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Myeloid Src kinases regulate phagocytosis and oxidative burst in pneumococcal meningitis by activating NADPH oxidase
Author(s) -
Paul Robert,
Obermaier Bianca,
Van Ziffle Jessica,
Angele Barbara,
Pfister HansWalter,
Lowell Clifford A.,
Koedel Uwe
Publication year - 2008
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0208118
Subject(s) - lyn , nadph oxidase , biology , phagocytosis , immunology , respiratory burst , streptococcus pneumoniae , myeloid , superoxide , innate immune system , signal transduction , microbiology and biotechnology , immune system , proto oncogene tyrosine protein kinase src , reactive oxygen species , biochemistry , antibiotics , enzyme
Myeloid cells, including neutrophils and macrophages, play important roles in innate immune defense against acute bacterial infections. Myeloid Src family kinases (SFKs) p59/61 hck (Hck), p58 c‐fgr (Fgr), and p53/56 lyn (Lyn) are known to control integrin β 2 signal transduction and FcγR‐mediated phagocytosis in leukocytes. In this study, we show that leukocyte recruitment into the cerebrospinal fluid space and bacterial clearance is hampered in mice deficient in all three myeloid SFKs ( hck −/− fgr −/− lyn −/− ) during pneumococcal meningitis. As a result, the hck −/− fgr −/− lyn −/− mice developed increased intracranial pressure and a worse clinical outcome (increased neurologic deficits and mortality) compared with wild‐type mice. Impaired bacterial killing was associated with a lack of phagocytosis and superoxide production in triple knockout neutrophils. Moreover, in hck −/− fgr −/− lyn −/− neutrophils, phosphorylation of p40 phox was absent in response to pneumococcal stimulation, indicating a defect in NAPDH oxidase activation. Mice lacking the complement receptor 3 (CR3; CD11b/CD18), which belongs to the β 2 ‐integrin family, also displayed impaired host defense against pneumococci, along with defective neutrophil superoxide production, but cerebrospinal fluid pleocytosis was normal. Cerebral expression of cytokines and chemokines was not decreased in both mouse strains, indicating that CR3 and myeloid SFKs are dispensable for the production of inflammatory mediators. Thus, our study demonstrates the pivotal role of myeloid SFKs and CR3 in mounting an effective defense against CNS infection with Streptococcus pneumonia by regulating phagocytosis and NADPH oxidase‐dependent superoxide production. These data support the role of SFKs as critical mediators of CR3 signal transduction in host defense.