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

Alexander P De Porto,Zhe Liu,Onno J De Boer,Alex F De Vos,Regina De Beer,Tom Van Der Poll,Joris J T H Roelofs,Joke M M Den Haan,Sandrine Florquin,Rudi W Hendriks,Cornelis Van ‘T Veer

doi:10.3389/fimmu.2021.723967

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 in vivo. Previous studies have indicated that lack of (natural) antibodies is paramount for impaired host defense against Streptococcus (S.) pneumoniae 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-Btkfl/Y mice was unaltered despite a reduced capacity of Btk-deficient alveolar macrophages to respond to pneumococci. Mrp8cre-Btkfl/Y mice with a neutrophil specific paucity in Btk expression, however, demonstrated impaired antibacterial defense. Neutrophils of Mrp8cre-Btkfl/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 ex vivo. 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 S. pneumoniae in vivo.

Highlights

Bruton’s tyrosine kinase (Btk) is a versatile signaling protein belonging to the Tyrosine kinase Expressed in hepatocellular Carcinoma (TEC) family and is expressed in the hematopoietic lineage, except in T cells and plasma cells [1,2,3]
The results of our study reveal that natural antibodies provide partial protection to pneumosepsis evoked by S. pneumoniae and that Btk in myeloid cells, in neutrophils, is required for host defense against this pathogen
In Cd19-Btk+ mice, Btk protein was detected in B cells at slightly higher level as compared to wild type (WT) mice [as reported [26]], but not in alveolar macrophages, lung dendritic cells, neutrophils or monocytes (Figure S3A)

Summary

Introduction

Bruton’s tyrosine kinase (Btk) is a versatile signaling protein belonging to the Tyrosine kinase Expressed in hepatocellular Carcinoma (TEC) family and is expressed in the hematopoietic lineage, except in T cells and plasma cells [1,2,3]. Treatment with intravenous immunoglobulins (IVIG) has significantly improved the prognosis of patients with XLA [13] which has led to the dogma that the role of Btk in myeloid cells is insignificant. This dogma was supported by the finding that X-linked immune deficiency (Xid) mice, which carry a mutation in the Btk gene leading to defective Btk signaling, were able to completely clear intravenously administered S. pneumoniae preincubated with natural antibodies against pneumococcal cell wall components such as phosphocholine [10, 14]

Methods

Results

Conclusion