Multiple sclerosis and demyelinating disorders最新文献

Serum- and glucocorticoid-regulated kinase 1 (SGK1) is a serine/threonine kinase that plays important roles in the cellular stress response. While SGK1 has been reported to restrain inflammatory immune responses, the molecular mechanisms involved remain elusive, especially in oral bacteria-induced inflammatory milieu. Here, we found that SGK1 curtails Porphyromonas gingivalis-induced inflammatory responses through maintaining levels of tumor necrosis factor receptor-associated factor (TRAF) 3, thereby suppressing NF-κB signaling. Specifically, SGK1 inhibition significantly enhances production of proinflammatory cytokines, including tumor necrosis factor α, interleukin (IL)-6, IL-1β, and IL-8 in P. gingivalis-stimulated innate immune cells. The results were confirmed with siRNA and LysM-Cre-mediated SGK1 KO mice. Moreover, SGK1 deletion robustly increased NF-κB activity and c-Jun expression but failed to alter the activation of mitogen-activated protein kinase signaling pathways. Further mechanistic data revealed that SGK1 deletion elevates TRAF2 phosphorylation, leading to TRAF3 degradation in a proteasome-dependent manner. Importantly, siRNA-mediated traf3 silencing or c-Jun overexpression mimics the effect of SGK1 inhibition on P. gingivalis-induced inflammatory cytokines and NF-κB activation. In addition, using a P. gingivalis infection-induced periodontal bone loss model, we found that SGK1 inhibition modulates TRAF3 and c-Jun expression, aggravates inflammatory responses in gingival tissues, and exacerbates alveolar bone loss. Altogether, we demonstrated for the first time that SGK1 acts as a rheostat to limit P. gingivalis-induced inflammatory immune responses and mapped out a novel SGK1-TRAF2/3-c-Jun-NF-κB signaling axis. These findings provide novel insights into the anti-inflammatory molecular mechanisms of SGK1 and suggest novel interventional targets to inflammatory diseases relevant beyond the oral cavity.

Background: Treatment algorithms for neuromyelitis optica spectrum disorder (NMOSD) vary, and sparse data exist regarding the impact of initial treatments on disease course. We aimed to determine whether administration of rituximab during first hospitalization reduces 1-year readmission rates.

Methods: We conducted a retrospective cohort study of subjects with NMOSD using the Pediatric Health Information System database from 2005-2015. Subjects were ages 1 to 21 years who received glucocorticoids and an ICD-9-CM code indicating neuromyelitis optica (NMO) during first hospitalization. All subjects had at least 12 months of continuous enrollment. The primary exposure was ≥1 rituximab dose during first hospitalization. We tested for the association of rituximab use with all-cause re-hospitalization, the primary outcome, using survival analysis. Re-hospitalization was considered if a hospital admission occurred > 30 days after initial discharge with exclusion of admissions with re-dosing of rituximab and data were censored at 12 months. Secondary outcomes included time to and median duration of re-hospitalization using 25^th percentiles of survival time and the Wilcoxon-rank sum test, respectively.

Results: Of 180 subjects who met inclusion criteria, 71.7% were female and the median age was 13 years (IQR: 10, 15). 52 subjects (28.9%) received rituximab during first hospitalization, and there was an increasing trend in rituximab use over time (p<0.01). Overall, 36.7% of children were readmitted and time to readmission was a median of 365 days (IQR: 138, 365). Rituximab exposure was not associated with re-hospitalization (adjusted HR: 0.71: 95% CI: 0.38, 1.34) nor a reduced time to re-hospitalization. Median duration of re-hospitalization was 2 days shorter in the rituximab exposed group (p=0.02). Receipt of physical therapy, a surrogate marker for neurologic impairment, during first hospitalization was associated with re-admission within 12 months (adjusted HR: 4.81; 95% CI: 1.14, 20.29).

Conclusions: Among children with NMOSD, first-line administration of rituximab was not associated with risk of or time to re-hospitalization. Rituximab use was found to be associated with a shorter duration of re-hospitalization. Need for physical therapy during first hospitalization was independently associated with an increased risk of re-admission.