As a cytoplasmic protein tyrosine kinase, Bruton's tyrosine kinase (Btk) is widely considered as a vital kinase in many aspects of different physiologic processes. It is engaged in many important signalling pathways related to the immune response, such as the B cell receptor pathway, pattern‐recognition receptor pathway, and triggering receptor expressed on myeloid cell pathway. Recent studies have increasingly focused on the important role of Btk in various inflammatory diseases, which are related to Btk expression in myeloid innate immune cells, such as macrophages, dendritic cells and neutrophils. Although some investigations have explored the role of Btk in microbial infections, many aspects remain elusive, and some of the results are opposite and controversial. Considering the complicated and multiple roles of Btk in the immune system, we summarized the engagement of Btk signalling in various pathogenic microorganism infections, the possible mechanisms involved and its therapeutic potential in the control of infectious diseases.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Acetaminophen (APAP) is a kind of widely used drug for the treatment of pain and fever. It is reported that its overdose can cause serious liver failure. 1 In Europe and the United States, APAP-induced acute liver injury (ALI) has become one of the primary causes of liver failure and thus arises widespread concern and research in the world. 2 Abundant evidences have suggested that both innate and adaptive immune cells, such as macrophages, neutrophils and T cells, played critical roles in APAP-induced ALI. 3,4 It is now clear that neutrophils have important homeostatic functions in various organ systems including liver, 5,6 but what the role of neutrophils plays in APAP-induced ALI still remains elusive. 7,8 Neutrophils, a type of polymorphonuclear leukocytes, are the first-line guardians of the innate immune system. Normally, neutrophils are not activated and move slowly in peripheral blood circulation without direction. The half-life of neutrophils is only 6-7 hours. 9 Once the pathogen invades or the endogenous stimulants releases, the pattern recognition receptors can recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Then, inflammatory reaction occurs and neutrophils are activated. 10,11 The activated neutrophils in peripheral circulation will tend to move towards the injury site. The migration of neutrophils involves rolling, activation and adhesion. 12,13 They then participate in the inflammatory process through phagocytosis, degranulation and extracellular traps (NETs). 14 On the one hand, neutrophils are drawn from the blood to sterility inflammatory site, which contribute to wound healing. On the other hand, their prolonged half-life, release of granule proteins such as myeloperoxidase (MPO), neutrophil serine proteases (NSPs), lipocalin 2 (LCN2), human neutrophil peptide (HNP), excessive infiltration and uncontrolled activation may lead to destruction of normal tissue structures and serious inflammations. 15 Therefore, how neutrophils play in APAP-induced ALI has aroused great controversy. In this review, we outline the neutrophil's
There is no effective treatment for acute liver failure (ALF) except for an artificial liver support system (ALSS) and liver transplant. Bruton tyrosine kinase (Btk) plays important immunoregulatory roles in the inflammatory diseases, but its possible function in ALF remains to be characterized. In this study, we detected the phosphorylation level of Btk in ALF mouse liver and analyzed the protective effects of Btk inhibitor on survival rate and liver damage in ALF mouse models. We measured the expression levels of various inflammatory cytokines in the ALF mouse liver and primary human monocytes. In addition, we examined the expression of the NLRP3 inflammasome in mouse models with or without Btk inhibition. Clinically, we observed the dynamic changes of Btk expression in PBMCs of ALSS-treated patients. Our results showed that Btk was upregulated significantly in the experimental ALF mouse models and that Btk inhibition alleviated liver injury and reduced the mortality in these models. The protective effect of Btk inhibitors on ALF mice partially depended on the suppression of NLRP3 inflammasome signaling. Clinical investigations revealed that the dynamic changes of Btk expression in PBMCs could predict the effect of ALSS treatment. Our work shows that Btk inhibition is an effective therapeutic strategy for ALF. Moreover, Btk is a useful indicator to predict the therapeutic effect of ALSS on liver failure, which might have great value in clinical practice.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.