Cutting edge: MyD88 controls phagocyte NADPH oxidase function and killing of gram-negative bacteria.
MyD88 is an adaptor protein for the TLR family of proteins that has been implicated as a critical mediator of innate immune responses to pathogen detection. In this study, we report that MyD88 plays a crucial role in killing Gram-negative bacteria by primary macrophages via influencing NADPH oxidase function. Peritoneal macrophages from MyD88-/- mice exhibited a marked inability to kill Escherichia coli (F18) or an attenuated strain of Salmonella typhimurium (sseB) in vitro. This defect in killing was due to diminished NADPH oxidase-mediated production of superoxide anion in response to bacteria by MyD88-/- phagocytes as a consequence of defective NADPH oxidase assembly. Defective oxidase assembly in MyD88-deficient macrophages resulted from impaired p38 MAPK activation and subsequent phosphorylation of p47phox. Together these data demonstrate a pivotal role for MyD88 in killing Gram-negative bacteria via modulation of NADPH oxidase activity in phagocytic cells.
Laroux
F Stephen
FS
Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Romero
Xavier
X
Wetzler
Lee
L
Engel
Pablo
P
Terhorst
Cox
C
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology*; D006090:Gram-Negative Bacteria / Q000276:immunology*; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88; D019255:NADPH Oxidases / Q000502:physiology*; D010587:Phagocytosis; D010766:Phosphorylation; D011971:Receptors, Immunologic / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases