Mast cells induce blood brain barrier damage in SCD by causing endoplasmic reticulum stress in the endothelium

Huy Tran, Aditya Mittal, Varun Sagi, Kathryn Luk, Aithanh Nguyen, Mihir Gupta, Julia Nguyen, Yann Lamarre, Jianxun Lei, Alonso Guedes, Kalpna Gupta

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Endothelial dysfunction underlies the pathobiology of cerebrovascular disease. Mast cells are located in close proximity to the vasculature, and vasoactive mediators released upon their activation can promote endothelial activation leading to blood brain barrier (BBB) dysfunction. We examined the mechanism of mast cell-induced endothelial activation via endoplasmic reticulum (ER) stress mediated P-selectin expression in a transgenic mouse model of sickle cell disease (SCD), which shows BBB dysfunction. We used mouse brain endothelial cells (mBECs) and mast cells-derived from skin of control and sickle mice to examine the mechanisms involved. Compared to control mouse mast cell conditioned medium (MCCM), mBECs incubated with sickle mouse MCCM showed increased, structural disorganization and swelling of the ER and Golgi, aggregation of ribosomes, ER stress marker proteins, accumulation of galactose-1-phosphate uridyl transferase, mitochondrial dysfunction, reactive oxygen species (ROS) production, P-selectin expression and mBEC permeability. These effects of sickle-MCCM on mBEC were inhibited by Salubrinal, a reducer of ER stress. Histamine levels in the plasma, skin releasate and in mast cells of sickle mice were higher compared to control mice. Compared to control BBB permeability was increased in sickle mice. Treatment of mice with imatinib, Salubrinal, or P-selectin blocking antibody reduced BBB permeability in sickle mice. Mast cells induce endothelial dysfunction via ER stress-mediated P-selectin expression. Mast cell activation contributes to ER stress mediated endothelial P-selectin expression leading to increased endothelial permeability and impairment of BBB. Targeting mast cells and/or ER stress has the potential to ameliorate endothelial dysfunction in SCD and other pathobiologies.

Original languageEnglish (US)
Article number56
Pages (from-to)1-12
Number of pages12
JournalFrontiers in Cellular Neuroscience
Volume13
DOIs
StatePublished - Jan 29 2019

Fingerprint

Endoplasmic Reticulum Stress
Sickle Cell Anemia
Blood-Brain Barrier
Mast Cells
Endothelium
P-Selectin
Permeability
Endothelial Cells
Conditioned Culture Medium
Brain
UDPglucose-Hexose-1-Phosphate Uridylyltransferase
Cerebrovascular Disorders
Skin
Blocking Antibodies
Heat-Shock Proteins
Ribosomes
Endoplasmic Reticulum
Histamine
Transgenic Mice
Reactive Oxygen Species

Keywords

  • Blood brain barrier
  • Endoplasmic reticulum stress
  • Endothelial cell
  • Mast cell
  • P-selectin
  • Sickle cell disease

PubMed: MeSH publication types

  • Journal Article

Cite this

Mast cells induce blood brain barrier damage in SCD by causing endoplasmic reticulum stress in the endothelium. / Tran, Huy; Mittal, Aditya; Sagi, Varun; Luk, Kathryn; Nguyen, Aithanh; Gupta, Mihir; Nguyen, Julia; Lamarre, Yann; Lei, Jianxun; Guedes, Alonso; Gupta, Kalpna.

In: Frontiers in Cellular Neuroscience, Vol. 13, 56, 29.01.2019, p. 1-12.

Research output: Contribution to journalArticle

Tran, Huy ; Mittal, Aditya ; Sagi, Varun ; Luk, Kathryn ; Nguyen, Aithanh ; Gupta, Mihir ; Nguyen, Julia ; Lamarre, Yann ; Lei, Jianxun ; Guedes, Alonso ; Gupta, Kalpna. / Mast cells induce blood brain barrier damage in SCD by causing endoplasmic reticulum stress in the endothelium. In: Frontiers in Cellular Neuroscience. 2019 ; Vol. 13. pp. 1-12.
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AU - Nguyen, Aithanh

AU - Gupta, Mihir

AU - Nguyen, Julia

AU - Lamarre, Yann

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AU - Guedes, Alonso

AU - Gupta, Kalpna

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AB - Endothelial dysfunction underlies the pathobiology of cerebrovascular disease. Mast cells are located in close proximity to the vasculature, and vasoactive mediators released upon their activation can promote endothelial activation leading to blood brain barrier (BBB) dysfunction. We examined the mechanism of mast cell-induced endothelial activation via endoplasmic reticulum (ER) stress mediated P-selectin expression in a transgenic mouse model of sickle cell disease (SCD), which shows BBB dysfunction. We used mouse brain endothelial cells (mBECs) and mast cells-derived from skin of control and sickle mice to examine the mechanisms involved. Compared to control mouse mast cell conditioned medium (MCCM), mBECs incubated with sickle mouse MCCM showed increased, structural disorganization and swelling of the ER and Golgi, aggregation of ribosomes, ER stress marker proteins, accumulation of galactose-1-phosphate uridyl transferase, mitochondrial dysfunction, reactive oxygen species (ROS) production, P-selectin expression and mBEC permeability. These effects of sickle-MCCM on mBEC were inhibited by Salubrinal, a reducer of ER stress. Histamine levels in the plasma, skin releasate and in mast cells of sickle mice were higher compared to control mice. Compared to control BBB permeability was increased in sickle mice. Treatment of mice with imatinib, Salubrinal, or P-selectin blocking antibody reduced BBB permeability in sickle mice. Mast cells induce endothelial dysfunction via ER stress-mediated P-selectin expression. Mast cell activation contributes to ER stress mediated endothelial P-selectin expression leading to increased endothelial permeability and impairment of BBB. Targeting mast cells and/or ER stress has the potential to ameliorate endothelial dysfunction in SCD and other pathobiologies.

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