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Myeloid Src family kinases (SFKs) p59\/61hck (Hck), p58c-fgr (Fgr), and p53\/56lyn (Lyn) are known to control integrin \u03b22 signal transduction and Fc\u03b3R-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\u2212\/\u2212fgr\u2212\/\u2212lyn\u2212\/\u2212) during pneumococcal meningitis. As a result, the hck\u2212\/\u2212fgr\u2212\/\u2212lyn\u2212\/\u2212 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\u2212\/\u2212fgr\u2212\/\u2212lyn\u2212\/\u2212 neutrophils, phosphorylation of p40phox 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 \u03b22-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.<\/jats:p>","DOI":"10.1189\/jlb.0208118","type":"journal-article","created":{"date-parts":[[2008,7,15]],"date-time":"2008-07-15T01:07:28Z","timestamp":1216084048000},"page":"1141-1150","source":"Crossref","is-referenced-by-count":21,"title":["Myeloid Src kinases regulate phagocytosis and oxidative burst in pneumococcal meningitis by activating NADPH oxidase"],"prefix":"10.1093","volume":"84","author":[{"given":"Robert","family":"Paul","sequence":"first","affiliation":[{"name":"Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University , Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Obermaier","sequence":"additional","affiliation":[{"name":"Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University , Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Van Ziffle","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of California , San Francisco, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Angele","sequence":"additional","affiliation":[{"name":"Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University , Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Walter","family":"Pfister","sequence":"additional","affiliation":[{"name":"Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University , Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clifford A","family":"Lowell","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University of California , San Francisco, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Koedel","sequence":"additional","affiliation":[{"name":"Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University , Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2008,7,14]]},"reference":[{"key":"2023032712385458400_","doi-asserted-by":"crossref","first-page":"L129","DOI":"10.1152\/ajplung.00261.2005","article-title":"Src protein tyrosine kinase family and acute inflammatory responses","volume":"291","author":"Okutani","year":"2006","journal-title":"Am. 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