Bruton’s Tyrosine Kinase: An Emerging Key Player in Innate Immunity

Weber, Alexander N.R.; Bittner, Zsofia; Liu, Xiao; Dang, Truong‐Minh; Radsak, Markus P.; Brunner, Cornelia

doi:10.3389/fimmu.2017.01454

Cited by 223 publications

(201 citation statements)

References 60 publications

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“…Specifically, BTK is important for B cell survival due to its role in downstream BCR signaling, and therefore its inhibition decreases autoantibody production and modulates B cell cytokine release and antigen presentation [8]. BTK inhibition would also interfere with TLR and Fc receptor mediated signaling, thereby limiting the damage induced by autoantibody deposition within tissues [11,18]. Thus, BTK inhibition would target both the adaptive and innate arms of the immune system involved in disease pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…BTK is also thought to be important in macrophage polarization, and has been shown to favor an M2 phenotype that could be beneficial in ameliorating disease [22]. Furthermore, BTK is relevant to the NLRP3 inflammasome pathway [11,23,24] which has been linked to LN pathogenesis [25], both in immune cells such as macrophages [11], and local resident cells such as podocytes [26–28]. Our data showed decreased expression of IL-1b with BI-BTK-1 treatment, consistent with inhibition of NLRP3 activation.…”

Section: Discussionmentioning

confidence: 99%

“…The role of BTK in BCR signaling is exemplified by the impaired B cell development and function observed in human X-linked agammaglobulinemia [9] and X-linked immunodeficiency mice that harbor specific BTK mutations [10]. BTK is also required for Fcgamma receptor signaling which mediates immune complex activation of myeloid cell types such as monocytes and macrophages[11]. Inhibition of BTK would consequently target two major cellular contributors to disease pathogenesis in LN.…”

Section: Introductionmentioning

confidence: 99%

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BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis

Chalmers

Glynn

Garcia

et al. 2018

Clinical Immunology

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Lupus nephritis is a common disease manifestation of SLE, in which immune complex deposition and macrophage activation are important contributors to disease pathogenesis. Bruton’s tyrosine kinase (BTK) plays an important role in both B cell and FcgammaR mediated myeloid cell activation. In the current study, we examined the efficacy of BI-BTK-1, a recently described irreversible BTK inhibitor, in the classical NZB×NZW F1 (NZB/W) and MRL/lpr spontaneous mouse models of SLE. NZB/W mice were randomly assigned to a treatment (0.3 mg/kg, 1 mg/kg, 3 mg/kg and 10 mg/kg) or control group and began treatment at 22 weeks of age. The experimental setup was similar in MRL/lpr mice, but with a single treated (10 mg/kg, beginning at 8–9 weeks of age) and control group. A separate experiment was performed in the MRL/lpr strain to assess the ability of BI-BTK-1 to reverse established kidney disease. Early treatment with BI-BTK-1 significantly protected NZB/W and MRL/lpr mice from the development of proteinuria, correlating with significant renal histological protection, decreased anti-DNA titers, and increased survival in both strains. BI-BTK-1 treated mice displayed a significant decrease in nephritis-associated inflammatory mediators (e.g. LCN2 and IL-6) in the kidney, combined with a significant inhibition of immune cell infiltration and accumulation. Importantly, BI-BTK-1 treatment resulted in the reversal of established kidney disease. BTK inhibition significantly reduced total B cell numbers and all B cell subsets (immature, transitional, follicular, marginal zone, and class switched) in the spleen of NZB/W mice. Overall, the significant efficacy of BIBTK-1 in ameliorating multiple pathological endpoints associated with kidney disease in two distinct murine models of spontaneous lupus nephritis provides a strong rationale for BTK inhibition as a promising treatment approach for lupus nephritis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis

Chalmers

Glynn

Garcia

et al. 2018

Clinical Immunology

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“…Btk dramatically and extensively affects all stages of B cell development, including proliferation, maturation, differentiation, apoptosis and cell migration . Recent studies have increasingly focused on the awareness of Btk roles in other innate immune cells, such as macrophages, dendritic cells (DCs) and neutrophils . Btk deficiency decreases the number of monocytes/macrophages.…”

Section: Role Of Btk In Immune Cells and Its Signalling Pathwaysmentioning

confidence: 99%

Effects of BTK signalling in pathogenic microorganism infections

Zhou

Guo

et al. 2019

J Cellular Molecular Medi

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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.

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“…Indeed, the pharmacologic intervention of BTK by ibrutinib has been approved to treat mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenstrom macroglubulinemia . BTK has also been involved in multiple roles of innate immune cells including dendritic cells, monocytes, neutrophils, and macrophages . In this context, BTK has been shown to regulate osteoclast differentiation .…”

Section: Introductionmentioning

confidence: 99%

A novel Bruton's tyrosine kinase inhibitor, acalabrutinib, suppresses osteoclast differentiation and Porphyromonas gingivalis lipopolysaccharide‐induced alveolar bone resorption

Pokhrel

Kim

et al. 2018

Journal of Periodontology

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Background Periodontitis is not only one of the most prevalent inflammatory diseases among adults, but also commonly linked to numerous systemic conditions including cardiovascular diseases, stroke, and diabetes. Although osteoclasts are responsible for the alveolar bone resorption during periodontitis pathogenesis, the development of pharmacologic strategies targeting these cells has not been vastly fruitful. Methods Bone marrow macrophages were cultured in the presence of macrophage‐colony stimulating factor (M‐CSF) and receptor activator of nuclear factor κB ligand (RANKL) to examine the direct effect of acalabrutinib on osteoclastogenesis. Ca2+ oscillation and nuclear localization of NFATc1 in osteoclast precursors were examined to determine the precise molecular mechanism. LPS‐induced alveolar bone loss model was employed for studying effect in in vivo bone resorption. Results Acalabrutinib directly inhibited RANKL and LPS‐induced in vitro osteoclast differentiation. In addition, acalabrutinib inhibited RANKL‐induced phosphorylation of mitogen‐activated protein kinases and reduced the expression of NF‐κB. The inhibitory mechanism involved suppression of Ca2+ oscillation in osteoclast precursors resulting in the decreased NFATc1 expression and nuclear localization, which is a crucial prerequisite for osteoclastogenesis. The administration of acalabrutinib significantly reduced P. gingivalis lipopolysaccharide‐induced alveolar bone erosion in mice. Conclusion These data indicate that acalabrutinib is an effective inhibitor of osteoclastogenesis both in vitro and in vivo, with a potential for a novel strategy against bone destruction by periodontitis.

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Bruton’s Tyrosine Kinase: An Emerging Key Player in Innate Immunity

Cited by 223 publications

References 60 publications

BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis

BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis

Effects of BTK signalling in pathogenic microorganism infections

A novel Bruton's tyrosine kinase inhibitor, acalabrutinib, suppresses osteoclast differentiation and Porphyromonas gingivalis lipopolysaccharide‐induced alveolar bone resorption

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