House dust mites (HDMs) are one of the most significant environmental allergens in the establishment of the so-called "Atopic March." It is known that the immune response to HDM is Th2 dominant, but the innate mechanisms leading to HDM-induced type 2 responses are still not completely understood. A number of innate immune receptors have been implicated in the response to HDM including toll-like receptors, C-type lectin receptors, and protease activated receptors. NOD2 is a member of the NOD-like receptor family, which has been reported to be involved in the establishment of type 2 immunity and in blocking respiratory tolerance. NOD2 mediates its effects through its downstream effector kinase, receptor interacting protein (RIP2). It has not been shown if RIP2 is involved in the innate response to HDM and in the resulting generation of type 2 immunity. Furthermore, the role of RIP2 in modulating allergic airway inflammation has been controversial. In this study, we show that RIP2 is activated in airway epithelial cells in response to HDM and is important for the production of CCL2. Using a murine HDM asthma model, we demonstrate that lung pathology, local airway inflammation, inflammatory cytokines, HDM-specific IgG antibody production, and HDM-specific Th2 responses are all reduced in RIP2 knockout mice compared to WT animals. These data illustrate that RIP2 can be activated by a relevant allergic stimulus and that such activation can contribute to allergic airway inflammation. These findings also suggest that RIP2 inhibitors might have some efficacy in down-regulating the inflammatory response in type 2 dominated diseases.
Active learning has been shown to improve student outcomes and learning, yet organic chemistry instructors have been slow to adopt these pedagogies. The Chemistry Collaborations, Workshops, and Communities of Scholars (cCWCS) Active Learning in Organic Chemistry (ALOC) workshops have sought to facilitate the adoption of active learning methods by helping participants define active learning and understand best practices, persuading them to incorporate these practices into their teaching, and supporting their implementation efforts through an online community, Organic Educational Resources (OrganicERs.org). The effectiveness of the workshops was measured over a two-year period using teaching self-efficacy and teaching practices instruments. Comparison to pre-workshop self-efficacy surveys found significant and sustained gains for knowledge about and belief in the efficacy of active learning methods (d = 1.18 compared to pre-workshop responses) and confidence in intention to implement (d = 0.60). Belief that they were implementing more active learning in their classrooms (d = 0.85) was corroborated by the teaching practices survey and survey of class time allocation which also showed statistically significant (p < 0.001) and sustained growth in student centered teaching (d = 1.00), formative assessment (d = 1.04), student–student interactions (d = 0.96), and the amount of class time spent with students working in groups (d = 0.68) for the workshop participants. Gains for participants in the 3 hour Active Learning in Organic Chemistry workshops at the 2016 Biennial Conference on Chemical Education (BCCE) were smaller than those in the 4 day ALOC workshops, but still meaningful. These results indicate that the 2015 and 2016 Active Learning in Organic Chemistry faculty development workshops effectively increased participants’ knowledge about, belief in the efficacy of, and implementation of active learning methods.
Exposure to house dust mite (HDM) is highly associated with the development of allergic asthma. The adaptive immune response to HDM is largely Th2 and Th17 dominant, and a number of innate immune receptors have been identified that recognize HDM to initiate these responses. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is a cytosolic sensor of peptidoglycan, which is important for Th2 and Th17 polarization. NOD2 mediates its signaling through its downstream effector kinase, receptorinteracting serine/threonine protein kinase 2 (RIP2). We have previously shown that RIP2 promotes HDM-associated allergic airway inflammation and Th2 and Th17 immunity, acting early in the HDM response and likely within airway epithelial cells. However, the consequences of inhibiting RIP2 during this critical period has not yet been examined. In this study, we pharmacologically inhibited RIP2 activity during the initial exposure to allergen in an acute HDM model of asthma and determined the effect on the subsequent development of allergic airway disease. We show that early inhibition of RIP2 was sufficient to reduce lung histopathology and local airway inflammation while reducing the Th2 immune response. Using a chronic HDM asthma model, we demonstrate that inhibition of RIP2, despite attenuating airway inflammation and airway remodeling, was insufficient to reduce airway hyperresponsiveness. These data demonstrate the potential of pharmacological targeting of this kinase in asthma and support further development and optimization of RIP2-targeted therapies. ImmunoHorizons, 2020, 4: 825-836.
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