Phagocytosis in the retina promotes local insulin production in the eye.

The retina is highly metabolically active, relying on glucose uptake and aerobic glycolysis. Situated in close contact to photoreceptors, a key function of cells in the retinal pigment epithelium (RPE) is phagocytosis of damaged photoreceptor outer segments (POS). Here we identify RPE as a local source of insulin in the eye that is stimulated by POS phagocytosis. We show that Ins2 messenger RNA and insulin protein are produced by RPE cells and that this production correlates with RPE phagocytosis of POS. Genetic deletion of phagocytic receptors ('loss of function') reduces Ins2, whereas increasing the levels of the phagocytic receptor MerTK ('gain of function') increases Ins2 production in male mice. Contrary to pancreas-derived systemic insulin, RPE-derived local insulin is stimulated during starvation, which also increases RPE phagocytosis. Global or RPE-specific Ins2 gene deletion decreases retinal glucose uptake in starved male mice, dysregulates retinal physiology, causes defects in phototransduction and exacerbates photoreceptor loss in a mouse model of retinitis pigmentosa. Collectively, these data identify RPE cells as a phagocytosis-induced local source of insulin in the retina, with the potential to influence retinal physiology and disease.

Apple cider vinegar soaks do not alter the skin bacterial microbiome in atopic dermatitis.

INTRODUCTION: Atopic dermatitis is a common skin disease characterized by altered cutaneous immunity in which patients often exhibit lower skin microbiota diversity compared to healthy skin and are prone to colonization by Staphylococcus aureus. Apple cider vinegar has been shown to have antibacterial effects; however, its effects on the skin microbiome have not previously been well-described. OBJECTIVES: We aimed to examine the effects of topical dilute apple cider vinegar soaks on Staphylococcus aureus abundance, skin bacterial microbiome composition, and skin bacterial microbiome diversity in atopic dermatitis participants compared to healthy skin. METHODS: Eleven subjects with atopic dermatitis and 11 healthy controls were enrolled in this randomized, non-blinded, single-institution, split-arm pilot study. Subjects soaked one forearm in dilute apple cider vinegar (0.5% acetic acid) and the other forearm in tap water for 10 minutes daily. Skin bacteria samples were collected from subjects' volar forearms before and after 14 days of treatment. 16S sequencing was used to analyze Staphylococcus aureus abundance and skin bacterial microbiome composition, and alpha diversity of microbiota were determined using Shannon diversity index. RESULTS: There was no difference in skin bacterial microbiome in atopic dermatitis subjects after 2 weeks of daily water or apple cider vinegar treatments (p = 0.056 and p = 0.22, respectively), or in mean abundance of S. aureus on apple cider vinegar-treated forearms (p = 0.60). At 2 weeks, the skin bacterial microbiomes of healthy control subjects were not significantly different from the skin bacterial microbiome of atopic dermatitis subjects (p = 0.14, 0.21, 0.12, and 0.05). CONCLUSIONS: Our results suggest that daily soaks in 0.5% apple cider vinegar are not an effective method of altering the skin bacterial microbiome in atopic dermatitis. Further studies are needed to explore the effects of different concentrations of apple cider vinegar on skin microflora and disease severity. TRIAL NUMBER: UVA IRB-HSR #19906.

Nuclear Transit and HIV LTR Binding of NF-κB Subunits Held by IκB Proteins: Implications for HIV-1 Activation.

No effective therapy to eliminate the HIV latently infected cell reservoir has been developed. One approach, "shock and kill", employs agents that activate HIV, subsequently killing the activated infected cells and/or virus. Shock and kill requires agents that safely and effectively activate HIV. One class of activation agents works through classical NF-κB pathways, but global NF-κB activators are non-specific and toxic. There exist two major IκBs: IκBα, and IκBε, which hold activating NF-κB subunits in the cytoplasm, releasing them for nuclear transit upon cell stimulation. IκBα was considered the main IκB responsible for gene expression regulation, including HIV activation. IκBε is expressed in cells constituting much of the latent HIV reservoir, and IκBε knockout mice have a minimal phenotype, suggesting that IκBε could be a valuable target for HIV activation and reservoir depletion. We previously showed that targeting IκBε yields substantial increases in HIV expression. Here, we show that IκBε holds c-Rel and p65 activating NF-κB subunits in the cytoplasm, and that targeting IκBε with siRNA produces a strong increase in HIV expression associated with enhanced c-Rel and p65 transit to the nucleus and binding to the HIV LTR of the activating NF-κBs, demonstrating a mechanism through which targeting IκBε increases HIV expression. The findings suggest that it may be helpful to develop HIV activation approaches, acting specifically to target IκBε and its interactions with the NF-κBs.