Browsing by Subject "Lupus Erythematosus, Systemic"
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Item Dysfunctional neuroimmune pathways promote the development and maintenance of lupus hypertension(2020-05) Pham, Grace S.; Mathis, Keisa W.; Rickards, Caroline A.; Goulopoulou, Styliani; Cunningham, J. Thomas; Ma, Rong; Mathew, Stephen O.Hypertension afflicts nearly half of the adults in the United States and the majority of cases have no known cause. Chronic inflammation has been implicated in the development and maintenance of hypertension, and autoimmunity may comprise one of its sources. Hypertension is highly prevalent in the autoimmune disease systemic lupus erythematosus (SLE), in which chronic aberrant inflammation may be a causative factor. Endogenous neuroimmune pathways, such as the hypothalamic-pituitary-adrenal (HPA) axis and the cholinergic anti-inflammatory pathway, likely contribute to this phenomenon. The HPA axis is a classical neuroimmune mechanism that senses peripheral inflammation via afferent vagal fibers, culminating in the release of the anti-inflammatory hormone cortisol. Previous studies have characterized HPA axis dysfunction in SLE, but less is known about how this dysregulation specifically impacts the hypertension that occurs in the setting of SLE. A second neuroimmune interaction, the cholinergic anti-inflammatory pathway, is an efferent vagus nerve-to-spleen mechanism that relies on T cell-produced acetylcholine to quell inflammation in acute settings and may be hypoactive in chronic inflammatory diseases like SLE. Notably, both of these neuroimmune mechanisms depend on vagus nerve function, identifying the vagus as a potential target for neuromodulation. Furthermore, the relationship between chronic inflammation and hypertension validates the investigation of neuroimmune pathway dysfunction towards novel mechanisms of hypertension. Herewithin, the HPA axis and cholinergic anti-inflammatory pathway are investigated using the well-established NZBWF1 mouse model of lupus hypertension. Our findings are that (1) administration of an inflammatory stimulus that activates vagal afferents elicits comparable neuronal activation in the paraventricular nucleus of the hypothalamus, compared to control mice, despite heightened peripheral inflammation; (2) amplification of efferent vagus nerve activity reduces blood pressure and renal inflammation; and (3) chronic unilateral vagotomy paradoxically results in decreased blood pressure and renal inflammation. Taken together, these findings identify dysfunction in two neuroimmune pathways while demonstrating that interventions targeting these pathways may have therapeutic benefits in lupus hypertension. In terms of future impact, these results may promote continuing inquiry in a more recently discovered neuroimmune pathway (i.e., cholinergic anti-inflammatory pathway), as well as reinstate curiosity in an older, abandoned area of research (i.e., HPA).Item Sex differences in toll like receptor 7-mediated renal injury in a murine model of autoimmune-induced hypertension(2020-05) D'Souza, Bradley M.; Mathis, Keisa W.; Hodge, Lisa M.; Phillips, Nicole R.Systemic lupus erythematosus (SLE) is a female-dominant autoimmune disease associated with hypertension. We confirmed that SLE develops later in life in male vs. female SLE mice (35 vs. [less than] 30 weeks), yet both sexes develop hypertension by 35 weeks. Renal injury is a factor in hypertensive female SLE mice only, so we aimed to investigate this latent sex difference. We hypothesized that increased toll-like receptor 7 (TLR7), an immune mediator that instigates tissue damage, promotes renal injury in female SLE mice. We found that renal cortical expression of TLR7 was indeed higher in female SLE mice. In a follow-up study we found that renal hemodynamics were impaired in female SLE mice, but not males. Our data suggest that while the hypertension in female SLE mice may be due to renal mechanisms, hypertension in males is not. Future studies will dissect sex-specific factors that should be considered when treating hypertensive patients with underlying autoimmunity.Item The impact of early life stressors on the progression of SLE(2021-08) Hartman, Rusty L.; Mathis, Keisa W.; Cunningham, J. Thomas; Hodge, Lisa M.; Tune, Johnathan D.Our preliminary studies show that an established model of systemic lupus erythematosus (SLE), the female NZBWF1 mouse, had worsened indices of disease later in life when the mice were shipped to our institution at an early age during the summer. We hypothesized that interleukin (IL)-6-induced release of heat shock protein 90 (HSP90) is upregulated in response to this summer early-life stressor, thus accelerating autoimmunity and renal disease in female SLE mice. To begin to study this, we measured renal IL-6 and HSP90 in 6-week-old female NZBWF1 mice that were shipped in winter or summer months and found that both were elevated immediately following summer compared to winter travel. Our findings indicate that the mediators associated with early-life travel/seasonal stressors may predict the progression of autoimmunity in SLE-prone mice. Other findings here within highlight the specificity of this effect in the kidney and describe sex differences in the observed phenomena.Item The Impact of Travel Stressors on the Pathogenesis of Autoimmunity in Female Lupus Mice(2022-05) Dinh, Viet Q.; Mathis, Keisa W.; Ma, Rong; Cunningham, J. Thomas; Basha, RiyazPreliminary studies found that an established model of systemic lupus erythematosus, the female NZBWF1 mouse, developed heightened disease severity later in life when shipped to UNTHSC during summer due to travel stressors. We hypothesized that this was partly due to early life stress that the mice experienced, and that eliminating these stressors will attenuate disease severity. We measured biomarkers of disease severity in NZBWF1 mice that were shipped as adults and compared with mice that were shipped in early life along with mice that were not shipped at all. We found that long-term biomarkers were higher in adult travel mice compared to early life travel mice, that these biomarkers were higher in summer mice compared to winter mice, and that non-travelling mice had the highest levels. Our findings indicate that adulthood stress exacerbates disease progression in NZBWF1 mice, and that seasonal factors impacted lupus pathogenesis in these adult mice.