CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo

Rare autosomal dominant mutations in the gene encoding the keratinocyte signaling molecule, Caspase Recruitment Domain-Containing Protein 14 (CARD14), have been associated with an increased susceptibility to psoriasis but the physiological impact of CARD14 gain-of-function mutations remains to be fully determined in vivo. Here, we report that heterozygous mice harboring a CARD14 gain-of-function mutation (Card14ΔE138) spontaneously develop a chronic psoriatic phenotype with characteristic scaling skin lesions, epidermal thickening, keratinocyte hyperproliferation, hyperkeratosis and immune cell infiltration. Affected skin of these mice is characterized by elevated expression of anti-microbial peptides, chemokines and cytokines (including Th17 cell-signature cytokines), and an immune infiltrate rich in neutrophils, myeloid cells and T-cells, reminiscent of human psoriatic skin. Disease pathogenesis was driven by the IL-23/IL-17 axis and neutralization of IL-23p19, the key cytokine in maintaining Th17 cell polarization, significantly reduced skin lesions and the expression of antimicrobial peptides and pro-inflammatory cytokines. Therefore, hyperactivation of CARD14 alone is sufficient to orchestrate the complex immunopathogenesis that drives Th17-mediated psoriasis skin disease in vivo

IL-31 expression by inflammatory cells is preferentially elevated in atopic dermatitis

Interleukin-31 (IL-31) is a recently discovered cytokine expressed in many human tissues, and predominantly by activated CD4+ T cells. IL-31 signals through a heterodimeric receptor consisting of IL-31 receptor alpha (IL-31RA) and oncostatin M receptor beta (OSMR). Earlier studies have shown involvement of IL-31 and its receptor components IL-31RA and OSMR in atopic dermatitis, pruritus and Th2-weighted inflammation at the mRNA level. The aim of this study was to investigate IL-31 protein expression in skin of such conditions. Immunohisto-chemical staining for IL-31, IL-31RA and OSMR was performed in formalin-fixed paraffin-embedded biopsy specimens. IL-31 expression was increased in the inflammatory infiltrates from skin biopsies taken from subjects with atopic dermatitis, compared with controls (p ≤ 0.05). IL-31, IL-31RA and OSMR protein immunoreactivity was not increased in biopsies from subjects with other Th2-weighted and pruritic skin diseases. Our results confirm, at the protein level, the relationship between IL-31 expression and atopic dermatitis. Our results do not support a general relationship between expression of IL-31/IL-31R and pruritic or Th2-mediated diseases

CARD14 Gain-of-Function Mutation Alone Is Sufficient to Drive IL-23/IL-17-Mediated Psoriasiform Skin Inflammation In Vivo.

Rare autosomal dominant mutations in the gene encoding the keratinocyte signaling molecule CARD14, have been associated with an increased susceptibility to psoriasis, but the physiological impact of CARD14 gain-of-function mutations remains to be fully determined in vivo. Here, we report that heterozygous mice harboring a CARD14 gain-of-function mutation (Card14ΔE138) spontaneously develop a chronic psoriatic phenotype with characteristic scaling skin lesions, epidermal thickening, keratinocyte hyperproliferation, hyperkeratosis, and immune cell infiltration. Affected skin of these mice is characterized by elevated expression of anti-microbial peptides, chemokines, and cytokines (including T helper type 17 cell-signature cytokines) and an immune infiltrate rich in neutrophils, myeloid cells, and T cells, reminiscent of human psoriatic skin. Disease pathogenesis was driven by the IL-23/IL-17 axis, and neutralization of IL-23p19, the key cytokine in maintaining T helper type 17 cell polarization, significantly reduced skin lesions and the expression of antimicrobial peptides and proinflammatory cytokines. Therefore, hyperactivation of CARD14 alone is sufficient to orchestrate the complex immunopathogenesis that drives T helper type 17-mediated psoriasis skin disease in vivo

Getting to implementation: Adaptation of an implementation playbook

IntroductionImplementation strategies supporting the translation of evidence into practice need to be tailored and adapted for maximum effectiveness, yet the field of adapting implementation strategies remains nascent. We aimed to adapt “Getting To Outcomes”® (GTO), a 10-step implementation playbook designed to help community-based organizations plan and evaluate behavioral health programs, into “Getting To Implementation” (GTI) to support the selection, tailoring, and use of implementation strategies in health care settings.MethodsOur embedded evaluation team partnered with operations, external facilitators, and site implementers to employ participatory methods to co-design and adapt GTO for Veterans Health Administration (VA) outpatient cirrhosis care improvement. The Framework for Reporting Adaptations and Modifications to Evidenced-based Implementation Strategies (FRAME-IS) guided documentation and analysis of changes made pre- and post-implementation of GTI at 12 VA medical centers. Data from multiple sources (interviews, observation, content analysis, and fidelity tracking) were triangulated and analyzed using rapid techniques over a 3-year period.ResultsAdaptations during pre-implementation were planned, proactive, and focused on context and content to improve acceptability, appropriateness, and feasibility of the GTI playbook. Modifications during and after implementation were unplanned and reactive, concentrating on adoption, fidelity, and sustainability. All changes were collaboratively developed, fidelity consistent at the level of the facilitator and/or implementer.ConclusionGTO was initially adapted to GTI to support health care teams' selection and use of implementation strategies for improving guideline-concordant medical care. GTI required ongoing modification, particularly in steps regarding team building, context assessment, strategy selection, and sustainability due to difficulties with step clarity and progression. This work also highlights the challenges in pragmatic approaches to collecting and synthesizing implementation, fidelity, and adaptation data.Trial registrationThis study was registered on ClinicalTrials.gov (Identifier: NCT04178096)