Cerebellar dysfunction is associated with overexpression of proinflammatory cytokine genes in lupus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology accompanied by central nervous system involvement in up to 60% of patients. The current study chronicles the expression of cerebellar dysfunction in SLE using MRL-lpr/lpr mice as the experimental model. These mice spontaneously develop an illness that has immunological and clinical features of human lupus. We found that MRL-lpr/lpr mice manifest severe and progressive behavioral disturbances indicative of cerebellar dysfunction beginning at 11 weeks of age. Although the lpr gene is known to induce autoimmune features, immunologically normal mice rendered congenic for lpr failed to exhibit disturbances in cerebellar function. Because lupus is a cytokine-driven disease and overexpression of certain proinflammatory cytokines has been associated with neurodegeneration, the relationship between cerebellar dysfunction and cytokine gene expression was examined. Relative to immunologically normal CBA/J mice, the cerebellum of young (11-15 weeks of age) MRL-lpr/lpr mice contained high levels of interleukin (IL)-6 and interferon-gamma (IFNgamma) mRNA, which became even more pronounced in old (22-30 weeks of age) autoimmune mice. mRNA levels for the cytokines IL-1beta and IL-10 were elevated in the cerebellum of old, but not young, MRL-lpr/lpr mice relative to CBA/J. In contrast, the levels of cerebellar transcripts for IL-3 and tumor necrosis factor-alpha were comparable in autoimmune and normal mice, indicating that enhanced gene expression of IL-6, IFNgamma, IL-1beta, and IL-10 was selective. These results suggest a potential role for certain proinflammatory cytokines in the pathogenesis of cerebellar disturbances in SLE.

Dendritic Cells from Lupus-Prone Mice Are Defective in Repressing Immunoglobulin Secretion

“…Consistent with this model, CpG-stimulated DCs from SLE patients produced lower levels of IL-6 (48), whereas endothelial cells (49 -51), mesangial cells in the kidney (52,53), and infiltrating monocytes/macrophages (54) secrete elevated levels of IL-6. This suggests that IL-6 plays a beneficial role when released in a local microenvironment between myDCs and autoreactive B cells, but when elevated systemically, it induces inflammation, tissue destruction, and spontaneous Ig production by activated B cells (41,(55)(56)(57). Therapies aimed at neutralizing the inflammatory effects of IL-6 may have short-term benefits in treating lupus nephritis; however, they are likely to promote loss of tolerance in newly emerging B cells during innate immune activation.…”

Spotlight on the role of hormonal factors in the emergence of autoreactive B-lymphocytes

“…Finally, environmental estrogens may exert effects on B cells and cytokines in a manner reminiscent of the actions ascribed to natural estrogens. lupus nephritis [118] and neurologic lupus [119]. Also, some lupus patients with central nervous system involvement display increased concentrations of IL-6 in the cerebrospinal fluid.…”

IL-6 regulation of synaptic function in the CNS

“…In lpr/lpr mice, a mouse model of SLE, a depressive-like phenotype was observed in the forced swim and tail suspension tests and the depressive-like behaviors were shown to be associated with increased levels of IL-6 protein in the hippocampus and prefrontal cortex (Sukoff Rizzo et al, 2012). Increased levels of IL-6 and IL-1β mRNA were observed in the hippocampus and cerebellum of the lpr/lpr mice and correlated with behavioral dysfunction (Tomita et al, 2001a, 2001b). Mice with colon carcinoma cell-induced peripheral tumor showed memory impairment and depression-like behavior in behavioral tests (open field test, tail suspension test and object recognition memory test) and these behaviors were associated with increased levels of IL-6 mRNA in the hippocampus (Yang et al, 2014).…”