Figure 9.

Schematic diagram representing the role of Bruton's tyrosine kinase (BTK) in the pathophysiology of sepsis. LPS is released from Gram-negative bacteria which activate the TLR4 signaling pathway and the release of PepG from Gram-positive bacteria activate the TLR2 signaling pathway. BTK is involved in the activation of TLR4 and TLR2 by binding to MyD88 and TRIF thus activating their representative signaling cascades. The activation of the MyD88 signaling pathway, leads to the activation of NF-κB and the production of pro-inflammatory cytokines. Additionally, BTK activates the NLRP3 inflammasome by binding to the ASC component of the inflammasome. Once active the NLRP3 inflammasome cleaves pro-IL-1β to active IL-1β. The production of chemokines from NF-κB activation results in the recruitment of neutrophils and macrophages. Excessive inflammation from the cytokine storm and innate immune cells results in multiple organ failure/injury. The use of BTK inhibitors such as ibrutinib or acalabrutinib supress sepsis-induced inflammation and thus multiple-organ failure/injury.