Neutrophil cannibalism triggers transforming growth factor β1 production and self regulation of neutrophil inflammatory function in monosodium urate monohydrate crystal–induced inflammation in mice
- 25 February 2013
- journal article
- Published by Wiley in Arthritis & Rheumatism
- Vol. 65 (3), 815-823
- https://doi.org/10.1002/art.37822
Abstract
Objective To identify macrophage‐independent sources of transforming growth factor β1 (TGFβ1) production during monosodium urate monohydrate (MSU) crystal–induced inflammation and to determine how TGFβ1 alters MSU crystal–recruited neutrophil functions. Methods C57BL/6J mice were injected intraperitoneally with MSU crystals with or without TGFβ1‐neutralizing antibody. MSU crystal–recruited peritoneal and blood neutrophils were purified and cultured ex vivo. Peritoneal neutrophils were treated with the caspase inhibitor Q‐VD‐OPh, anti‐TGFβ1 antibody, or fluorochrome‐labeled apoptotic neutrophils. Neutrophils were analyzed for expression of annexin V, caspase 3, and TGFβ1 by flow cytometry or fluorescence microscopy, for superoxide production using the redox‐sensitive dye water‐soluble tetrazolium 1, and for TGFβ1 and interleukin‐1β (IL‐1β) production by enzyme‐linked immunosorbent assay. Results Eighteen hours after MSU crystal administration in vivo, TGFβ1 levels were elevated in peritoneal lavage fluids, and a significant number of peritoneal neutrophils were TGFβ1+. Purified blood or peritoneal neutrophils cultured ex vivo showed TGFβ1+ neutrophils coexpressing the apoptosis marker caspase 3 and increased TGFβ1 production, both of which dropped following inhibition of apoptosis. Live neutrophils that had phagocytosed apoptotic neutrophils showed greatest TGFβ1 expression. Superoxide production by purified MSU crystal–recruited neutrophils ex vivo was enhanced by anti‐TGFβ1 antibody treatment. Neutrophils purified from the peritoneum of MSU crystal–challenged mice treated with anti‐TGFβ1 antibody produced elevated levels of superoxide, but neutrophil IL‐1β production was unaffected. Conclusion Neutrophil cannibalism and TGFβ1 production have the potential to make a significant contribution to the controlled resolution of neutrophil‐driven inflammatory diseases such as gout.Keywords
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