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Review
. 2018 Nov 13;19(11):3588.
doi: 10.3390/ijms19113588.

From Systemic Inflammation to Neuroinflammation: The Case of Neurolupus

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Free PMC article
Review

From Systemic Inflammation to Neuroinflammation: The Case of Neurolupus

Mykolas Bendorius et al. Int J Mol Sci. .
Free PMC article

Abstract

It took decades to arrive at the general consensus dismissing the notion that the immune system is independent of the central nervous system. In the case of uncontrolled systemic inflammation, the relationship between the two systems is thrown off balance and results in cognitive and emotional impairment. It is specifically true for autoimmune pathologies where the central nervous system is affected as a result of systemic inflammation. Along with boosting circulating cytokine levels, systemic inflammation can lead to aberrant brain-resident immune cell activation, leakage of the blood⁻brain barrier, and the production of circulating antibodies that cross-react with brain antigens. One of the most disabling autoimmune pathologies known to have an effect on the central nervous system secondary to the systemic disease is systemic lupus erythematosus. Its neuropsychiatric expression has been extensively studied in lupus-like disease murine models that develop an autoimmunity-associated behavioral syndrome. These models are very useful for studying how the peripheral immune system and systemic inflammation can influence brain functions. In this review, we summarize the experimental data reported on murine models developing autoimmune diseases and systemic inflammation, and we explore the underlying mechanisms explaining how systemic inflammation can result in behavioral deficits, with a special focus on in vivo neuroimaging techniques.

Keywords: autoimmunity; behavior; blood–brain barrier; magnetic resonance imaging (MRI); murine model; neuropsychiatric lupus (NPSLE); systemic lupus erythematosus (SLE).

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Tests used for behavioral evaluation of mice. (A) Forced-swim test (or Porsolt test) used to assess depressive-like behavior; (B) elevated plus-maze and (C) dark/light preference test to measure anxiety-like behavior; (D) Morris water maze (or paddling test) [53]; (E) T-maze that is considered very sensitive to alteration in hippocampal pathways.
Figure 2
Figure 2
Cerebral abnormalities measured in MRL+/+ and MRL/lpr mice. Conventional mid-axial T2-weighted MRI revealed a dilation of ventricles (red arrow) in 16-week-old female MRL/lpr mice (B) as compared to the age-matched counterparts MRL+/+mice (A). In the MRL/lpr strain, this enlargement is more remarkable on the left side, as revealed by analysis of the right/left ventricle volume ratio (C). Furthermore, a significant loss of brain weight was detected in these mice (D), even if the normalized volume of CSF did not show significant difference between both strains (E). Statistics: All data were analyzed with unpaired t test, and significance was defined as p < 0.05 (*) Errors bars are mean standard deviation. Sample size is indicated as n. Abbreviations: CSF, cerebrospinal fluid; lpr, lymphoproliferation; MRI, magnetic resonance imaging; MRL, Murphy Roths Large.
Figure 3
Figure 3
Acute excitotoxicity in NPSLE. The binding of anti-NMDAR Abs to NMDAR allows the free entry of calcium ions (1). Intracellularly, the ions are taken up by mitochondria in order to buffer incoming calcium, leading to increased cellular respiration and ROS production. Concomitant with the increase in calcium concentration, the mitochondrial membrane potential collapses, and MPTPs open (2). Consequently, proapoptotic molecules (e.g., Cyt c, AIF) are released, and apoptosis (controlled neuronal death) occurs (3). On the other hand, calcium can activate cytosolic enzymes (e.g., phospholipases, proteases, endonucleases) that will damage neurons intracellularly, leading to necrosis (4). Abbreviations: Ab, antibody; AIF, apoptosis-inducing factor; Cyt c, cytochrome c; MPTP, mitochondrial permeability transition pore; NMDAR, N-methyl-d-aspartate receptor; ROS, reactive oxygen species.
Figure 4
Figure 4
Neuroinflammatory model of NPSLE. In the CNS, under normal physiological conditions, microglial cells act as resident immune cells of the CNS and notably eliminate apoptotic cells. Systemic inflammation renders the BBB permeable to circulating inflammatory factors, for example, certain cytokines and autoAbs (e.g., anti-NMDAR) (1). After penetration into the brain, anti-NMDAR Abs can induce apoptotic death of neurons through the process of “excitotoxicity” (2). On the other hand, microglial cells can eliminate dendritic spines (the anatomical location of synapses) through a mechanism called “synaptic pruning” (3). Hypothetically, anti-neuronal autoAbs bind neuronal antigens recognized by the complement factor C1q (synthetized by the CNS), leading to the production of C3b. Dendritic processes displaying C3b are recognized and phagocytosed by microglia. Furthermore, CNS cells activated following BBB’s leakage upregulate ICAM-1 and VCAM-1 and modulate cytokine expression, resulting in the recruitment of peripheral immune cells (4). CD4+ T cells infiltrate the CP and the brain parenchyma, while CD19+ B cells are only found in the CP. This suggests that CD4+ T cells might sample the brain environment in the parenchyma and activate CD19+ B cells in the CP, leading to the production of Abs that circulate into the CSF. Abbreviations: Ab, antibody; BBB, blood–brain barrier; BCSFB, blood–cerebrospinal-fluid barrier; CNS, central nervous system; CP, choroid plexus; CSF, cerebrospinal fluid; ICAM-1, intercellular adhesion molecule-1; NMDAR, N-methyl-d-aspartate receptor; VCAM, vascular cell adhesion protein 1.

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