Leucine-rich repeat-containing 33 (LRRC33) is an anchor protein also known by the name NRROS (negative regulator of reactive oxygen species). LRRC33 is a key regulator of transforming growth factor beta-1 (TGFB1) specifically required for microglia function in the nervous system. TGF-beta-1 activation mediated by LRRC33/NRROS is highly localized: there is little spreading of TGF-beta-1 activated from one microglial cell to neighboring microglia, suggesting the existence of localized and selective activation of TGF-beta-1 by LRRC33/NRROS. LRRC33 also plays a critical role in desensitizing TLR signaling in case of excessive activation, because TLR signaling may lead to unwarranted inflammation with hazardous outcomes¹.

Located in cell surface, LRRC33 involved in several processes, including microglia development, sequestering of TGFB in extracellular matrix, and TGFB1 activation. Required for activation of latent TGFB1 in macrophages and microglia: associates specifically via disulfide bonds with the Latency-associated peptide (LAP), which is the regulatory chain of TGFB1, and regulates integrin-dependent activation of TGFB1. Also plays a critical role in desensitizing TLR signaling².

TGF-β is synthesized as a latent form (L-TGF-β) containing a 25-kDa N-terminal latency-associated peptide (LAP) and a 12-kDa C-terminal growth factor (mTGF-β) domain. LRRC33 (NRROS), present L-TGF-β on the plasma membrane of myeloid lineage cells (e.g., macrophages, dendritic cells, and microglia). Therefore, specific presentation and storage of L-TGF-β in different extracellular microenvironment by different anchor proteins serve as a critical regulatory mechanism of TGF-β signal in various biological contexts³.

As a TGF-β associated milieu molecule, mice lacking LRRC33 exhibit increased lysosomal content, decreased ramification, and altered transcriptional profile. Altered TGF-β levels could modulate microglial state and function in neurodegenerative disease. Microglia in the brains of LRRC33 (Nrros) knockout mice resemble brain border macrophages and are less ramified and have increased lysosomal content, an indicator of increased phagocytic activity.  TGF-β levels are elevated in the brain and CSF of Alzheimer’s disease (AD), Parkinson’s disease (PD), and Frontotemporal Dementia (FTD) patients⁴.

LRRC33 plays a role in Toll-like receptor (TLR) signaling. LRRC33 is TLR homolog that contains 17 putative LRRs in the extracellular region but lacks a cytoplasmic Toll/IL-1 receptor (TIR) domain. Expression of LRRC33 appears to be ubiquitous with high level of expression found in bone marrow, thymus, liver, lung, intestine, and spleen. The LRRs of LRRC33 is required for the interaction with TLR and negatively regulates TLR signaling. By that, inhibiting effect on NF-κB and AP-1 activation as well as cytokine production. This is a mechanism of restraining excessive inflammation and controlling homeostasis for innate immunity¹.