Cyclosporine a directly affects human and mouse b cell migration in vitro by disrupting a hIF-1 αdependent, o2 sensing, molecular switch
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 c...
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| Format: | Article |
| Language: | English |
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BMC
2020-03-01
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| Series: | BMC Immunology |
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| Online Access: | http://link.springer.com/article/10.1186/s12865-020-0342-8 |
| _version_ | 1818501869269417984 |
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| author | Shannon P Hilchey Mukta G Palshikar Jason A Emo Dongmei Li Jessica Garigen Jiong Wang Eric S Mendelson Valentina Cipolla Juilee Thakar Martin S Zand |
| author_facet | Shannon P Hilchey Mukta G Palshikar Jason A Emo Dongmei Li Jessica Garigen Jiong Wang Eric S Mendelson Valentina Cipolla Juilee Thakar Martin S Zand |
| author_sort | Shannon P Hilchey |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T21:02:13Z |
| format | Article |
| id | doaj.art-16390000a60548519adb800aa171d3e4 |
| institution | Directory Open Access Journal |
| issn | 1471-2172 |
| language | English |
| last_indexed | 2024-12-10T21:02:13Z |
| publishDate | 2020-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Immunology |
| spelling | doaj.art-16390000a60548519adb800aa171d3e42022-12-22T01:33:45ZengBMCBMC Immunology1471-21722020-03-0121111810.1186/s12865-020-0342-8Cyclosporine a directly affects human and mouse b cell migration in vitro by disrupting a hIF-1 αdependent, o2 sensing, molecular switchShannon P Hilchey0Mukta G Palshikar1Jason A Emo2Dongmei Li3Jessica Garigen4Jiong Wang5Eric S Mendelson6Valentina Cipolla7Juilee Thakar8Martin S Zand9University of Rochester Medical CenterDivision of NephrologyUniversity of RochesterBiophysics, Structural, and Computational Biology ProgramUniversity of Rochester Medical CenterDivision of NephrologyUniversity of RochesterClinical and Translational Science InstituteUniversity of RochesterClinical and Translational Science InstituteUniversity of Rochester Medical CenterDivision of NephrologyUniversity of Rochester Medical CenterDivision of NephrologyUniversity of Rochester Medical CenterDivision of NephrologyUniversity of RochesterDepartment of Microbiology and ImmunologyUniversity of Rochester Medical CenterDivision of NephrologyAbstract 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.http://link.springer.com/article/10.1186/s12865-020-0342-8HIF-1 αHypoxiaB cellsCXCR4/CXCL12CXCR5/CXCL13Chemotaxis |
| spellingShingle | Shannon P Hilchey Mukta G Palshikar Jason A Emo Dongmei Li Jessica Garigen Jiong Wang Eric S Mendelson Valentina Cipolla Juilee Thakar Martin S Zand Cyclosporine a directly affects human and mouse b cell migration in vitro by disrupting a hIF-1 αdependent, o2 sensing, molecular switch BMC Immunology HIF-1 α Hypoxia B cells CXCR4/CXCL12 CXCR5/CXCL13 Chemotaxis |
| title | Cyclosporine a directly affects human and mouse b cell migration in vitro by disrupting a hIF-1 αdependent, o2 sensing, molecular switch |
| title_full | Cyclosporine a directly affects human and mouse b cell migration in vitro by disrupting a hIF-1 αdependent, o2 sensing, molecular switch |
| title_fullStr | Cyclosporine a directly affects human and mouse b cell migration in vitro by disrupting a hIF-1 αdependent, o2 sensing, molecular switch |
| title_full_unstemmed | Cyclosporine a directly affects human and mouse b cell migration in vitro by disrupting a hIF-1 αdependent, o2 sensing, molecular switch |
| title_short | Cyclosporine a directly affects human and mouse b cell migration in vitro by disrupting a hIF-1 αdependent, o2 sensing, molecular switch |
| title_sort | cyclosporine a directly affects human and mouse b cell migration in vitro by disrupting a hif 1 αdependent o2 sensing molecular switch |
| topic | HIF-1 α Hypoxia B cells CXCR4/CXCL12 CXCR5/CXCL13 Chemotaxis |
| url | http://link.springer.com/article/10.1186/s12865-020-0342-8 |
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