Lipocalin-2 is a pathogenic determinant and biomarker of neuropsychiatric lupus

Elise V. Mike, Hadijat M. Makinde, Maria E. Gulinello, Kamala Vanarsa, Leal Herlitz, Gaurav Gadhvi, Deborah R. Winter, Chandra Mohan, John G. Hanly, C. C. Mok, Carla M. Cuda, Chaim Putterman

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Neuropsychiatric manifestations in lupus (NPSLE) affect ∼20–40% of patients. In the central nervous system, lipocalin-2 (LCN2) can promote injury through mechanisms directly linked to NPSLE, including brain barrier disruption, neurotoxicity, and glial activation. Since LCN2 is elevated in lupus and has been implicated in neuroinflammation, we investigated whether LCN2 is required for the pathogenesis of NPSLE. Here, we investigated the effects of LCN2 deficiency on the development of neurobehavioral deficits in the B6.Sle1.Sle3 (Sle1,3) mouse lupus model. Sle1,3 mice exhibited depression-like behavior and impaired spatial and recognition memory, and these deficits were attenuated in Sle1,3-LCN2KO mice. Whole-brain flow cytometry showed a significant increase in brain infiltrating leukocytes in Sle1,3 mice that was not reduced by LCN2 deficiency. RNA sequencing on sorted microglia revealed that several genes differentially expressed between B6 and Sle1,3 mice were regulated by LCN2, and that these genes are key mediators of the neuroinflammatory cascade. Importantly, LCN2 is upregulated in the cerebrospinal fluid of NPSLE patients across 2 different ethnicities. Our findings establish the Sle1,3 strain as an NPSLE model, demonstrate that LCN2 is a major regulator of the detrimental neuroimmune response in NPSLE, and identify CSF LCN2 as a novel biomarker for NPSLE.

Original languageEnglish (US)
JournalJournal of Autoimmunity
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Biomarkers
Brain
RNA Sequence Analysis
Lipocalin-2
Memory Disorders
Microglia
Granulocyte-Macrophage Colony-Stimulating Factor
Neuroglia
Genes
Cerebrospinal Fluid
Flow Cytometry
Leukocytes
Central Nervous System
Depression
Wounds and Injuries

Keywords

  • Lipocalin-2
  • Microglia
  • Neuroinflammation
  • Neuropsychiatric lupus
  • RNA-seq

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Lipocalin-2 is a pathogenic determinant and biomarker of neuropsychiatric lupus. / Mike, Elise V.; Makinde, Hadijat M.; Gulinello, Maria E.; Vanarsa, Kamala; Herlitz, Leal; Gadhvi, Gaurav; Winter, Deborah R.; Mohan, Chandra; Hanly, John G.; Mok, C. C.; Cuda, Carla M.; Putterman, Chaim.

In: Journal of Autoimmunity, 01.01.2018.

Research output: Contribution to journalArticle

Mike, EV, Makinde, HM, Gulinello, ME, Vanarsa, K, Herlitz, L, Gadhvi, G, Winter, DR, Mohan, C, Hanly, JG, Mok, CC, Cuda, CM & Putterman, C 2018, 'Lipocalin-2 is a pathogenic determinant and biomarker of neuropsychiatric lupus', Journal of Autoimmunity. https://doi.org/10.1016/j.jaut.2018.08.005
Mike, Elise V. ; Makinde, Hadijat M. ; Gulinello, Maria E. ; Vanarsa, Kamala ; Herlitz, Leal ; Gadhvi, Gaurav ; Winter, Deborah R. ; Mohan, Chandra ; Hanly, John G. ; Mok, C. C. ; Cuda, Carla M. ; Putterman, Chaim. / Lipocalin-2 is a pathogenic determinant and biomarker of neuropsychiatric lupus. In: Journal of Autoimmunity. 2018.
@article{713ef257bce24e2aa78172c5b40b9761,
title = "Lipocalin-2 is a pathogenic determinant and biomarker of neuropsychiatric lupus",
abstract = "Neuropsychiatric manifestations in lupus (NPSLE) affect ∼20–40{\%} of patients. In the central nervous system, lipocalin-2 (LCN2) can promote injury through mechanisms directly linked to NPSLE, including brain barrier disruption, neurotoxicity, and glial activation. Since LCN2 is elevated in lupus and has been implicated in neuroinflammation, we investigated whether LCN2 is required for the pathogenesis of NPSLE. Here, we investigated the effects of LCN2 deficiency on the development of neurobehavioral deficits in the B6.Sle1.Sle3 (Sle1,3) mouse lupus model. Sle1,3 mice exhibited depression-like behavior and impaired spatial and recognition memory, and these deficits were attenuated in Sle1,3-LCN2KO mice. Whole-brain flow cytometry showed a significant increase in brain infiltrating leukocytes in Sle1,3 mice that was not reduced by LCN2 deficiency. RNA sequencing on sorted microglia revealed that several genes differentially expressed between B6 and Sle1,3 mice were regulated by LCN2, and that these genes are key mediators of the neuroinflammatory cascade. Importantly, LCN2 is upregulated in the cerebrospinal fluid of NPSLE patients across 2 different ethnicities. Our findings establish the Sle1,3 strain as an NPSLE model, demonstrate that LCN2 is a major regulator of the detrimental neuroimmune response in NPSLE, and identify CSF LCN2 as a novel biomarker for NPSLE.",
keywords = "Lipocalin-2, Microglia, Neuroinflammation, Neuropsychiatric lupus, RNA-seq",
author = "Mike, {Elise V.} and Makinde, {Hadijat M.} and Gulinello, {Maria E.} and Kamala Vanarsa and Leal Herlitz and Gaurav Gadhvi and Winter, {Deborah R.} and Chandra Mohan and Hanly, {John G.} and Mok, {C. C.} and Cuda, {Carla M.} and Chaim Putterman",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.jaut.2018.08.005",
language = "English (US)",
journal = "Journal of Autoimmunity",
issn = "0896-8411",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Lipocalin-2 is a pathogenic determinant and biomarker of neuropsychiatric lupus

AU - Mike, Elise V.

AU - Makinde, Hadijat M.

AU - Gulinello, Maria E.

AU - Vanarsa, Kamala

AU - Herlitz, Leal

AU - Gadhvi, Gaurav

AU - Winter, Deborah R.

AU - Mohan, Chandra

AU - Hanly, John G.

AU - Mok, C. C.

AU - Cuda, Carla M.

AU - Putterman, Chaim

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Neuropsychiatric manifestations in lupus (NPSLE) affect ∼20–40% of patients. In the central nervous system, lipocalin-2 (LCN2) can promote injury through mechanisms directly linked to NPSLE, including brain barrier disruption, neurotoxicity, and glial activation. Since LCN2 is elevated in lupus and has been implicated in neuroinflammation, we investigated whether LCN2 is required for the pathogenesis of NPSLE. Here, we investigated the effects of LCN2 deficiency on the development of neurobehavioral deficits in the B6.Sle1.Sle3 (Sle1,3) mouse lupus model. Sle1,3 mice exhibited depression-like behavior and impaired spatial and recognition memory, and these deficits were attenuated in Sle1,3-LCN2KO mice. Whole-brain flow cytometry showed a significant increase in brain infiltrating leukocytes in Sle1,3 mice that was not reduced by LCN2 deficiency. RNA sequencing on sorted microglia revealed that several genes differentially expressed between B6 and Sle1,3 mice were regulated by LCN2, and that these genes are key mediators of the neuroinflammatory cascade. Importantly, LCN2 is upregulated in the cerebrospinal fluid of NPSLE patients across 2 different ethnicities. Our findings establish the Sle1,3 strain as an NPSLE model, demonstrate that LCN2 is a major regulator of the detrimental neuroimmune response in NPSLE, and identify CSF LCN2 as a novel biomarker for NPSLE.

AB - Neuropsychiatric manifestations in lupus (NPSLE) affect ∼20–40% of patients. In the central nervous system, lipocalin-2 (LCN2) can promote injury through mechanisms directly linked to NPSLE, including brain barrier disruption, neurotoxicity, and glial activation. Since LCN2 is elevated in lupus and has been implicated in neuroinflammation, we investigated whether LCN2 is required for the pathogenesis of NPSLE. Here, we investigated the effects of LCN2 deficiency on the development of neurobehavioral deficits in the B6.Sle1.Sle3 (Sle1,3) mouse lupus model. Sle1,3 mice exhibited depression-like behavior and impaired spatial and recognition memory, and these deficits were attenuated in Sle1,3-LCN2KO mice. Whole-brain flow cytometry showed a significant increase in brain infiltrating leukocytes in Sle1,3 mice that was not reduced by LCN2 deficiency. RNA sequencing on sorted microglia revealed that several genes differentially expressed between B6 and Sle1,3 mice were regulated by LCN2, and that these genes are key mediators of the neuroinflammatory cascade. Importantly, LCN2 is upregulated in the cerebrospinal fluid of NPSLE patients across 2 different ethnicities. Our findings establish the Sle1,3 strain as an NPSLE model, demonstrate that LCN2 is a major regulator of the detrimental neuroimmune response in NPSLE, and identify CSF LCN2 as a novel biomarker for NPSLE.

KW - Lipocalin-2

KW - Microglia

KW - Neuroinflammation

KW - Neuropsychiatric lupus

KW - RNA-seq

UR - http://www.scopus.com/inward/record.url?scp=85052755508&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052755508&partnerID=8YFLogxK

U2 - 10.1016/j.jaut.2018.08.005

DO - 10.1016/j.jaut.2018.08.005

M3 - Article

C2 - 30174216

AN - SCOPUS:85052755508

JO - Journal of Autoimmunity

JF - Journal of Autoimmunity

SN - 0896-8411

ER -