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- Title
Cyclosporine a directly affects human and mouse b cell migration in vitro by disrupting a hIF-1 αdependent, o2 sensing, molecular switch.
- Authors
Hilchey, Shannon P; Palshikar, Mukta G; Emo, Jason A; Li, Dongmei; Garigen, Jessica; Wang, Jiong; Mendelson, Eric S; Cipolla, Valentina; Thakar, Juilee; Zand, Martin S
- Abstract
Background: Hypoxia 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-1 α 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-1 α 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. Results: We demonstrate that O 2 tension is a previously unrecognized Bc regulatory switch, altering CXCR4 and CXCR5 chemokine receptor signaling in activated Bc through HIF-1 α expression, and controlling critical aspects of Bc migration. Our data demonstrate that calcineurin inhibition hinders this O 2 regulatory switch in primary human Bc. Conclusion: This previously unrecognized effect of calcineurin inhibition directly on human Bc has significant and direct clinical implications.
- Subjects
B cells; CELL migration; MOLECULAR switches; CYCLOSPORINE; CHEMOKINE receptors; CXCR4 receptors; IMMUNOGLOBULIN class switching
- Publication
BMC Immunology, 2020, Vol 21, Issue 1, p1
- ISSN
1471-2172
- Publication type
Article
- DOI
10.1186/s12865-020-0342-8