X-linked immunodeficient mice with no functional Bruton's tyrosine kinase are protected from sepsis-induced multiple organ failure
We previously reported the Bruton's tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib improve outcomes in a mouse model of polymicrobial sepsis. Now we show that genetic deficiency of the BTK gene alone in Xid mice confers protection against cardiac, renal, and liver injury in polymi...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Frontiers Media
2020
|
| _version_ | 1797096511387992064 |
|---|---|
| author | O'Riordan, CE Purvis, GSD Collotta, D Krieg, N Wissuwa, B Sheikh, MH Ferreira Alves, G Mohammad, S Callender, LA Coldewey, SM Collino, M Greaves, DR Thiemermann, C |
| author_facet | O'Riordan, CE Purvis, GSD Collotta, D Krieg, N Wissuwa, B Sheikh, MH Ferreira Alves, G Mohammad, S Callender, LA Coldewey, SM Collino, M Greaves, DR Thiemermann, C |
| author_sort | O'Riordan, CE |
| collection | OXFORD |
| description | We previously reported the Bruton's tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib improve outcomes in a mouse model of polymicrobial sepsis. Now we show that genetic deficiency of the BTK gene alone in Xid mice confers protection against cardiac, renal, and liver injury in polymicrobial sepsis and reduces hyperimmune stimulation (“cytokine storm”) induced by an overwhelming bacterial infection. Protection is due in part to enhanced bacterial phagocytosis in vivo, changes in lipid metabolism and decreased activation of NF-κB and the NLRP3 inflammasome. The inactivation of BTK leads to reduced innate immune cell recruitment and a phenotypic switch from M1 to M2 macrophages, aiding in the resolution of sepsis. We have also found that BTK expression in humans is increased in the blood of septic non-survivors, while lower expression is associated with survival from sepsis. Importantly no further reduction in organ damage, cytokine production, or changes in plasma metabolites is seen in Xid mice treated with the BTK inhibitor ibrutinib, demonstrating that the protective effects of BTK inhibitors in polymicrobial sepsis are mediated solely by inhibition of BTK and not by off-target effects of this class of drugs. |
| first_indexed | 2024-03-07T04:42:53Z |
| format | Journal article |
| id | oxford-uuid:d2430e64-2d5f-410b-ac25-3a6881e27ffd |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:42:53Z |
| publishDate | 2020 |
| publisher | Frontiers Media |
| record_format | dspace |
| spelling | oxford-uuid:d2430e64-2d5f-410b-ac25-3a6881e27ffd2022-03-27T08:02:39ZX-linked immunodeficient mice with no functional Bruton's tyrosine kinase are protected from sepsis-induced multiple organ failureJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d2430e64-2d5f-410b-ac25-3a6881e27ffdEnglishSymplectic ElementsFrontiers Media2020O'Riordan, CEPurvis, GSDCollotta, DKrieg, NWissuwa, BSheikh, MHFerreira Alves, GMohammad, SCallender, LAColdewey, SMCollino, MGreaves, DRThiemermann, CWe previously reported the Bruton's tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib improve outcomes in a mouse model of polymicrobial sepsis. Now we show that genetic deficiency of the BTK gene alone in Xid mice confers protection against cardiac, renal, and liver injury in polymicrobial sepsis and reduces hyperimmune stimulation (“cytokine storm”) induced by an overwhelming bacterial infection. Protection is due in part to enhanced bacterial phagocytosis in vivo, changes in lipid metabolism and decreased activation of NF-κB and the NLRP3 inflammasome. The inactivation of BTK leads to reduced innate immune cell recruitment and a phenotypic switch from M1 to M2 macrophages, aiding in the resolution of sepsis. We have also found that BTK expression in humans is increased in the blood of septic non-survivors, while lower expression is associated with survival from sepsis. Importantly no further reduction in organ damage, cytokine production, or changes in plasma metabolites is seen in Xid mice treated with the BTK inhibitor ibrutinib, demonstrating that the protective effects of BTK inhibitors in polymicrobial sepsis are mediated solely by inhibition of BTK and not by off-target effects of this class of drugs. |
| spellingShingle | O'Riordan, CE Purvis, GSD Collotta, D Krieg, N Wissuwa, B Sheikh, MH Ferreira Alves, G Mohammad, S Callender, LA Coldewey, SM Collino, M Greaves, DR Thiemermann, C X-linked immunodeficient mice with no functional Bruton's tyrosine kinase are protected from sepsis-induced multiple organ failure |
| title | X-linked immunodeficient mice with no functional Bruton's tyrosine kinase are protected from sepsis-induced multiple organ failure |
| title_full | X-linked immunodeficient mice with no functional Bruton's tyrosine kinase are protected from sepsis-induced multiple organ failure |
| title_fullStr | X-linked immunodeficient mice with no functional Bruton's tyrosine kinase are protected from sepsis-induced multiple organ failure |
| title_full_unstemmed | X-linked immunodeficient mice with no functional Bruton's tyrosine kinase are protected from sepsis-induced multiple organ failure |
| title_short | X-linked immunodeficient mice with no functional Bruton's tyrosine kinase are protected from sepsis-induced multiple organ failure |
| title_sort | x linked immunodeficient mice with no functional bruton s tyrosine kinase are protected from sepsis induced multiple organ failure |
| work_keys_str_mv | AT oriordance xlinkedimmunodeficientmicewithnofunctionalbrutonstyrosinekinaseareprotectedfromsepsisinducedmultipleorganfailure AT purvisgsd xlinkedimmunodeficientmicewithnofunctionalbrutonstyrosinekinaseareprotectedfromsepsisinducedmultipleorganfailure AT collottad xlinkedimmunodeficientmicewithnofunctionalbrutonstyrosinekinaseareprotectedfromsepsisinducedmultipleorganfailure AT kriegn xlinkedimmunodeficientmicewithnofunctionalbrutonstyrosinekinaseareprotectedfromsepsisinducedmultipleorganfailure AT wissuwab xlinkedimmunodeficientmicewithnofunctionalbrutonstyrosinekinaseareprotectedfromsepsisinducedmultipleorganfailure AT sheikhmh xlinkedimmunodeficientmicewithnofunctionalbrutonstyrosinekinaseareprotectedfromsepsisinducedmultipleorganfailure AT ferreiraalvesg xlinkedimmunodeficientmicewithnofunctionalbrutonstyrosinekinaseareprotectedfromsepsisinducedmultipleorganfailure AT mohammads xlinkedimmunodeficientmicewithnofunctionalbrutonstyrosinekinaseareprotectedfromsepsisinducedmultipleorganfailure AT callenderla xlinkedimmunodeficientmicewithnofunctionalbrutonstyrosinekinaseareprotectedfromsepsisinducedmultipleorganfailure AT coldeweysm xlinkedimmunodeficientmicewithnofunctionalbrutonstyrosinekinaseareprotectedfromsepsisinducedmultipleorganfailure AT collinom xlinkedimmunodeficientmicewithnofunctionalbrutonstyrosinekinaseareprotectedfromsepsisinducedmultipleorganfailure AT greavesdr xlinkedimmunodeficientmicewithnofunctionalbrutonstyrosinekinaseareprotectedfromsepsisinducedmultipleorganfailure AT thiemermannc xlinkedimmunodeficientmicewithnofunctionalbrutonstyrosinekinaseareprotectedfromsepsisinducedmultipleorganfailure |