SHIP-2 inhibits human microglia-like cell function in a TREM2 independent manner

Abstract

Abstract Microglia are a crucial component of the immune response in neurodegenerative diseases including Alzheimer’s Disease (AD). The Triggering Receptor Expressed on Myeloid Cells #2 (TREM2) mediates microglial phagocytosis and migration, and promotes metabolic homeostasis. Src homology domain-containing inositol 5-phosphatase 1 (SHIP-1) inhibits TREM2 in myeloid cells like macrophages and osteoclasts. SHIP-2, a paralog of SHIP-1, inhibits other myeloid cell receptors including Macrophage Colony-Stimulating Factor (M-CSF). We hypothesize that SHIP-2, inhibits TREM2-mediated microglial functions. To test our hypothesis, we studied the effect of pharmacological inhibition of SHIP-2 (and SHIP-1) in the function of wild-type (HMC3WT) and Trem2−/− human microglia-like cells (HMC3T2KO), which predominantly express SHIP-2 compared to SHIP-1. HMC3WT displayed superior phagocytic ability of oligomerized amyloid β and apoptotic neurons, have a larger lysosomal compartment, and have increased mitochondrial activity compared to HMC3T2KO. Treatment with a pan SHIP-1/2 inhibitor (SHIPi) K161 significantly improved the phagocytic uptake of fluorescently tagged oligomerized Aβ42 in both HMC3WT and HMC3T2KO. K161 treatment resulted in an enlarged lysosomal compartment and increased mitochondrial activity in both HMC3WT and HMC3T2KO. Our data suggests that, in cases of low SHIP-1 expression, pan SHIP inhibition improves microglia-like cell functions independently of TREM2. Further studies to look for SHIP2-TREM2 interactions and the effect of SHIP-1 expression in combination with SHIPi treatment in HMC3 cell function are underway. SHIPi are non-toxic in HCM3 cells and may offer potential treatment options for AD. Supported by grants from NIH (1RF1AG059717-01)