IL-10 administration reduces PGE-2 levels and promotes CR3-mediated clearance of Escherichia coli K1 by phagocytes in meningitis.
Ineffectiveness of antibiotics in treating neonatal Escherichia coli K1 meningitis and the emergence of antibiotic-resistant strains evidently warrants new prevention strategies. We observed that administration of interleukin (IL)-10 during high-grade bacteremia clears antibiotic-sensitive and -resistant E. coli from blood of infected mice. Micro-CT studies of brains from infected animals displayed gross morphological changes similar to those observed in infected human neonates. In mice, IL-10, but not antibiotic or anti-TNF antibody treatment prevented brain damage caused by E. coli. IL-10 administration elevated CR3 expression in neutrophils and macrophages of infected mice, whereas infected and untreated mice displayed increased expression of FcgammaRI and TLR2. Neutrophils or macrophages pretreated with IL-10 ex vivo exhibited a significantly greater microbicidal activity against E. coli compared with cells isolated from wild-type or IL-10-/- mice. The protective effect of IL-10 was abrogated when CR3 was knocked-down in vivo by siRNA. The increased expression of CR3 in phagocytes was caused by inhibition of prostaglandin E-2 (PGE-2) levels, which were significantly increased in neutrophils and macrophages upon E. coli infection. These findings describe a novel modality of IL-10-mediated E. coli clearance by diverting the entry of bacteria via CR3 and preventing PGE-2 formation in neonatal meningitis.
Mittal
Rahul
R
Division of Infectious Diseases, Department of Pathology, Childrens Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA.
Gonzalez-Gomez
Ignacio
I
Panigrahy
Ashok
A
Goth
Kerstin
K
Bonnet
Richard
R
Prasadarao
Nemani V
NV
D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology; D016470:Bacteremia / Q000150:complications / Q000276:immunology / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D015232:Dinoprostone / Q000378:metabolism*; D004926:Escherichia coli / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D016753:Interleukin-10 / Q000008:administration & dosage* / Q000172:deficiency / Q000494:pharmacology*; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D020814:Meningitis, Escherichia coli / Q000150:complications / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D010586:Phagocytes / Q000187:drug effects / Q000382:microbiology*; D010587:Phagocytosis / Q000187:drug effects; D016019:Survival Analysis; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
D000906:Antibodies; D016177:Macrophage-1 Antigen; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015232:Dinoprostone