X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure.

Caroline E O'Riordan,Nadine Krieg,David R Greaves,Gustavo Ferreira Alves,Christoph Thiemermann,Madeeha H Sheikh,Massimo Collino,Bianka Wissuwa,Lauren A Callender,Shireen Mohammad,Debora Collotta,Gareth S D Purvis,Sina M Coldewey

doi:10.3389/fimmu.2020.581758

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.

Highlights

Sepsis is a common and life-threatening condition caused by a dysregulated host response to an infection, either bacterial, fungal, or viral [1]
We report here for the first time that genetic inactivation of Bruton’s tyrosine kinase (BTK) is responsible for conferring protection against multiple organ failure in a clinically relevant model of sepsis
Most importantly we have shown that the inactivation of BTK in X-linked immunodeficiency (Xid) mice results in an increase of bacterial phagocytosis in macrophages and neutrophils, increasing bacterial clearance in both peritoneum and blood

Summary

Introduction

Sepsis is a common and life-threatening condition caused by a dysregulated host response to an infection, either bacterial, fungal, or viral [1]. Xid-Mice Are Protected From Sepsis development of pharmacological treatments for sepsis-induced organ dysfunction [5]. BTK is involved in the activation of the toll-like receptor (TLR) signaling pathways (by binding to the TIR domain of TLR4 and TLR’s adaptor molecules MyD88, and Mal) and the NLRP3 inflammasome (by binding to the ASC component) [7,8,9]. Activation of both the TLR signaling pathway and the NLRP3 inflammasome play a pivotal role in the pathophysiology of sepsis [10, 11]. The expression of BTK is not restricted to B cells, as BTK is expressed in cells of myeloid lineage, including macrophages and neutrophils [12, 13], activation of which contributes to the pathophysiology of sepsis

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