title: Apoptotic cells ameliorate chronic intestinal inflammation by enhancing regulatory B-cell function.
abstract: Apoptosis is a programmed physiological death of unwanted cells, and handling of apoptotic cells (ACs) is thought to have profound effects on immune-mediated disorders. However, there is scant information regarding the role of ACs in intestinal inflammation, in which immune homeostasis is a major concern. To investigate this, we injected ACs into a severe combined immunodeficiency adoptive transfer model of chronic colitis in the presence and absence of cotransferred whole B or regulatory B cell (Breg)-depleted B cells. We also injected syngeneic ACs into AKR/N mice as a control and into milk fat globule-epidermal growth factor 8 knockout mice deficient of phagocytic function. Chronic colitis severity was significantly reduced in the AC as opposed to the phosphate-buffered saline group with cotransferred whole B cells. The AC-mediated effect was lost in the absence of B cells or presence of Breg-depleted B cells. In addition, ACs induced splenic B cells to secrete significantly increased levels of interleukin 10 in AKR/N mice but not milk fat globule-epidermal growth factor 8 knockout mice. Apoptotic leukocytes were induced by reactive oxygen species during granulocyte/monocyte apheresis therapy in rabbits and H2O2-induced apoptotic neutrophils ameliorated mice colitis. Our results indicate that ACs are protective only in the presence of B cells and phagocytosis of ACs induced interleukin 10 producing Bregs. Thus, the ameliorative effect seen in this study might have been exerted by AC-induced Bregs through increased production of the immunosuppressive cytokine interleukin 10, whereas an AC-mediated effect may contribute to the anti-inflammatory effect of granulocyte/monocyte apheresis as a novel therapeutic mechanism for inflammatory bowel disease.
authors.affiliation: *Department of Internal Medicine II, School of Medicine, Shimane University, Izumo, Japan; †Department of Gastrointestinal Endoscopy, Shimane University Hospital, Izumo, Japan; and ‡Research Division, JIMRO Co. Ltd., Takasaki, Japan.
authors.forename: Md Mesbah Uddin
authors.initials: MM
authors.lastname: Ansary
authors.forename: Shunji
authors.initials: S
authors.lastname: Ishihara
authors.forename: Akihiko
authors.initials: A
authors.lastname: Oka
authors.forename: Ryusaku
authors.initials: R
authors.lastname: Kusunoki
authors.forename: Naoki
authors.initials: N
authors.lastname: Oshima
authors.forename: Takafumi
authors.initials: T
authors.lastname: Yuki
authors.forename: Kousaku
authors.initials: K
authors.lastname: Kawashima
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Maegawa
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Kashiwagi
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kinoshita
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D060151:B-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger; D017382:Reactive Oxygen Species