Complement-induced impairment of innate immunity during sepsis.
This study defines the molecular basis for defects in innate immunity involving neutrophils during cecal ligation/puncture (CLP)-induced sepsis in rats. Blood neutrophils from CLP rats demonstrated defective phagocytosis and defective assembly of NADPH oxidase, the latter being due to the inability of p47(phox) to translocate from the cytosol to the cell membrane of neutrophils after cell stimulation by phorbol ester (PMA). The appearance of these defects was prevented by in vivo blockade of C5a in CLP rats. In vitro exposure of neutrophils to C5a led to reduced surface expression of C5aR and defective assembly of NADPH oxidase, as defined by failure in phosphorylation of p47(phox) and its translocation to the cell membrane, together with failure in phosphorylation of p42/p44 mitogen-activated protein kinases. These data identify a molecular basis for defective innate immunity involving neutrophils during sepsis.
Huber-Lang
Markus S
MS
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Younkin
Ellen M
EM
Sarma
J Vidya
JV
McGuire
Stephanie R
SR
Lu
Kristina T
KT
Guo
Ren Feng
RF
Padgaonkar
Vaishalee A
VA
Curnutte
John T
JT
Erickson
Richard
R
Ward
Peter A
PA
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D002432:Cecum; D015936:Complement C5a / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007106:Immune Sera / Q000008:administration & dosage; D007113:Immunity, Innate; D007116:Immunization, Passive; D008026:Ligation; D048369:MAP Kinase Kinase 1; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D010585:Phagocyte Bactericidal Dysfunction / Q000276:immunology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011677:Punctures; D051381:Rats; D020318:Rats, Long-Evans; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000032:analysis / Q000037:antagonists & inhibitors; D016897:Respiratory Burst / Q000276:immunology*; D018805:Sepsis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology
D015703:Antigens, CD; D007106:Immune Sera; D010750:Phosphoproteins; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D015936:Complement C5a; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate