Journal Article

A Novel Microglia-Specific Transcriptional Signature Correlates With Behavioral Deficits in Neuropsychiatric Lupus

Gadhvi, Gaurav T., Cuda, Carla M., Winter, Deborah R., Lavine, Jeremy A., Dominguez, Salina T., Mayr, Maximilian G., Makinde, Hadijat M., Putterman, Chaim, Procissi, Daniele, Mike, Elise V., Droho, Steven, Bloomfield, Christina L., Kando, Mary J., Stock, Ariel D.

2020

Overview

Neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) affect over one-half of SLE patients, yet underlying mechanisms remain largely unknown. We demonstrate that SLE-prone mice (CReCOM) develop NP-SLE, including behavioral deficits prior to systemic autoimmunity, reduced brain volumes, decreased vascular integrity, and brain-infiltrating leukocytes. NP-SLE microglia exhibit numerical expansion, increased synaptic uptake, and a more metabolically active phenotype. Microglia from multiple SLE-prone models express a \"NP-SLE signature\" unrelated to type I interferon. Rather, the signature is associated with lipid metabolism, scavenger receptor activity and downregulation of inflammatory and chemotaxis processes, suggesting a more regulatory, anti-inflammatory profile. NP-SLE microglia also express genes associated with disease-associated microglia (DAM), a subset of microglia thought to be instrumental in neurodegenerative diseases. Further, expression of \"NP-SLE\" and \"DAM\" signatures correlate with the severity of behavioral deficits in young SLE-prone mice prior to overt systemic disease. Our data are the first to demonstrate the predictive value of our newly identified microglia-specific \"NP-SLE\" and \"DAM\" signatures as a surrogate for NP-SLE clinical outcomes and suggests that microglia-intrinsic defects precede contributions from systemic SLE for neuropsychiatric manifestations.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Acoustics / Amygdala / Animals / Antigens / Association Learning / Autoimmunity / behavior / Blood-Brain Barrier / Chemotaxis / Clinical outcomes / Cytokines / DAM / Disease Models, Animal / Down-regulation / Female / Females / Genetic Predisposition to Disease / Gray Matter - diagnostic imaging / Gray Matter - pathology / Immunology / Inflammation / Leukocytes / Lipid metabolism / Lupus / Lupus Erythematosus, Systemic - complications / Lupus Erythematosus, Systemic - genetics / Lupus Erythematosus, Systemic - immunology / Lupus Erythematosus, Systemic - pathology / Lupus Vasculitis, Central Nervous System - genetics / Lupus Vasculitis, Central Nervous System - immunology / Lupus Vasculitis, Central Nervous System - pathology / Macrophages - metabolism / Magnetic resonance imaging / Maze Learning / Memory Disorders - etiology / Memory Disorders - genetics / Memory Disorders - immunology / Mice / Mice, Inbred MRL lpr / Mice, Mutant Strains / Microglia / Microglia - metabolism / Migraine / Morris Water Maze Test / Motor ability / Neurodegenerative diseases / Neurological complications / NP-SLE / Organ Size / Pathology / Phenotypes / Predictive Value of Tests / Prepulse Inhibition / Reflex, Startle / Scavenger receptors / SLE / Systemic diseases / Systemic lupus erythematosus / Transcriptome / White Matter - diagnostic imaging / White Matter - pathology