Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a high incidence of neuropsychiatric involvement. Signs and symptoms of neuropsychiatric SLE (NPSLE) are among the earliest and most common manifestations in lupus patients, and can occur independently of non-neurologic disease. In the MRL/lpr strain as well, a commonly used murine lupus model, behavioral changes consistent with severe depression and impaired cognition are evident in young animals before increased autoantibody titers and other major organ involvement. These and other studies indicate that NPSLE is indeed a primary disease manifestation. Nevertheless, despite the high prevalence of NPSLE and its poor prognosis, the pathogenesis is not well understood and optimal treatment is still unclear. Previous studies have largely focused on potential etiological factors such as autoantibodies and neurodegeneration that often become apparent only relatively late after onset of SLE. These factors do not adequately explain the early onset of NPSLE observed in lupus mice or in many patients. Among putative regulators of early CNS dysfunction, cytokines can both directly and indirectly promote negative CNS outcomes via a range of different mechanisms. These include effects on autoantibodies, increasing secretion of cytokines and other inflammatory mediators, loss of integrity of the blood brain barrier (BBB), and alteration of neurotransmitter metabolism. Members of the TNF superfamily are important in the pathogenesis of SLE. TWEAK is a secreted member of this cytokine superfamily, with pleotropic effects on multiple cell types, including promotion of inflammation and context-dependent effects on cell survival and apoptosis. The TWEAK receptor, Fn14, is expressed in astrocytes, microglia, brain microvascular endothelial cells, and neurons. Furthermore, TWEAK induces the release of other inflammatory cytokines known to play a role in NPSLE. Recently, we found that Fn14 deficient MRL/lpr lupus mice display significantly less depression and cognitive abnormalities than Fn14 sufficient MRL/lpr littermates, while human NPSLE is associated with high TWEAK levels in the CSF. Our preliminary studies strongly support the hypotheses that 1) TWEAK plays a major role in the etiology of NPSLE;2) TWEAK blockade may be a novel approach for the treatment of neuropsychiatric disease. In this proposal, we will confirm the role of TWEAK in the pathogenesis of NPSLE, examine the mechanisms by which TWEAK signaling induces neurobehavioral abnormalities in lupus, and study the therapeutic potential of TWEAK inhibition for treating manifestations of NPSLE.

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Signs and symptoms of neuropsychiatric SLE are among the earliest and most common manifestations in lupus patients, and can occur independently of non-neurologic disease. However, the pathogenesis is not well understood and optimal treatment is still unclear. In this proposal, we will explore the role of the TNF family member cytokine TWEAK and its receptor Fn14 in the pathogenesis of neuropsychiatric lupus in murine models, and the therapeutic potential of blocking this pathway.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Mancini, Marie
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Albert Einstein College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
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Mike, Elise V; Makinde, Hadijat M; Der, Evan et al. (2018) Neuropsychiatric Systemic Lupus Erythematosus Is Dependent on Sphingosine-1-Phosphate Signaling. Front Immunol 9:2189
Jain, Shweta; Stock, Ariel; Macian, Fernando et al. (2018) A Distinct T Follicular Helper Cell Subset Infiltrates the Brain in Murine Neuropsychiatric Lupus. Front Immunol 9:487
Gelb, Sivan; Stock, Ariel D; Anzi, Shira et al. (2018) Mechanisms of neuropsychiatric lupus: The relative roles of the blood-cerebrospinal fluid barrier versus blood-brain barrier. J Autoimmun 91:34-44
Vasquez-Canizares, Natalia; Wahezi, Dawn; Putterman, Chaim (2017) Diagnostic and prognostic tests in systemic lupus erythematosus. Best Pract Res Clin Rheumatol 31:351-363
Chalmers, Samantha A; Wen, Jing; Shum, Justine et al. (2017) CSF-1R inhibition attenuates renal and neuropsychiatric disease in murine lupus. Clin Immunol 185:100-108
Stock, Ariel D; Gelb, Sivan; Pasternak, Ofer et al. (2017) The blood brain barrier and neuropsychiatric lupus: new perspectives in light of advances in understanding the neuroimmune interface. Autoimmun Rev 16:612-619
Wen, Jing; Doerner, Jessica; Chalmers, Samantha et al. (2016) B cell and/or autoantibody deficiency do not prevent neuropsychiatric disease in murine systemic lupus erythematosus. J Neuroinflammation 13:73
Wen, Jing; Stock, Ariel D; Chalmers, Samantha A et al. (2016) The role of B cells and autoantibodies in neuropsychiatric lupus. Autoimmun Rev 15:890-5
Wen, Jing; Chen, Christopher Holden; Stock, Ariel et al. (2016) Intracerebroventricular administration of TNF-like weak inducer of apoptosis induces depression-like behavior and cognitive dysfunction in non-autoimmune mice. Brain Behav Immun 54:27-37
Doerner, Jessica; Chalmers, Samantha A; Friedman, Adam et al. (2016) Fn14 deficiency protects lupus-prone mice from histological lupus erythematosus-like skin inflammation induced by ultraviolet light. Exp Dermatol 25:969-976

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