title: Myeloid Src kinases regulate phagocytosis and oxidative burst in pneumococcal meningitis by activating NADPH oxidase.
abstract: 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 beta(2) signal transduction and FcgammaR-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 beta(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.
authors.affiliation: Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University, Marchioninistr. 15, D-81377 Munich, Germany. robert.paul@med.uni-muenchen.de
authors.forename: Robert
authors.initials: R
authors.lastname: Paul
authors.forename: Bianca
authors.initials: B
authors.lastname: Obermaier
authors.forename: Jessica
authors.initials: J
authors.lastname: Van Ziffle
authors.forename: Barbara
authors.initials: B
authors.lastname: Angele
authors.forename: Hans-Walter
authors.initials: HW
authors.lastname: Pfister
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: Uwe
authors.initials: U
authors.lastname: Koedel
mesh_terms: D000818:Animals; D015923:Complement C1r / Q000235:genetics; D003176:Complement C3 / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006801:Humans; D007700:Kinetics; D008586:Meningitis, Pneumococcal / Q000201:enzymology* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000201:enzymology / Q000502:physiology*; D019255:NADPH Oxidases / Q000378:metabolism*; D010587:Phagocytosis; D011518:Proto-Oncogene Proteins / Q000172:deficiency; D051572:Proto-Oncogene Proteins c-hck / Q000172:deficiency; D016897:Respiratory Burst / Q000502:physiology*; D019061:src-Family Kinases / Q000172:deficiency / Q000502:physiology*
chemical_list: D003176:Complement C3; D016207:Cytokines; D011518:Proto-Oncogene Proteins; D019255:NADPH Oxidases; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck; C060902:lyn protein-tyrosine kinase; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases; D015923:Complement C1r