CReCOM Brain Macrophages
A Novel Microglia-Speciﬁc Transcriptional Signature Correlates With Behavioral Deﬁcits in Neuropsychiatric Lupus, Frontiers in Immunology, Feb 2020. Neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) affect over one-half of SLE patients, yet underlying mechanisms remain largely unknown. We isolated brain-infiltrating macrophages from aged SLE-prone mice (CReCOM, CD11cC8). We demonstrate that CReCOM mice 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.