ORAI1 and ORAI2 modulate murine neutrophil calcium signaling, cellular activation, and host defense

Derayvia Grimes, Ryan Johnson, Madeline Pashos, Celeste Cummings, Chen Kang, Georgia R. Sampedro, Eric Tycksen, Helen J. McBride, Rajan Sah, Clifford A. Lowell, Regina A. Clemens

Research output: Contribution to journalArticlepeer-review

Abstract

Calcium signals are initiated in immune cells by the process of store-operated calcium entry (SOCE), where receptor activation triggers transient calcium release from the endoplasmic reticulum, followed by opening of plasma-membrane calcium-release activated calcium (CRAC) channels. ORAI1, ORAI2, and ORAI3 are known to comprise the CRAC channel; however, the contributions of individual isoforms to neutrophil function are not well understood. Here, we show that loss of ORAI1 partially decreases calcium influx, while loss of both ORAI1 and ORAI2 completely abolishes SOCE. In other immune-cell types, loss of ORAI2 enhances SOCE. In contrast, we find that ORAI2-deficient neutrophils display decreased calcium influx, which is correlated with measurable differences in the regulation of neutrophil membrane potential via KCa3.1. Decreased SOCE in ORAI1-, ORAI2-, and ORAI1/2-deficient neutrophils impairs multiple neutrophil functions, including phagocytosis, degranulation, leukotriene, and reactive oxygen species (ROS) production, rendering ORAI1/2-deficient mice highly susceptible to staphylococcal infection. This study demonstrates that ORAI1 and ORAI2 are the primary components of the neutrophil CRAC channel and identifies subpopulations of neutrophils where cell-membrane potential functions as a rheostat to modulate the SOCE response. These findings have implications for mechanisms that modulate neutrophil function during infection, acute and chronic inflammatory conditions, and cancer.

Original languageEnglish
Pages (from-to)24403-24414
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number39
DOIs
StatePublished - Sep 29 2020

Keywords

  • Calcium signaling
  • Membrane potential
  • Neutrophil
  • ORAI1
  • Store-operated calcium entry

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