Bibliographic Details
| Title: |
X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure. |
| Authors: |
O'Riordan, Caroline E., Purvis, Gareth S. D., Collotta, Debora, Krieg, Nadine, Wissuwa, Bianka, Sheikh, Madeeha H., Ferreira Alves, Gustavo, Mohammad, Shireen, Callender, Lauren A., Coldewey, Sina M., Collino, Massimo, Greaves, David R., Thiemermann, Christoph |
| Source: |
Frontiers in Immunology; 10/7/2020, Vol. 11, pN.PAG-N.PAG, 20p |
| Subject Terms: |
PROTEIN-tyrosine kinases, MULTIPLE organ failure, CYTOKINE release syndrome, BACTERIAL diseases, MICE |
| Abstract: |
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. [ABSTRACT FROM AUTHOR] |
|
Copyright of Frontiers in Immunology is the property of Frontiers Media S.A. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| Database: |
Complementary Index |
