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The butyrophilin 1a1 knockout mouse revisited: Ablation of Btn1a1 leads to concurrent cell death and renewal in the mammary epithelium during lactation.

ABSTRACT: Butyrophilin 1A1 (BTN1A1) is implicated in the secretion of lipid droplets from mammary epithelial cells as a membrane receptor, which forms a secretion complex with the redox enzyme, xanthine oxidoreductase (XDH). The first evidence that BTN1A1 functions in this process was the generation of Btn1a1 ^-/- mouse lines, in which lipid secretion was disrupted and large unstable droplets were released into alveolar spaces with fragmented surface membranes. We have revisited one of these mutant mouse lines using RNAseq and proteomic analysis to assess the consequences of ablating the Btn1a1 gene on the expression of other genes and proteins. Disruption of intact Btn1a1 protein expression led to a large build-up of Xdh in the cytoplasm, induction of acute phase response genes and Lif-activation of Stat3 phosphorylation. At peak lactation, approx. 10% of the cells were dying, as assessed by TUNEL-analysis of nuclear DNA. Possible cell death pathways included expression of caspase 8 and activated caspase 3, autophagy, Slc5a8-mediated inactivation of survivin (Birc5), and pStat3-mediated lysosomal lysis, the latter of which is the principal death route in involuting wild type cells. Milk secretion was prolonged by renewal of the secretory epithelium, as evidenced by the upregulation of Ki67 in approx. 10% of cell nuclei and expression of cyclins and Fos/Jun. These data highlight the plasticity of the mammary epithelium and the importance of functional BTN1A1 expression for maintenance of terminally differentiated secretory cells and optimal milk production throughout lactation.

SUBMITTER: Jeong J

PROVIDER: S-EPMC8664049 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Butyrophilin 1A1 (BTN1A1) was first identified as a major integral protein of both the apical surface of mammary epithelial cells during lactation and the surface membrane surrounding lipid droplets in milk. Current evidence supports a role for BTN1A1 in the secretion of milk lipids as a membrane receptor, which forms a secretion complex with the redox enzyme, xanthine oxidoreductase (XDH). Capping of cytoplasmic lipid droplets with BTN1A1 and XDH serves to envelop the droplets with cellular membranes at the cell apex as an initial step in their subsequent release from the cell. The first evidence that BTN1A1 functions in this process was the generation of Btn1a1-/- mice, in which lipid secretion was disrupted and large unstable droplets were released into alveolar spaces with fragmented surface membranes. We have revisited this mutant mouse line using RNAseq and proteomic analysis to fully assess the consequences of ablating the Btn1a1 gene on the expression of other genes and proteins. Disruption of Btn1a1 expression led to a large build-up of Xdh (6-fold over wild-type levels) in the cytoplasm, induction of acute phase response genes and Lif-activation of STAT3 phosphorylation. At peak lactation, approx. 10% of the cells were dying, as assessed by TUNEL-analysis of nuclear DNA. Cell death appeared to proceed through expression of caspase 8 and activated caspase 3 and not via lysosomal lysis, which is the principal route for elimination of cells during mammary involution in wild-type mice. Other potential death pathways include autophagy and Slc5a8-mediated inactivation of survivin (Birc5). Milk secretion was prolonged by renewal of the secretory epithelium, as evidenced by the expression of cyclins, Fos/Jun and upregulation of Ki67 in approx. 10% of secretory cell nuclei. Thus a 21-day lactation cycle can be maintained, despite significant cell death by compensatory cell division, provided a milking stimulus is maintained. These data highlight the importance of BTN1A1 expression for the maintenance of terminally differentiated mammary epithelial cells and optimal milk production throughout lactation. From a practical standpoint, the complimentary RNAseq and proteomics data should provide a useful reference database for gene and protein expression in C57/Bl6 mice at peak lactation.

Project description:ObjectiveThe cytokine profile of human milk may be a key indicator of mammary gland health and has been linked to infant nutrition, growth, and immune system development. The current study examines the extent to which mammary epithelium permeability (MEP) is associated with cytokine profiles during established lactation within a sample of US mothers.MethodsParticipants were drawn from a previous study of human milk cytokines. The present analysis includes 162 participants (98 Black, 64 White) with infants ranging from 1 to 18 months of age. Levels of cytokines were determined previously. Here we measure milk sodium (Na) and potassium (K) levels with ion-selective probes. Two approaches were used to define elevated MEP: Na levels ≥10 mmol/L and Na/K ratios greater than 0.6. Associations between maternal-infant characteristics, elevated MEP, and twelve analytes (IL-6, IL-8, TNFα, IL-1β, FASL, VEGFD, FLT1, bFGF, PLGF, EGF, leptin, adiponectin) were examined using bivariate associations, principal components analysis, and multivariable logistic regression models.ResultsElevated MEP was observed in 12 and 15% of milk samples as defined by Na and Na/K cutoffs, respectively. The odds of experiencing elevated MEP (defined by Na ≥ 10 mmol/L) were higher among Black participants and declined with older infant age. All cytokines, except leptin, were positively correlated with either Na or the Na/K ratio. A pro-inflammatory factor (IL-6, IL-8, TNFα, IL-1β, EGF) and a tissue remodeling factor (FASL, VEGFD, FLT1, bFGF, PLGF, adiponectin) each contributed uniquely to raising the odds of elevated MEP as defined by either Na or the Na/K ratio.ConclusionThis exploratory analysis of MEP and cytokine levels during established lactation indicates that elevated MEP may be more common in US populations than previously appreciated and that individuals identifying as Black may have increased odds of experiencing elevated MEP based on current definitions. Research aimed at understanding the role of MEP in mammary gland health or infant growth and development should be prioritized.

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The butyrophilin 1a1 knockout mouse revisited: Ablation of Btn1a1 leads to concurrent cell death and renewal in the mammary epithelium during lactation.

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