title: The mechanism underlying the appearance of late apoptotic neutrophils and subsequent TNF-α production at a late stage during Staphylococcus aureus bioparticle-induced peritoneal inflammation in inducible NO synthase-deficient mice.
abstract: During inflammation, neutrophils infiltrate into the involved site and undergo apoptosis. Early apoptotic neutrophils are then cleared by phagocytes, leading to resolution of the inflammation, whereas if late apoptotic neutrophils are accumulated for some reason, they provoke proinflammatory responses such as TNF-α production. To determine how endogenously produced nitric oxide (NO) regulates neutrophil apoptosis and the resolution of inflammation, we compared peritoneal inflammation induced by Staphylococcus aureus bioparticles in wild type mice with that in inducible NO synthase (iNOS)-deficient ones. In this model, NO production was largely dependent on iNOS, the NO level peaking at 24 h. There were increases in the numbers of neutrophils and late apoptotic ones at 24 h in iNOS-deficient mice as compared with in wild type ones, and consequently TNF-α production at 36 h in iNOS-deficient mice. On the other hand, the administration of a NO donor to iNOS-deficient mice at 12 h decreased the numbers of neutrophils and late apoptotic ones at 24 h, and thereafter TNF-α production at 36 h. In addition, coculturing of macrophages with late apoptotic neutrophils caused TNF-α production and a NO donor inhibited the transmigration of neutrophils in a dose-dependent manner. Collectively, these results suggest a novel mechanism that endogenously produced NO suppresses neutrophil accumulation at a late stage of inflammation, thereby preventing the appearance of late apoptotic neutrophils and subsequent proinflammatory responses.
authors.affiliation: Department of Biomolecular Science, Faculty of Science, Toho University, Funabashi, Chiba, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Shibata
authors.forename: Kisaburo
authors.initials: K
authors.lastname: Nagata
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D017209:Apoptosis; D002465:Cell Movement / Q000187:drug effects; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006834:Hydrazines / Q000494:pharmacology; D007150:Immunohistochemistry; D007249:Inflammation / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010537:Peritoneum / Q000382:microbiology / Q000473:pathology; D010587:Phagocytosis / Q000276:immunology; D013203:Staphylococcal Infections / Q000150:complications* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D006834:Hydrazines; D020030:Nitric Oxide Donors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D052247:Nitric Oxide Synthase Type II