IntroductionNegative regulator of reactive oxygen species (NRROS) gene (previously known as Lrrc33) produces a protein that functions as a general negative regulator of ROS production in phagocytes. ROS produced by phagocytes are essential for host defense but excessive ROS can cause collateral tissue damage during inflammatory processes and therefore needs to be tightly regulated. The predicted structure of NRROS contains a signal sequence, 21 putative leucine-rich repeat domains, a transmembrane domain, and a short cytoplasmic domain. NRROS is preferentially expressed in immune organs such as lymph nodes, thymus and spleen. Among leukocytes, myeloid cell subsets including macrophages, neutrophils and dendritic cells has the highest NRROS expression.(1)Microglia are specified phagocytes in the CNS parenchyma. They are vital in maintaining CNS homeostasis. Additionally, they control clearance of cellular debris and uptake of glutamate and other neurotransmitters. Defects in microglial function have been accompanying with neuroinflammation and disorders such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS). In addition to microglia in the CNS parenchyma, nonparenchymal perivascular macrophages (PVMs), subdural meningeal macrophages (MMs) and choroid plexus macrophages (CPMs) exist throughout the CNS at steady state.(2, 3)Canonical macrophage developmental factors such as PU.1, IL-34, CSFR1 and IRF8 have roles in microglial function and expansion. TGF-β and Sall1 were lately identified as unique factors that are essential for microglia development. NRROS is highly expressed in CNS-resident macrophages, containing microglia and PVMs. Loss of NRROS results in astrogliosis, defects in motor function and reduced lifespan. Mechanistically, NRROS expression is essential in microglia for differentiation during early embryonic development. In one study, it was shown that the CNS of NRROS-deficient mice lacks normal microglia and is instead populated by PVM-like cells (PLCs). These neurological phenotypes resulting from NRROS deficiency in mice were not associated with classical signs of neurodegeneration, neuroinflammation or increased ROS production as observed in the ALS model. Instead, NRROS deficiency resulted in a complete loss of CD11bhiCD45lo microglia with concomitant emergence of PLCs (PVM-like cells) in the CNS.(4)