Dataset Information

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.

SUBMITTER: Makinde HM

PROVIDER: S-EPMC7055359 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Makinde Hadijat M HM Winter Deborah R DR Procissi Daniele D Mike Elise V EV Stock Ariel D AD Kando Mary J MJ Gadhvi Gaurav T GT Droho Steven S Bloomfield Christina L CL Dominguez Salina T ST Mayr Maximilian G MG Lavine Jeremy A JA Putterman Chaim C Cuda Carla M CM

Frontiers in immunology 20200226

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 mult ...[more]

PMID: 32174913

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Project description:Background Neuropsychiatric lupus (NPSLE) refers to the neurological and psychiatric manifestations that are commonly observed in patients with systemic lupus erythematosus (SLE). An important question regarding the pathogenesis of NPSLE is whether the symptoms are caused primarily by CNS-intrinsic mechanisms or develop as a consequence of systemic autoimmunity. Currently used spontaneous mouse models for SLE have already contributed significantly to unraveling how systemic immunity affects the CNS. However, they are less suited when interested in CNS primary mechanisms. In addition, none of these models are based on genes that are associated with SLE. In this study, we evaluate the influence of A20, a well-known susceptibility locus for SLE, on behavior and CNS-associated changes in inflammatory markers. Furthermore, given the importance of environmental triggers for disease onset and progression, the influence of an acute immunological challenge was evaluated. Methods Female and male A20 heterozygous mice (A20+/−) and wildtype littermates were tested in an extensive behavioral battery. This was done at the age of 10±2weeks and 24 ± 2 weeks to evaluate the impact of aging. To investigate the contribution of an acute immunological challenge, LPS was injected intracerebroventricularly at the age of 10±2weeks followed by behavioral analysis. Underlying molecular mechanisms were evaluated in gene expression assays on hippocampus and cortex. White blood cell count and blood-brain barrier permeability were analyzed to determine whether peripheral inflammation is a relevant factor. Results A20 heterozygosity predisposes to cognitive symptoms that were observed at the age of 10 ± 2 weeks and 24 ± 2 weeks. Young A20+/− males and females showed a subtle cognitive phenotype (10±2weeks) with distinct neuroinflammatory phenotypes. Aging was associated with clear neuroinflammation in female A20+/− mice only. The genetic predisposition in combination with an environmental stimulus exacerbates the behavioral impairments related to anxiety, cognitive dysfunction and sensorimotor gating. This was predominantly observed in females. Furthermore, signs of neuroinflammation were solely observed in female A20+/− mice. All above observations were made in the absence of peripheral inflammation and of changes in blood-brain barrier permeability, thus consistent with the CNS-primary hypothesis. Conclusions We show that A20 heterozygosity is a predisposing factor for NPSLE. Further mechanistic insight and possible therapeutic interventions can be studied in this mouse model that recapitulates several key hallmarks of the disease. Highlights • A novel mouse model for neuropsychiatric lupus was established.• Loss of 1 copy of A20/TNFAIP3 leads to neuroinflammation and cognitive symptoms.• Female-specific neuroinflammation was seen with age.• An environmental stimulus worsens the behavioral impairments.• The results show that the brain is the primary affected site.

Dataset Information

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

Publications

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

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