.Īlzheimer’s disease (AD), the main cause of dementia, is a neurodegenerative disorder with limited treatment options. This study revealed for the first time the molecular mechanisms of LILRB2-mediated inhibition of TREM2 signaling in microglia and demonstrated a novel approach of enhancing TREM2-mediated microglia functions by blocking LILRB2-ligand interactions. In vivo studies showed significantly enhanced clustering of microglia around plaques with a prominent increase in microglial amyloid plaque phagocytosis when 5XFAD mice were treated with Ab29. Further, Ab29 enhanced microglia phagocytosis, TREM2 signaling, migration, and cytokine responses to the oAβ-lipoprotein complex in hMGL and microglia cell line HMC3. We identified a monoclonal antibody (Ab29) that blocks LILRB2/ligand interactions and prevents TREM2 signaling inhibition mediated by LILRB2. Upon co-ligation of the LILRB2 and TREM2 by shared ligands oAβ or PS, TREM2 signaling was significantly inhibited. We confirmed the expression of both LILRB2 and TREM2 in human brain microglia using immunofluorescence. Effects of the LILRB2 antagonist antibody on microglial responses to amyloid plaques were further studied in vivo using stereotaxic grafted microglia in 5XFAD mice. The biological effects of LILRB2 antagonist antibody (Ab29) were studied in human induced pluripotent stem cell (iPSC)–derived microglia (hMGLs) for migration, oAβ phagocytosis, and upregulation of inflammatory cytokines. To specifically interrogate LILRB2-ligand (oAβ and PS) interactions and microglia functions, we generated potent antagonistic LILRB2 antibodies with sub-nanomolar level activities. Here we study the negative regulation of TREM2 functions by leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), an inhibitory receptor bearing ITIM motifs. Triggering receptor expressed on myeloid cells 2 (TREM2) in association with DAP12 mediates signaling affecting microglia function. Microglia plays crucial roles in Alzheimer’s disease (AD) development.
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