Neuropsychiatric systemic lupus erythematosus persists despite attenuation of systemic disease in MRL/lpr mice

Stock, Ariel; Wen, Jing; Doerner, Jessica; Herlitz, Leal; Gulinello, Maria; Putterman, Chaim

doi:10.1186/s12974-015-0423-4

Cited by 51 publications

(43 citation statements)

References 65 publications

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“…Lupus patients exhibit neuropsychiatric manifestations that can occur at any stage of disease, even before the onset of other organ damage [24, 25]. Thus, NPSLE is believed to be a primary manifestation of SLE [25].…”

Section: Discussionmentioning

confidence: 99%

CSF-1R inhibition attenuates renal and neuropsychiatric disease in murine lupus

Chalmers

Wen

Shum

et al. 2017

Clinical Immunology

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Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that can affect multiple end organs. Kidney and brain are two of the organs most commonly involved in SLE. Past studies have suggested the importance of macrophages in the pathogenesis of lupus nephritis (LN). Furthermore, as the immune effectors of the brain, microglia have been implicated in pathways leading to neuropsychiatric SLE (NPSLE). We depleted macrophages and microglia using GW2580, a small colony stimulating factor-1 receptor (CSF-1R) kinase inhibitor, in MRL-lpr/lpr (MRL/lpr) mice, a classic murine lupus model that displays features of both LN and NPSLE. Treatment was initiated before the onset of disease, and mice were followed for the development of LN and neurobehavioral dysfunction throughout the study. Treatment with GW2580 significantly ameliorated kidney disease, as evidenced by decreased proteinuria, BUN, and improved renal histopathology, despite equivalent levels of IgG and C3 deposition in the kidneys of treated and control mice. We were able to confirm macrophage depletion within the kidney via IBA-1 staining. Furthermore, we observed specific improvement in the depression-like behavioral deficit of MRL/lpr mice with GW2580 treatment. Circulating antibody and autoantibody levels were, however, not affected. These results provide additional support for the role of macrophages as a potentially valuable therapeutic target in SLE. Inhibiting CSF-1 receptor signaling would be more targeted than current immunosuppressive therapies, and may hold promise for the treatment of renal and neuropsychiatric end organ disease manifestations.

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Section: Discussionmentioning

confidence: 99%

CSF-1R inhibition attenuates renal and neuropsychiatric disease in murine lupus

Chalmers

Wen

Shum

et al. 2017

Clinical Immunology

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“…Despite transfer of healthy MRL bone marrow to MRL/lpr mice, neurodegeneration, cellular infiltration, and BBB disruption occurred even in the presence of attenuated systemic disease. 60 Given the exacerbation of effects in tRA-and VARA-treated MRL/ lpr mice, future studies should focus on the endogenous contribution of retinoid signaling in the brain of lupus-prone mice using chimeric and pharmacotherapy studies.…”

Section: Discussionmentioning

confidence: 99%

All-Trans-Retinoic Acid Augments the Histopathological Outcome of Neuroinflammation and Neurodegeneration in Lupus-Prone MRL/lpr Mice

Theus

Sparks

Liao

et al. 2016

J Histochem Cytochem.

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Recently, we demonstrated that treatment with all- trans-retinoic acid (tRA) induced a paradoxical effect on immune activation during the development of autoimmune lupus. Here, we further describe its negative effects on mediating neuroinflammation and neurodegeneration. Female MRL/lpr mice were orally administered tRA or VARA (retinol mixed with 10% tRA) from 6 to 14 weeks of age. Both treatments had a significant effect on brain weight, which correlated with histopathological evidence of focal astrogliosis, meningitis, and ventriculitis. Infiltration of CD138- and Iba1-positve immune cells was observed in the third ventricle and meninges of treated mice that co-labeled with ICAM-1, indicating their inflammatory nature. Increased numbers of circulating plasma cells, autoantibodies, and total IgG were also apparent. IgG and C3 complement deposition in these brain regions were also prominent as was focal astrogliosis surrounding the ventricular lining and meninges. Using Fluoro-Jade staining, we further demonstrate that neuroinflammation was accompanied by neurodegeneration in the cortex of treated mice compared with vehicle controls. These findings indicate that vitamin A exposure exacerbates the immunogenic environment of the brain during the onset of systemic autoimmune disease. Vitamin A may therefore compromise the immuno-privileged nature of the central nervous system under a predisposed immunogenic environment.

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“…[7][8][9][10] MRL/lpr mice differ from the congenic MRL/ MpJ (MRL +/+ ) strain by the absence of the pro-apoptotic membrane Fas protein, due to a retroviral insertion in the Tnfrsf6 gene. [11][12][13] Using these mice, our studies also show that the loss of BBB integrity is complement dependent.…”

Section: M M U N O L O G Y O R I G I N a L A R T I C L Ementioning

confidence: 99%

C5a induces caspase‐dependent apoptosis in brain vascular endothelial cells in experimental lupus

et al. 2016

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SummaryBlood-brain barrier (BBB) dysfunction complicates central nervous system lupus, an important aspect of systemic lupus erythematosus. To gain insight into the underlying mechanism, vascular corrosion casts of brain were generated from the lupus mouse model, MRL/lpr mice and the MRL/MpJ congenic controls. Scanning electron microscopy of the casts showed loss of vascular endothelial cells in lupus mice compared with controls. Immunostaining revealed a significant increase in caspase 3 expression in the brain vascular endothelial cells, which suggests that apoptosis could be an important mechanism causing cell loss, and thereby loss of BBB integrity. Complement activation occurs in lupus resulting in increased generation of circulating C5a, which caused the endothelial layer to become 'leaky'. In this study, we show that C5a and lupus serum induced apoptosis in cultured human brain microvascular endothelial cells (HBMVECs), whereas selective C5a receptor 1 (C5aR1) antagonist reduced apoptosis in these cells, demonstrating C5a/C5aR1-dependence. Gene expression of initiator caspases, caspase 1 and caspase 8, and proapoptotic proteins death-associated protein kinase 1, Fas-associated protein (FADD), cell death-inducing DNA fragmentation factor 45 000 MW subunit A-like effector B (CIDEB) and BCL2-associated X protein were increased in HBMVECs treated with lupus serum or C5a, indicating that both the intrinsic and extrinsic apoptotic pathways could be critical mediators of brain endothelial cell apoptosis in this setting. Overall, our findings suggest that C5a/C5aR1 signalling induces apoptosis through activation of FADD, caspase 8/3 and CIDEB in brain endothelial cells in lupus. Further elucidation of the underlying apoptotic mechanisms mediating the reduced endothelial cell number is important in establishing the potential therapeutic effectiveness of C5aR1 inhibition that could prevent and/or reduce BBB alterations and preserve the physiological function of BBB in central nervous system lupus.

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Neuropsychiatric systemic lupus erythematosus persists despite attenuation of systemic disease in MRL/lpr mice

Cited by 51 publications

References 65 publications

CSF-1R inhibition attenuates renal and neuropsychiatric disease in murine lupus

CSF-1R inhibition attenuates renal and neuropsychiatric disease in murine lupus

All-Trans-Retinoic Acid Augments the Histopathological Outcome of Neuroinflammation and Neurodegeneration in Lupus-Prone MRL/lpr Mice

C5a induces caspase‐dependent apoptosis in brain vascular endothelial cells in experimental lupus

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