Investigating the role and regulation of GPNMB in progranulin-deficient macrophages.

Introduction: Progranulin (PGRN) is a holoprotein that is internalized and taken to the lysosome where it is processed to individual granulins (GRNs). PGRN is critical for successful aging, and insufficient levels of PGRN are associated with increased risk for developing neurodegenerative diseases like AD, PD, and FTD. A unifying feature among these diseases is dysregulation of peripheral immune cell populations. However, considerable gaps exist in our understanding of the function(s) of PGRN/GRNs in immune cells and their role in regulating central-peripheral neuroimmune crosstalk. One of the most upregulated genes and proteins in humans with GRN haploinsufficiency and in aged Methods: To address this gap, peritoneal macrophages (pMacs) from 5-to-6-month old WT and Results: We observed an increase in GPNMB protein and mRNA as a result of insufficient progranulin in peripheral immune cells at a very early age relative to previous reports on the brain. Stimulation-dependent cytokine release was decreased in the media of Discussion: These findings highlight the fact that knowledge of early-stage disease mechanism(s) in peripheral populations may inform treatment strategies to delay disease progression at an early, prodromal timepoint prior to development of neuroinflammation and CNS pathology.