Bruton’s Tyrosine Kinase-Mediated Signaling in Myeloid Cells Is Required for Protective Innate Immunity During Pneumococcal Pneumonia

Abstract

Bruton's tyrosine kinase (Btk) is a cytoplasmic kinase expressed in B cells and myeloid cells. It is essential for B cell development and natural antibody-mediated host defense against bacteria in humans and mice, but little is known about the role of Btk in innate host defense <i>in vivo</i>. Previous studies have indicated that lack of (natural) antibodies is paramount for impaired host defense against <i>Streptococcus (S.) pneumoniae</i> in patients and mice with a deficiency in functional Btk. In the present study, we re-examined the role of Btk in B cells and myeloid cells during pneumococcal pneumonia and sepsis in mice. The antibacterial defense of Btk^-/- mice was severely impaired during pneumococcal pneumosepsis and restoration of natural antibody production in Btk^-/- mice by transgenic expression of Btk specifically in B cells did not suffice to protect against infection. Btk^-/- mice with reinforced Btk expression in MhcII⁺ cells, including B cells, dendritic cells and macrophages, showed improved antibacterial defense as compared to Btk^-/- mice. Bacterial outgrowth in Lysmcre-Btk^fl/Y mice was unaltered despite a reduced capacity of Btk-deficient alveolar macrophages to respond to pneumococci. Mrp8cre-Btk^fl/Y mice with a neutrophil specific paucity in Btk expression, however, demonstrated impaired antibacterial defense. Neutrophils of Mrp8cre-Btk^fl/Y mice displayed reduced release of granule content after pulmonary installation of lipoteichoic acid, a gram-positive bacterial cell wall component relevant for pneumococci. Moreover, Btk deficient neutrophils showed impaired degranulation and phagocytosis upon incubation with pneumococci <i>ex vivo</i>. Taken together, the results of our study indicate that besides regulating B cell-mediated immunity, Btk is critical for regulation of myeloid cell-mediated, and particularly neutrophil-mediated, innate host defense against <i>S. pneumoniae in vivo</i>.