Cyclosporine a directly affects human and mouse b cell migration in vitro by disrupting a hIF-1 αdependent, o2 sensing, molecular switch.

Autor: 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
Předmět:
Zdroj: BMC Immunology; 3/18/2020, Vol. 21 Issue 1, p1-18, 18p
Abstrakt: 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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje