IL-33 potentiates histaminergic itch.

BACKGROUND: Itch is a common symptom that can greatly diminish quality of life. Histamine is a potent endogenous pruritogen, and while antihistamines are often the first-line treatment for itch, in conditions like chronic spontaneous urticaria (CSU), many patients remain symptomatic while receiving maximal doses. Mechanisms that drive resistance to antihistamines are poorly defined. OBJECTIVES: Signaling of the alarmin cytokine IL-33 in sensory neurons is postulated to drive chronic itch by inducing neuronal sensitization to pruritogens. Thus, we sought to determine if IL-33 can augment histamine-induced (histaminergic) itch. METHODS: Itch behavior was assessed in response to histamine after IL-33 or saline administration. Various stimuli and conditional and global knockout mice were utilized to dissect cellular mechanisms. Multiple existing transcriptomic data sets were evaluated, including single-cell RNA sequencing of human and mouse skin, microarrays of isolated mouse mast cells at steady state and after stimulation with IL-33, and microarrays of skin biopsy samples from subjects with CSU and healthy controls. RESULTS: IL-33 amplifies histaminergic itch independent of IL-33 signaling in sensory neurons. Mast cells are the top expressors of the IL-33 receptor in both human and mouse skin. When stimulated by IL-33, mouse mast cells significantly increase IL-13 levels. Enhancement of histaminergic itch by IL-33 relies on a mast cell- and IL-13-dependent mechanism. IL-33 receptor expression is increased in lesional skin of subjects with CSU compared to healthy controls. CONCLUSIONS: Our findings suggest that IL-33 signaling may be a key driver of histaminergic itch in mast cell-associated pruritic conditions such as CSU.

A Spatial Examination of COVID-19 Policies among Missouri School Districts.

BACKGROUND: As the COVID-19 pandemic spread, school district administrators in the United States were faced with difficult decisions regarding the implementation of virtual or in-person learning to reduce risk of infection throughout student and staff populations. While a coordinated effort with surrounding districts would be most beneficial when encountering a highly infectious respiratory-based infectious disease, the determinants of type of education delivery is unclear. METHODS: Data from the Missouri Department of Elementary and Secondary Education assessing education delivery method at each school district across the state of Missouri (n = 514) from August 2020 were used. This cross-sectional study, using results from a school district-level survey, local COVID-19 rates, and community-level sociodemographic characteristics, conducted a spatially adjusted analysis of variance (ANOVA) to determine associations between education delivery type and geographic-level sociogeographic characteristics. RESULTS: Among Missouri school districts, 172 (33.4%) reported starting the 2020-2021 academic year with an in-person policy, 52 (10.1%) with a distant/virtual policy, 242 (47.1%) in-person with a distance option, and 48 (9.3%) with a blended policy. This study found districts with lower household income levels were less likely to offer students any virtual learning options. Additionally, community COVID-19 infection rates were not associated with the selection of virtual or in-person education delivery. CONCLUSIONS: These findings suggest the presence of a specific school policy was spatially random in regard to neighboring community policies, even when accounting for community characteristics. The efficacy of policy is likely to benefit upon application of a spatial framework when addressing a crisis fundamentally tied to location. Future planning that highlights and focuses on regional coordination for community resilience in the face of a pandemic should incorporate data sources that inform decisions made for families, students, and communities.

IL-33 signaling in sensory neurons promotes dry skin itch.

BACKGROUND: Chronic pruritus, or itch, is common and debilitating, but the neuroimmune mechanisms that drive chronic itch are only starting to be elucidated. Recent studies demonstrate that the IL-33 receptor (IL-33R) is expressed by sensory neurons. However, whether sensory neuron-restricted activity of IL-33 is necessary for chronic itch remains poorly understood. OBJECTIVES: We sought to determine if IL-33 signaling in sensory neurons is critical for the development of chronic itch in 2 divergent pruritic disease models. METHODS: Plasma levels of IL-33 were assessed in patients with atopic dermatitis (AD) and chronic pruritus of unknown origin (CPUO). Mice were generated to conditionally delete IL-33R from sensory neurons. The contribution of neuronal IL-33R signaling to chronic itch development was tested in mouse models that recapitulate key pathologic features of AD and CPUO, respectively. RESULTS: IL-33 was elevated in both AD and CPUO as well as their respective mouse models. While neuron-restricted IL-33R signaling was dispensable for itch in AD-like disease, it was required for the development of dry skin itch in a mouse model that mirrors key aspects of CPUO pathology. CONCLUSIONS: These data highlight how IL-33 may be a predominant mediator of itch in certain contexts, depending on the tissue microenvironment. Further, this study provides insight into future therapeutic strategies targeting the IL-33 pathway for chronic itch.