Cyclosporine A Directly Affects Human and Mouse B cell Migration in vitro by Disrupting a HIF-1α Dependent, O2 Sensing, Molecular Switch

Abstract

AbstractBackgroundHypoxia is a potent molecular signal for cellular metabolism, mitochondrial function, and migration. Conditions of low oxygen tension trigger regulatory cascades mediated via the highly conserved HIF-1α post-translational modification system. In the adaptive immune response, B cells (Bc) are activated and differentiate under hypoxic conditions within lymph node germinal centers, and subsequently migrate to other compartments. During migration, they traverse through changing oxygen levels, ranging from 1-5% in the lymph node to 5-13% in the peripheral blood. Interestingly, the calcineurin inhibitor cyclosporine A is known to stimulate prolyl hydroxylase activity, resulting in HIF-1α destabilization and may alter Bc responses directly. Over 60% of patients taking calcineurin immunosuppressant medications have hypo-gammaglobulinemia and poor vaccine responses, putting them at high risk of infection with significantly increased morbidity and mortality.ResultsWe demonstrate that O2 tension is a previously unrecognized Bc regulatory switch, altering CXCR4 chemokine receptor signaling in activated Bc through HIF-1α expression and controlling critical aspects of Bc migration. Our data demonstrate that calcineurin inhibition hinders this O2 regulatory switch in primary human Bc.ConclusionThis previously unrecognized effect of calcineurin inhibition directly on human Bc has significant and direct clinical implications.