Apoptotic Cells Ameliorate Chronic Intestinal Inflammation by Enhancing Regulatory B-cell Function.

[severe combined immunodeficiency]

: 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 H 2 O 2 -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 .