The Tec family of protein tyrosine kinases, of which Bruton's tyrosine kinase (Btk) 1 is a prototypical member, is involved in a vast array of signaling pathways in cells of hematopoietic lineage. Btk is expressed in all hematopoietic cells except T lymphocytes and natural killer cells. It is critically important for B-cell development as well as mature B-cell activation and survival. It has also been shown to be important for IgEmediated activation of mast cells resulting in allergic reactions. Btk kinase activity and tyrosine phosphorylation have both been shown to increase upon cross-linking or stimulation of the B-cell receptor, the IgE receptor (Fc⑀RII), and a number of cytokine receptors such as those for IL-3, IL-5, IL-6, and IL-10, suggesting a general role for Btk in immune regulation (1-4). Whereas the molecular mechanisms by which the B-cell receptor regulates B-cell proliferation and survival are not well understood, Btk has recently been shown to lie downstream of the B-cell receptor on the pathway regulating activation of the key pro-inflammatory transcription factor NF B (5-8). The biological importance of the signaling function has been shown by naturally occurring loss of function mutations in Btk in human X-linked agammaglobulinemia and its murine counterpart, X-linked immunodeficiency (Xid). These diseases are characterized by a block in B-cell development and defects in B-cell signaling, and in X-linked agammaglobulinemia patients, mutations in Btk are associated associated with an increased frequency of bacterial infections in all organs (9). Studies in Xid mice have also shown reduced responses to LPS stimulation, with nitric oxide (NO) production decreased, and macrophage effector functions impaired (10 -12). This, coupled with the observation that responses to T-independent antigens are impaired in Xid mice, suggests a role for Btk in innate immune responses.Toll-like receptors (TLRs) have an essential function in both innate and adaptive immunity and have evolved to recognize, with high specificity, diverse microbial pathogens (13). TLR4, as the receptor for the Gram-negative bacterial product LPS, is the prototypical member of the family (numbered TLR1-10 in humans) of type I transmembrane receptors, which are characterized by an extracellular leucine-rich repeat domain and an intracellular Toll/IL-1 receptor (TIR) domain, responsible for signaling. Ligands for other family members (except TLR10) have been identified and include bacterial flagellin and unmethylated bacterial CpG motifs for TLR5 and TLR9, respectively; double-stranded RNA for TLR3; and the antiviral compound R-848 recognizing TLR7 and TLR8. Research into how these receptors signal has identified MyD88 and IL-1-receptorassociated kinases (IRAKs) as key proximal signaling components regulating activation of the pro-inflammatory transcription factor NF B in response to LPS (reviewed in Ref. 14). Important differences in the proteins recruited to the different TLR members have also been described. Both TLR2 (the receptor for...

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.

Mouse B cells lacking NFATc1 exhibit defective proliferation, survival, isotype class switching, cytokine production, and T cell help.

Our data suggest that XLA might result in part from genetic inflammasome deficiency and that NLRP3 inflammasome-linked inflammation could potentially be targeted pharmacologically through BTK.

Inflammation is a major factor in heart disease. IκB kinase (IKK) and its downstream target NF-κB are regulators of inflammation and are activated in cardiac disorders, but their precise contributions and targets are unclear. We analyzed IKK/NF-κB function in the heart by a gain-of-function approach, generating an inducible transgenic mouse model with cardiomyocyte-specific expression of constitutively active IKK2. In adult animals, IKK2 activation led to inflammatory dilated cardiomyopathy and heart failure. Transgenic hearts showed infiltration with CD11b + cells, fibrosis, fetal reprogramming, and atrophy of myocytes with strong constitutively active IKK2 expression. Upon transgene inactivation, the disease was reversible even at an advanced stage. IKK-induced cardiomyopathy was dependent on NF-κB activation, as in vivo expression of IκBα superrepressor, an inhibitor of NF-κB, prevented the development of disease. Gene expression and proteomic analyses revealed enhanced expression of inflammatory cytokines, and an IFN type I signature with activation of the IFN-stimulated gene 15 (ISG15) pathway. In that respect, IKK-induced cardiomyopathy resembled Coxsackievirus-induced myocarditis, during which the NF-κB and ISG15 pathways were also activated. Vice versa, in cardiomyocytes lacking the regulatory subunit of IKK (IKKγ/NEMO), the induction of ISG15 was attenuated. We conclude that IKK/NF-κB activation in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure by inducing an excessive inflammatory response and myocyte atrophy.transcription factors | transgenic mice