Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte IL-1α release.

BACKGROUND: Atopic dermatitis (AD) is associated with epidermal barrier defects, dysbiosis, and skin injury caused by scratching. In particular, the barrier-defective epidermis in patients with AD with loss-of-function filaggrin mutations has increased IL-1α and IL-1ß levels, but the mechanisms by which IL-1α, IL-1ß, or both are induced and whether they contribute to the aberrant skin inflammation in patients with AD is unknown. OBJECTIVE: We sought to determine the mechanisms through which skin injury, dysbiosis, and increased epidermal IL-1α and IL-1ß levels contribute to development of skin inflammation in a mouse model of injury-induced skin inflammation in filaggrin-deficient mice without the matted mutation (ft/ft mice). METHODS: Skin injury of wild-type, ft/ft, and myeloid differentiation primary response gene-88-deficient ft/ft mice was performed, and ensuing skin inflammation was evaluated by using digital photography, histologic analysis, and flow cytometry. IL-1α and IL-1ß protein expression was measured by means of ELISA and visualized by using immunofluorescence and immunoelectron microscopy. Composition of the skin microbiome was determined by using 16S rDNA sequencing. RESULTS: Skin injury of ft/ft mice induced chronic skin inflammation involving dysbiosis-driven intracellular IL-1α release from keratinocytes. IL-1α was necessary and sufficient for skin inflammation in vivo and secreted from keratinocytes by various stimuli in vitro. Topical antibiotics or cohousing of ft/ft mice with unaffected wild-type mice to alter or intermix skin microbiota, respectively, resolved the skin inflammation and restored keratinocyte intracellular IL-1α localization. CONCLUSIONS: Taken together, skin injury, dysbiosis, and filaggrin deficiency triggered keratinocyte intracellular IL-1α release that was sufficient to drive chronic skin inflammation, which has implications for AD pathogenesis and potential therapeutic targets.

Interventions affecting blood pressure variability and outcomes after intubating patients with spontaneous intracranial hemorrhage.

INTRODUCTION: Spontaneous intracranial hemorrhage (sICH) that increases intracranial pressure (ICP) is a life-threatening emergency often requiring intubation in Emergency Departments (ED). A previous study of intubated ED patients found that providing ≥5 interventions after initiating mechanical ventilation (pMVI) reduced mortality rate. We hypothesized that pMVIs would lower blood pressure variability (BPV) in patients with sICH and thus improve survival rates and neurologic outcomes. METHOD: We performed a retrospective study of adults, who were transferred to a quaternary medical center between 01/01/2011 and 09/30/2015 for sICH, received an extraventricular drain during hospitalization. They were identified by International Classification of Diseases, version 9 (430.XX, 431.XX), and procedure code 02.21. Outcomes were BPV indices, death, and being discharged home. RESULTS: We analyzed records from 147 intubated patients transferred from 40 EDs. Forty-one percent of patients received ≥5 pMVIs and was associated with lower median successive variation in systolic blood pressure (BPSV) (31,[IQR 18-45) compared with those receiving 4 or less pMVIs (38[IQR 16-70]], p = 0.040). Three pMVIs, appropriate tidal volume, sedative infusion, and capnography were significantly associated with lower BPV. In addition to clinical factors, BPSV (OR 26; 95% CI 1.2, >100) and chest radiography (OR 0.3; 95% CI 0.09, 0.9) were associated with mortality rate. Use of quantitative capnography (OR 8.3; 95%CI, 4.7, 8.8) was associated with increased likelihood of being discharged home. CONCLUSIONS: In addition to disease severity, individual pMVIs were significantly associated with BPV and patient outcomes. Emergency physicians should perform pMVIs more frequently to prevent BPV and improve patients' outcomes.