Pleiotropic consequences of Bruton tyrosine kinase deficiency in myeloid lineages lead to poor inflammatory responses

Abstract

Bruton tyrosine kinase (Btk), a nonreceptor-associated tyrosine kinase of the Tec family, appears to participate in many myeloid cell functions. We show that macrophages from X-linked immunodeficient (XID) mice lacking functional Btk cannot generate efficient bursts of reactive oxygen intermediates (ROIs). The induction of apoptotic cell death by inflammatory stimuli is also enhanced in XID macrophages. Phagocytosis of bacterial particles is only marginally affected in them.In vivo, XID mice show reduced severity of inflammatory diseases in models of experimental autoimmune encephalomyelitis (EAE), dextran sulfate sodium (DSS)-induced colitis, and carrageenan-induced acute edema. Also, polymorphonuclear neutrophil granulocytes (PMNs) in XID mice show poor ROI and nitric oxide (NO) induction, along with a reduction in PMN recruitment to peritoneal inflammation. XID mice show reduction in PMN numbers in peripheral blood, and their bone marrow shows a reduction in the numbers of both monocytic and granulocytic lineages, extending to the earliest progenitor populations. Thus, Btk is likely to play a significant role at multiple points during the development and functioning of the myeloid lineages, affecting the outcome of many infectious as well as noninfectious inflammatory events in vivo.

Analysis of the Effects of the Bruton's tyrosine kinase (Btk) Inhibitor Ibrutinib on Monocyte Fcγ Receptor (FcγR) Function

“…The lack of ibrutinib effect on monocyte/macrophage-mediated phagocytosis is in agreement with Mangla et al (32), who found that phagocytosis of heat-killed fluoresceinated E. coli was not affected in macrophages from Xid mice. This lack of effect is likely not due to insufficient levels of ibrutinib because we tested with levels of 1 and 10 M, and we saw effective blocking of Btk phosphorylation even at 1 M. In addition, it has been shown that as little as 1-10 nM is sufficient to block Fc␥R-mediated cytokine production in monocytes and THP-1 cells (19), which suggests that Btk kinase activity (and, most notably, its downstream Ca 2ϩ mobilization) is not required for phagocytosis.…”

“…This results in an arginine-to-cysteine change within the N-terminal region of Btk (37,38), which contains the pleckstrin homology region that interacts with protein kinase C (39). It has been shown previously that peritoneal macrophages from Xid mice do not show defects in their ability to ingest heat-killed Escherichia coli (32). Regarding Fc␥R-mediated phagocytosis, the xid gene was able to rescue the decreased ability of peritoneal macrophages from autoimmune-prone NZB mice to ingest opsonized sheep red blood cells (40).…”

Apoptosis-Inducing Factor Regulates Death in Peripheral T Cells

“…injection of 4% thioglycolate broth (Himedia). At 72 h postinjection, cells were harvested from the peritoneum and macrophages were isolated by plastic adherence as described previously (16). Purified populations were Ͼ90% CD11b ϩ .…”

Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model

“…BTK is a cytoplasmic, nonreceptor tyrosine kinase belonging to the TEC family of tyrosine kinases (7) and is expressed in all stages of B cell development, with the exception of long-lived, antibody-producing plasma cells (8,9). Besides B lymphocytes, many other hematopoietic cells also express BTK (5,(8)(9)(10), but clinically relevant functional impairment seems to be confined to this lineage. Thus, the severe clinical outcome of BTK mutations demonstrates the essential role of BTK already occurring in pre-B cell receptor signaling, which is a determinant for proliferation, differentiation, and survival of the early B cell stages (3,11,12).…”