A calcium-redox feedback loop controls human monocyte immune responses: The role of ORAI Ca ²⁺ channels

Abstract

In phagocytes, pathogen recognition is followed by Ca(2+) mobilization and NADPH oxidase 2 (NOX2)-mediated "oxidative burst," which involves the rapid production of large amounts of reactive oxygen species (ROS). We showed that ORAI Ca(2+) channels control store-operated Ca(2+) entry, ROS production, and bacterial killing in primary human monocytes. ROS inactivate ORAI channels that lack an ORAI3 subunit. Staphylococcal infection of mice reduced the expression of the gene encoding the redox-sensitive Orai1 and increased the expression of the gene encoding the redox-insensitive Orai3 in the lungs or in bronchoalveolar lavages. A similar switch from ORAI1 to ORAI3 occurred in primary human monocytes exposed to bacterial peptides in culture. These alterations in ORAI1 and ORAI3 abundance shifted the channel assembly toward a more redox-insensitive configuration. Accordingly, silencing ORAI3 increased the redox sensitivity of the channel and enhanced oxidation-induced inhibition of NOX2. We generated a mathematical model that predicted additional features of the Ca(2+)-redox interplay. Our results identified the ORAI-NOX2 feedback loop as a determinant of monocyte immune responses.

TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling

“…The positive regulation of Nox2 by TRPC3 observed in the present study suggests that there is indirect crosstalk between TRPC3 and other ROS-activated TRP channels through Nox2 activation. In phagocytes, which strongly express Nox2, sustained Ca 2+ entry through Orai1 store-operated Ca 2+ channels26 is sufficient to increase Nox2 activity in response to bacterial infection. Voltage-dependent H + channels27 also contribute to ROS production by acting to balance the charge on the membrane.…”

Crosstalk between calcium and reactive oxygen species signaling in cancer

“…The ensuing Ca 2+ signals activate Nox2 at the cell surface via PKC to produce O 2 • - and H 2 O 2 as part of the oxidative burst for the killing of the pathogen. Interestingly, a switch to a redox insensitive ORAI3/ORAI1 heteromultimer was also shown to occur in monocytes following bacterial infection [228]. A higher ORAI3/ORAI1 ratio was shown to reduce the Ca 2+ amplitude [229], but resulted in a prolonged Ca 2+ signal that was not inhibited by increases in ROS [228].…”

“…Interestingly, a switch to a redox insensitive ORAI3/ORAI1 heteromultimer was also shown to occur in monocytes following bacterial infection [228]. A higher ORAI3/ORAI1 ratio was shown to reduce the Ca 2+ amplitude [229], but resulted in a prolonged Ca 2+ signal that was not inhibited by increases in ROS [228]. The authors proposed this to be a mechanism that ensures killing of the pathogen, but avoids extensive tissue damage in response to sustained ROS bursts.…”

The role of STIM proteins in neutrophil functions

“…; Saul et al . ). The presence of two isoforms activated by different conditions increases the diversity of cellular responses towards pathogen‐ and host‐associated ligands, cytokines, and paracrine signals, a versatility enabling neutrophils to respond to a broad range of stimuli.…”

“…STIM2 is activated by mild ER Ca 2+ -store depletion and was initially proposed to regulate basal Ca 2+ homeostasis or to act as a STIM1 inhibitor (Soboloff et al 2006;Brandman et al 2007). Recent studies, however, showed that STIM2 actively regulates SOCE in neurons, melanoma or monocytes (Berna-Erro et al 2009;Stanisz et al 2014;Saul et al 2016). The presence of two isoforms activated by different conditions increases the diversity of cellular responses towards pathogen-and host-associated ligands, cytokines, and paracrine signals, a versatility enabling neutrophils to respond to a broad range of stimuli.…”