Arthritis 2013 July-3


Neutrophil Cannibalism Triggers Transforming Growth Factor b1 Production and Self Regulation of Neutrophil Inflammatory Function in Monosodium Urate Monohydrate Crystal-Induced Inflammation in Mice.

Arthritis & Rheumatism.2013 March;65(3):815-823. DOI 10.1002/art.37822

Stefanie Steiger and Jacquie L. Harper.

Malaghan Institute of Medical Research, PO Box 7060, Wellington 6242, New Zealand.

PMID: 23280587


Objective. To identify macrophage-independent sources of transforming growth factor β1 (TGFb1) production during monosodium urate monohydrate (MSU) crystal-induced inflammation and to determine how TGFb1 alters MSU crystal-recruited neutrophil functions.

Methods. C57BL/6J mice were injected intraperitoneally with MSU crystals with or without TGFb1-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-TGFb1 antibody, or fluorochrome-labeled apoptotic neutrophils. Neutrophils were analyzed for expression of annexin V, caspase 3, and TGFb1 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-1b) production by enzyme-linked immunosorbent assay

Results. Eighteen hours after MSU crystal administration in vivo, TGFb1 levels were elevated in peritoneal lavage fluids, and a significant number of peritoneal neutrophils were TGFb1+. Purified blood or peritoneal neutrophils cultured ex vivo showed TGFb1+ neutrophils coexpressing the apoptosis marker caspase 3 and increased TGFb1 production, both of which dropped following inhibition of apoptosis. Live neutrophils that had phagocytosed apoptotic neutrophils showed greatest TGFb1 expression. Superoxide production by purified MSU crystal-recruited neutrophils ex vivo was enhanced by anti-TGFb1 antibody treatment. Neutrophils purified from the peritoneum of MSU crystal-challenged mice treated with anti-TGFb1 antibody produced elevated levels of superoxide, but neutrophil IL-1b production was unaffected.

Conclusion. Neutrophil cannibalism and TGFb1 production have the potential to make a significant contribution to the controlled resolution of neutrophil-driven inflammatory diseases such as gout.


The work presented in this publication shows that the process of neutrophil cannibalism triggers the production of TGFb1 by neutrophils, which in turn suppresses neutrophil respiratory burst and acts as a nonessential moderator of IL-1b production. In this way neutrophils have the capacity to actively drive the spontaneous resolution of inflammation in gout and other neutrophilic inflammatory diseases.

Stefanie Steiger

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