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Role of Bruton’s tyrosine kinase in macrophage apoptosis

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Abstract

Macrophages and polymorphonuclear cells (PMNs) rapidly respond to microbial and immune inflammatory stimuli and die during these responses. We have shown earlier that many macrophage and PMN functions are compromised in x-linked immunodeficient (Xid) mice with functional deficiency in Bruton’s tyrosine kinase (Btk). We now report that Btk-deficient macrophages show enhanced susceptibility to apoptotic death on exposure to the microbial and immune inflammatory signals bacterial lipopolysaccharide (LPS) and interferon-gamma (IFNγ) in vitro. In vivo in mixed bone marrow (BM) chimeras Btk deficiency leads primarily to loss of peripheral macrophage numbers without affecting BM development, suggesting a role of inflammation-induced apoptosis in regulating macrophage life span. Surprisingly, Btk deficiency does not affect macrophage apoptosis induced by DNA damage or CD95 engagement. Reactive nitrogen and oxygen species also do not contribute to inflammation-induced apoptosis, but apoptotic process involves loss of mitochondrial potential, shows increased activation of caspase 9 and enhanced loss of Bcl-xL. The lack of pro-survival signaling through the Btk-phosphotidylinositol 3-kinase-Akt pathway, and persistent MEK signaling, lead to enhanced death in Btk-deficient macrophages only downstream of inflammatory triggers. These data underline the complex role of Btk in the regulation of macrophage survival and function.

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Acknowledgments

We thank Dr Apurva Sarin, National Centre for Biological Sciences, Bangalore, India, for discussions and critical inputs in the manuscript. This work was supported in part by grants from Council for Scientific and Industrial Research, Government of India (A.K., R.G.), Indian Council of Medical Research, Government of India (B.R., S. R., V.B.), Department of Science and Technology, Government of India (V.B.) and Department of Biotechnology, Government of India (A.G., S.R., V.B.). The National Institute of Immunology and Institute of Life Sciences are supported by the Department of Biotechnology, Government of India.

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The authors declare they have no conflict of interest.

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Author notes

  1. Anupriya Khare

    Present address: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Authors and Affiliations

  1. National Institute of Immunology, Aruna Asaf Ali Road, New Delhi, 110067, India

    Anupriya Khare, Bharathi Viswanathan, Rupali Gund, Nidhi Jain, Anna George, Satyajit Rath & Vineeta Bal

  2. Institute of Life Sciences, Bhubaneswar, India

    Balachandran Ravindran

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  1. Anupriya Khare
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Correspondence to Vineeta Bal.

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Anna George, Satyajit Rath, Vineeta Bal are Joint senior investigators.

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Khare, A., Viswanathan, B., Gund, R. et al. Role of Bruton’s tyrosine kinase in macrophage apoptosis. Apoptosis 16, 334–346 (2011). https://doi.org/10.1007/s10495-010-0569-6

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