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Blockade of store-operated calcium entry by BTP2 preserves anti-inflammatory gene expression in human peripheral

Divya Shankaranarayanan1, Madhav Mantri2, Mila Lagman3

  • 1Division of Nephrology and Hypertension, Department of Medicine, NewYork-Presbyterian-Weill Cornell Medicine, New York, NY, USA; Department of Transplantation Medicine, NewYork-Presbyterian Hospital-Weill Cornell Medicine, New York, NY, USA.

Human Immunology
|September 27, 2024
PubMed

Insights

Store-operated calcium entry (SOCE) blockade with BTP2 spares anti-inflammatory gene expression while inhibiting pro-inflammatory genes. This suggests SOCE inhibitors could treat autoimmune diseases and aid organ transplantation.

Area of Science:

  • Immunology
  • Cellular Signaling
  • Molecular Biology

Background:

  • Store-operated calcium entry (SOCE) is crucial for cellular signaling and immune responses.
  • Previous studies show SOCE inhibition suppresses pro-inflammatory gene expression.
  • The whole-transcriptome impact of SOCE blockade on gene expression remained largely unknown.

Purpose of the Study:

  • To investigate the effect of SOCE blockade on the human peripheral blood mononuclear cell transcriptome.
  • To identify global gene expression changes induced by BTP2, a SOCE inhibitor, in response to phytohemagglutinin stimulation.

Main Methods:

  • RNA sequencing (RNA-seq) was employed to analyze gene expression at the whole transcriptome level.
  • Preamplification-enhanced RT-qPCR assays were used to validate differential gene expression.
  • Multiparameter flow cytometry confirmed protein-level changes in IL2RA expression.

Main Results:

  • SOCE blockade by BTP2 spared the activation-induced expression of anti-inflammatory genes (e.g., IL10, TGFB1, FOXP3, CTLA4).
  • BTP2 inhibited the induced expression of pro-inflammatory (e.g., IFNG) and cytopathic (e.g., GZMB) genes.
  • BTP2 was confirmed to inhibit IL-2 receptor alpha chain (IL2RA) expression at the protein level, impacting T cell expansion.

Conclusions:

  • SOCE blockade selectively inhibits pro-inflammatory and cytopathic gene expression while preserving anti-inflammatory gene induction.
  • This selective modulation of immune gene expression suggests SOCE inhibitors are promising candidates for novel immunoregulatory drugs.
  • Potential therapeutic applications include treating autoimmune diseases and improving outcomes in organ transplantation.
Keywords:
BTP2CalciumGeneRNA-seqSOCE

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