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

Abstract

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.

Remodeling of Neurotransmission, Chemokine, and PI3K-AKT Signaling Genomic Fabrics in Neuropsychiatric Systemic Lupus Erythematosus

“…Most of the genes encoding proposed NPSLE biomarkers [ 16 ] did not prove to have a significant contribution to the lupus-prone cortical transcriptome of the MRL/ lpr , compared with its background control. However, an interesting observation regarding C1qtnf4 may prove useful for future investigations.…”

“…Gene biomarkers of a disease are usually selected from the genes with most frequently altered sequence or expression level when comparing a large population of sick persons with a demographically matched population of healthy individuals [ 15 , 16 ]. Frequent alteration indicates that their sequence and/or expression level are weakly protected by cellular homeostatic mechanisms as expected for non-essential players.…”

“…The hierarchy is topped by the Gene Master Regulator (GMR), which is the most influential gene of the phenotype, and, by consequence, the most legitimate target for gene therapy [ 18 ]. With GCH one can also evaluate how influential are some other interesting genes, including the proposed NPSLE biomarkers [ 16 , 19 ], for example. GCH scores of all quantified genes in each of the three phenotypes were determined with the Python software “GENE COMMANDING HEIGHT”, described in Reference [ 13 ].…”

“…Note the non-uniform (even opposite in some cases) regulation of genes from the same block. Figure 3d presents the WIRs of genes previously identified as possible NPSLE biomarkers [16] (extensive review of potential biomarkers can be found in Reference [30]). C1qtnf4 (C1q and tumor necrosis factor related protein 4; known to have enriched expression in the brain, and plays a role in the regulation of inflammation) had the largest (negative) contribution to the transcriptomic alterations in the cortex of MRL/lpr with respect to MRL/+ control.…”

Centrally Acting Angiotensin-Converting Enzyme Inhibitor Suppresses Type I Interferon Responses and Decreases Inflammation in the Periphery and the CNS in Lupus-Prone Mice

“…We have shown a constitutive increase in the IRGs in total brain lysates and in the kidney in the young MRL/lpr mice at 8 weeks of age, especially the key genes IRF7 and CXCL10. Whether the IFN signature is intrinsic to the brain is still under investigation (58,59). IRF7 is a key regulator of Type I IFN responses (47,60).…”