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Vascular endothelial cell-specific disruption of the profilin1 gene leads to severe multiorgan pathology and
Abigail Allen-Gondringer1, David Gau1, Christopher Varghese1
1Bioengineering, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Insights
Loss of Profilin1 (Pfn1) in endothelial cells causes severe health issues and inflammation, highlighting its critical role in mammalian survival. This study reveals Pfn1
Area of Science:
- Cell Biology
- Immunology
- Developmental Biology
Background:
- Profilin1 (Pfn1) regulates actin dynamics and is crucial for embryonic development.
- The role of endothelial Pfn1 in adult physiology and disease remains largely unexplored.
Purpose of the Study:
- To investigate the in vivo consequences of Pfn1 loss-of-function specifically in vascular endothelial cells (ECs).
- To elucidate the impact of endothelial Pfn1 deficiency on cellular pathologies and immune responses.
Main Methods:
- Generation of a mouse model with tamoxifen-inducible, EC-selective Pfn1 knockout (Pfn1EC-KO).
- Analysis of health complications, organ pathologies, and immune cell profiles following Pfn1 ablation in ECs.
- Assessment of cytokine/chemokine gene expression and key signaling pathway activation (IRF7, STAT1) in ECs and macrophages.
Main Results:
- Pfn1 ablation in adult ECs led to severe pathologies including cell death, infarcts, fibrosis, and reduced survival within 3 weeks.
- Endothelial Pfn1 deficiency promoted a proinflammatory immune environment, characterized by myeloid cell bias and elevated cytokines.
- Pfn1 depletion in ECs directly upregulated inflammatory gene expression and potentiated paracrine inflammatory signaling to macrophages, involving IRF7 and STAT1 activation.
Conclusions:
- Endothelial Pfn1 is indispensable for mammalian survival, with its loss triggering significant immunological consequences.
- Pfn1 plays a critical role in maintaining endothelial integrity and suppressing inflammation, unlike its tolerable loss in other cell types.
- Targeting endothelial Pfn1 may offer therapeutic strategies for inflammatory diseases.
Abstract:
Actin-binding protein Profilin1 is an important regulator of actin cytoskeletal dynamics in cells and critical for embryonic development in higher eukaryotes. The objective of the present study was to examine the consequence of loss-of-function of Pfn1 in vascular endothelial cells (ECs) in vivo. We utilized a mouse model engineered for tamoxifen-inducible biallelic inactivation of the Pfn1 gene selectively in EC (Pfn1EC-KO). Widespread deletion of EC Pfn1 in adult mice leads to severe health complications presenting overt pathologies (endothelial cell death, infarct, and fibrosis) in major organ systems and evidence for inflammatory infiltrates, ultimately compromising the survival of animals within 3 weeks of gene ablation. Mice deficient in endothelial Pfn1 exhibit selective bias toward the proinflammatory myeloid-derived population of immune cells, a finding further supported by systemic elevation of proinflammatory cytokines. We further show that triggering Pfn1 depletion not only directly upregulates proinflammatory cytokine/chemokine gene expression in EC but also potentiates the paracrine effect of EC on proinflammatory gene expression in macrophages. Consistent with these findings, we provide further evidence for increased activation of Interferon Regulatory Factor 7 (IRF7) and STAT1 in EC when depleted of Pfn1. Collectively, these findings for the first time demonstrate a prominent immunological consequence of loss of endothelial Pfn1 and an indispensable role of endothelial Pfn1 in mammalian survival unlike tolerable phenotypes of Pfn1 loss in other differentiated cell types.
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