A calcium-redox feedback loop controls human monocyte immune responses: The role of ORAI Ca2+ channels

In phagocytes, pathogen recognition is followed by Ca2+ 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 Ca2+ channels control store-operated Ca2+ 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 Ca2+-redox interplay. Our results identified the ORAI-NOX2 feedback loop as a determinant of monocyte immune responses.