Vascular endothelial cell-specific disruption of the <i>profilin1</i> gene leads to severe multi-organ pathology and inflammation causing mortality
نویسندگان
چکیده
Abstract Actin-binding protein Profilin1 is an important regulator of actin cytoskeletal dynamics in cells, and critical for embryonic development higher eukaryotes. The objective the present study was to examine consequence loss-of-function Pfn1 vascular endothelial cells (ECs) vivo. We utilized a mouse model engineered tamoxifen-inducible bi-allelic inactivation gene selectively EC (Pfn1EC-KO). Widespread deletion adult mice leads severe health complications presenting overt pathologies (endothelial cell death, infarct, fibrosis) major organ systems evidence inflammatory infiltrates, ultimately compromising survival animals within 3 weeks ablation. Mice deficient exhibit selective bias towards pro-inflammatory myeloid-derived population immune finding further supported by systemic elevation cytokines. show that triggering depletion not only directly upregulates cytokine/chemokine expression but also potentiates paracrine effect on macrophages. Consistent with these findings, we provide increased activation Interferon Regulatory Factor 7 (IRF7) STAT1 when depleted Pfn1. Collectively, findings first time demonstrate prominent immunological loss Pfn1, indispensable role mammalian unlike tolerable phenotypes other differentiated types.
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ژورنال
عنوان ژورنال: PNAS nexus
سال: 2023
ISSN: ['2752-6542']
DOI: https://doi.org/10.1093/pnasnexus/pgad305