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Creators/Authors contains: "Joseph, Ivor"

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  1. Abstract

    RAB11 small GTPases and associated recycling endosome have been localized to mitotic spindles and implicated in regulating mitosis. However, the physiological significance of such regulation has not been observed in mammalian tissues. We have used newly engineered mouse models to investigate intestinal epithelial renewal in the absence of single or double isoforms of RAB11 family members: Rab11a and Rab11b. Comparing with single knockouts, mice with compound ablation demonstrate a defective cell cycle entry and robust mitotic arrest followed by apoptosis, leading to a total penetrance of lethality within 3 days of gene ablation. UponRab11deletionex vivo, enteroids show abnormal mitotic spindle formation and cell death. Untargeted proteomic profiling of Rab11a and Rab11b immunoprecipitates has uncovered a shared interactome containing mitotic spindle microtubule regulators. Disrupting Rab11 alters kinesin motor KIF11 function and impairs bipolar spindle formation and cell division. These data demonstrate that RAB11A and RAB11B redundantly control mitotic spindle function and intestinal progenitor cell division, a mechanism that may be utilized to govern the homeostasis and renewal of other mammalian tissues.

     
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  3. Abstract

    Paneth cells (PCs), a specialized secretory cell type in the small intestine, are increasingly recognized as having an essential role in host responses to microbiome and environmental stresses. Whether and how commensal and pathogenic microbes modify PC composition to modulate inflammation remain unclear. Using newly developed PC‐reporter mice under conventional and gnotobiotic conditions, we determined PC transcriptomic heterogeneity in response to commensal and invasive microbes at single cell level. Infection expands the pool of CD74+PCs, whose number correlates with auto or allogeneic inflammatory disease progressions in mice. Similar correlation was found in human inflammatory disease tissues. Infection‐stimulated cytokines increase production of reactive oxygen species (ROS) and expression of a PC‐specific mucosal pentraxin (Mptx2) in activated PCs. A PC‐specific ablation ofMyD88reduced CD74+PC population, thus ameliorating pathogen‐induced systemic disease. A similar phenotype was also observed in mice lacking Mptx2. Thus, infection stimulates expansion of a PC subset that influences disease progression.

     
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  4. Abstract

    A number of studies have examined the effects of 1,25‐dihydroxyvitamin D3(1,25(OH)2D3) on intestinal inflammation driven by immune cells, while little information is currently available about its impact on inflammation caused by intestinal epithelial cell (IEC) defects. Mice lacking IEC‐specificRab11aa recycling endosome small GTPase resulted in increased epithelial cell production of inflammatory cytokines, notably IL‐6 and early onset of enteritis. To determine whether vitamin D supplementation may benefit hosts with epithelial cell‐originated mucosal inflammation, we evaluated in vivo effects of injected 1,25(OH)2D3or dietary supplement of a high dose of vitamin D on the gut phenotypes of IEC‐specificRab11aknockout mice (Rab11aΔIEC). 1,25(OH)2D3administered at 25 ng, two doses per mouse, by intraperitoneal injection, reduced inflammatory cytokine production in knockout mice compared to vehicle‐injected mice. Remarkably, feeding mice with dietary vitamin D supplementation at 20,000 IU/kg spanning fetal and postnatal developmental stages led to improved bodyweights, reduced immune cell infiltration, and decreased inflammatory cytokines. We found that these vitamin D effects were accompanied by decreased NF‐κB (p65) in the knockout intestinal epithelia, reduced tissue‐resident macrophages, and partial restoration of epithelial morphology. Our study suggests that dietary vitamin D supplementation may prevent and limit intestinal inflammation in hosts with high susceptibility to chronic inflammation.

     
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