title: Role of Bruton's tyrosine kinase in macrophage apoptosis.
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.
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Road, New Delhi, India.
authors.forename: Anupriya
authors.initials: A
authors.lastname: Khare
authors.forename: Bharathi
authors.initials: B
authors.lastname: Viswanathan
authors.forename: Rupali
authors.initials: R
authors.lastname: Gund
authors.forename: Nidhi
authors.initials: N
authors.lastname: Jain
authors.forename: Balachandran
authors.initials: B
authors.lastname: Ravindran
authors.forename: Anna
authors.initials: A
authors.lastname: George
authors.forename: Satyajit
authors.initials: S
authors.lastname: Rath
authors.forename: Vineeta
authors.initials: V
authors.lastname: Bal
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D053222:Fas Ligand Protein / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000378:metabolism*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D008070:Lipopolysaccharides; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D051020:bcl-X Protein; D019014:fas Receptor; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases