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

被引：10

作者：

de Porto, Alexander P. ^{[1
,2
]}

Liu, Zhe ^{[1
,2
]}

de Beer, Regina ^{[1
,2
]}

Florquin, Sandrine ^{[3
]}

Roelofs, Joris J. T. H. ^{[3
]}

de Boer, Onno J. ^{[3
]}

den Haan, Joke M. M. ^{[4
]}

Hendriks, Rudi W. ^{[5
]}

van 't Veer, Cornelis ^{[1
,2
]}

van der Poll, Tom ^{[1
,2
,6
]}

de Vos, Alex F. ^{[1
,2
]}

机构：

[1] Univ Amsterdam, Amsterdam Univ Med Ctr UMC, Acad Med Ctr, Ctr Expt & Mol Med CEMM, Amsterdam, Netherlands

[2] Amsterdam Univ Med Ctr UMC, Amsterdam Infect & Immun Inst AI&II, Amsterdam, Netherlands

[3] Univ Amsterdam, Amsterdam Univ Med Ctr UMC, Acad Med Ctr, Dept Pathol, Amsterdam, Netherlands

[4] Vrile Univ Amsterdam, Amsterdam Univ Med Ctr UMC, Dept Mol Cell Biol & Immunol, Amsterdam, Netherlands

[5] Univ Med Ctr, Erasmus Med Ctr Rotterdam, Dept Pulm Med, Rotterdam, Netherlands

[6] Univ Amsterdam, Amsterdam Univ Med Ctr UMC, Acad Med Ctr, Div Infect Dis, Amsterdam, Netherlands

来源：

FRONTIERS IN IMMUNOLOGY | 2021年 / 12卷

关键词：

BTK; Bruton's tyrosine kinase; X-linked immunodeficiency; natural antibodies; Streptococcus pneumoniae; pneumonia; sepsis; myeloid cells; mice; X-LINKED AGAMMAGLOBULINEMIA; HOST-DEFENSE; STREPTOCOCCUS-PNEUMONIAE; NEUTROPHIL RECRUITMENT; ALVEOLAR MACROPHAGES; INTEGRIN ACTIVATION; TRANSGENIC MICE; BTK; EXPRESSION; DEFICIENCY;

D O I：

10.3389/fimmu.2021.723967

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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-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 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.

引用

页数：15

共 78 条

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