Abstract
Bruton’s tyrosine kinase (BTK) was initially discovered as a critical mediator of B cell receptor signaling in the development and functioning of adaptive immunity. Growing evidence also suggests multiple roles for BTK in mononuclear cells of the innate immune system, especially in dendritic cells and macrophages. For example, BTK has been shown to function in Toll-like receptor-mediated recognition of infectious agents, cellular maturation and recruitment processes, and Fc receptor signaling. Most recently, BTK was additionally identified as a direct regulator of a key innate inflammatory machinery, the NLRP3 inflammasome. BTK has thus attracted interest not only for gaining a more thorough basic understanding of the human innate immune system but also as a target to therapeutically modulate innate immunity. We here review the latest developments on the role of BTK in mononuclear innate immune cells in mouse versus man, with specific emphasis on the sensing of infectious agents and the induction of inflammation. Therapeutic implications for modulating innate immunity and critical open questions are also discussed.
Highlights
Since the first description of X-linked agammaglobulinemia (XLA, OMIM entry 300300) [1] and the identification of Bruton’s tyrosine kinase (BTK) as its genetic cause [2], BTK has been widely characterized as a critical mediator of B cell receptor (BCR) signaling and adaptive immunity [3]
Totaling a molecular weight of approximately 77 kDa, BTK contains an N-terminal Pleckstrin homology domain that binds membrane phosphatidylinositol [3,4,5]trisphosphate (PIP3), and Tec homology, Src homology (SH) 3, and SH2 domains involved in BTK in Innate Immunity protein-protein interactions
Y551 is phosphorylated by the kinases Syk or Lyn during BCR signaling and promotes the catalytic activity of BTK and subsequent Y223 autophosphorylation
Summary
Since the first description of X-linked agammaglobulinemia (XLA, OMIM entry 300300) [1] and the identification of Bruton’s tyrosine kinase (BTK) as its genetic cause [2], BTK has been widely characterized as a critical mediator of B cell receptor (BCR) signaling and adaptive immunity [3]. Innate immune contributions for BTK in in vivo infection models with Btk gene knockout or Xid mice have to be interpreted with care (see below), a role for BTK/Btk in the sensing of multiple microbes has been reported: Sensing and antimicrobial responses to Listeria monocytogenes [9], Staphylo coccus aureus [10], dengue virus [11], and Aspergillus fumigatus [12] were shown to depend on BTK This effect may in part be due to BTK’s involvement in the sensing of microbes via multiple Toll-like receptors (TLRs)—TLR2 [13, 14], TLR3 [11], TLR4 [14, 15], TLR7/8 [14, 16, 17], and TLR9 [9, 17, 18] on human and mouse macrophages and dendritic cells (DC). Phosphorylation and apoptosis-related genes was observed in XLA patients [24] In contrast to these proimmune innate functions of BTK, the kinase was shown to negatively regulate TLR-induced cytokine release from primary human innate immune cells [25]. The observed link with caspase-11 [33] may indicate an additional role for BTK in the non-canonical NLRP3 inflammasome that depends on caspase-11 in mice and caspase-4/-5 in humans for intracellular LPS sensing [57]—a notion intriguing for further study
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