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

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

doi:10.3389/fimmu.2020.00230

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

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.

Original language	English (US)
Article number	230
Journal	Frontiers in immunology
Volume	11
DOIs	https://doi.org/10.3389/fimmu.2020.00230
State	Published - Feb 26 2020

Funding

This work was supported by the Northwestern University Behavioral Phenotyping Core, Center for Translational Imaging, Next Generation Sequencing Core, and the Northwestern University - Flow Cytometry Core Facility supported by Cancer Center Support Grant (NCI CA060553). Flow Cytometry Cell Sorting was performed on a BD FACSAria SORP system, purchased through the support of NIH 1S10OD011996-01. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory which is supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Funding. These studies were supported by training grants from the NIH to HM (T32-AR007611) and EM (T32-GM007288); a NIH Research Supplement to Promote Diversity in Health-Related Research (3R01AR065594-02W1) to EM; a R01 grant (3R01AR065594) to CP and a K01 grant (5K01AR060169) to CC from the National Institute of Arthritis and Musculoskeletal Diseases; a Novel Research grant from the Lupus Research Alliance to CC (637405). These studies were supported by training grants from the NIH to HM (T32-AR007611) and EM (T32-GM007288); a NIH Research Supplement to Promote Diversity in Health-Related Research (3R01AR065594-02W1) to EM; a R01 grant (3R01AR065594)

Keywords

DAM
NP-SLE
SLE
behavior
interferon
lupus
microglia

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Makinde, H. M., Winter, D. R., Procissi, D., Mike, E. V., Stock, A. D., Kando, M. J., Gadhvi, G. T., Droho, S., Bloomfield, C. L., Dominguez, S. T., Mayr, M. G., Lavine, J. A., Putterman, C., & Cuda, C. M. (2020). A Novel Microglia-Specific Transcriptional Signature Correlates With Behavioral Deficits in Neuropsychiatric Lupus. Frontiers in immunology, 11, Article 230. https://doi.org/10.3389/fimmu.2020.00230

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title = "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.",

keywords = "DAM, NP-SLE, SLE, behavior, interferon, lupus, microglia",

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

note = "Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2020 Makinde, Winter, Procissi, Mike, Stock, Kando, Gadhvi, Droho, Bloomfield, Dominguez, Mayr, Lavine, Putterman and Cuda.",

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Makinde, HM , Winter, DR , Procissi, D, Mike, EV, Stock, AD, Kando, MJ, Gadhvi, GT, Droho, S, Bloomfield, CL, Dominguez, ST, Mayr, MG, Lavine, JA, Putterman, C & Cuda, CM 2020, 'A Novel Microglia-Specific Transcriptional Signature Correlates With Behavioral Deficits in Neuropsychiatric Lupus', Frontiers in immunology, vol. 11, 230. https://doi.org/10.3389/fimmu.2020.00230

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T1 - A Novel Microglia-Specific Transcriptional Signature Correlates With Behavioral Deficits in Neuropsychiatric Lupus

AU - Makinde, Hadijat M.

AU - Winter, Deborah R.

AU - Procissi, Daniele

AU - Mike, Elise V.

AU - Stock, Ariel D.

AU - Kando, Mary J.

AU - Gadhvi, Gaurav T.

AU - Droho, Steven

AU - Bloomfield, Christina L.

AU - Dominguez, Salina T.

AU - Mayr, Maximilian G.

AU - Lavine, Jeremy A.

AU - Putterman, Chaim

AU - Cuda, Carla M.

PY - 2020/2/26

Y1 - 2020/2/26

N2 - 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.

AB - 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.

KW - DAM

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KW - SLE

KW - behavior

KW - interferon

KW - lupus

KW - microglia

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JO - Frontiers in immunology

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ER -

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

Abstract

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