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

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

doi:10.3389/fimmu.2020.00230

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.

Highlights

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that arises from the combination of genetic and environmental factors, culminating in destructive tissue injury to multiple organ systems including the central nervous system (CNS)
Since CReCOM mice develop SLE-like disease with age and do not display kidney pathology until 8 months of age [14], we determined whether these mice exhibit NP-SLElike disease prior to end-organ pathology
CReCOM mice showed a higher %Prepulse inhibition (PPI) at the 12 KHz prepulse frequency compared to WT mice (Figure 1C), indicating an inability to adapt to the acoustic stimuli even when preceded by a weaker signal

Summary

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that arises from the combination of genetic and environmental factors, culminating in destructive tissue injury to multiple organ systems including the central nervous system (CNS). Incidence varies widely among evaluated cohorts [1], nearly one-half of patients experience primary, or disease-related, manifestations of CNS disease, known as neuropsychiatric SLE (NP-SLE). NP-SLE can be subdivided into focal or diffuse syndromes. Focal NP-SLE presents as focal seizures, strokes, movement disorders and/or migraine or cluster headache and may involve a predominant ischemic-vascular pathway [1]. Patients with diffuse NP-SLE present with symptoms including psychosis, mood disorder, cognitive dysfunction, acute confusional states, headaches other than migraine, or cluster headache and/or anxiety disorders [1]. Despite the devastating impact of both focal and diffuse NP-SLE on health-related quality of life, underlying disease mechanisms remain largely unknown, often leading to palliative rather than therapeutic protocols [1]

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