Apoptotic human cells inhibit migration of granulocytes via release of lactoferrin
Irini Bournazou, John D. Pound, Rodger Duffin, Stylianos Bournazos, Lynsey A. Melville, Simon B. Brown, Adriano G. Rossi, Christopher D. Gregory
Irini Bournazou, John D. Pound, Rodger Duffin, Stylianos Bournazos, Lynsey A. Melville, Simon B. Brown, Adriano G. Rossi, Christopher D. Gregory
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Research Article Immunology

Apoptotic human cells inhibit migration of granulocytes via release of lactoferrin

Abstract

Apoptosis is a noninflammatory, programmed form of cell death. One mechanism underlying the non-phlogistic nature of the apoptosis program is the swift phagocytosis of the dying cells. How apoptotic cells attract mononuclear phagocytes and not granulocytes, the professional phagocytes that accumulate at sites of inflammation, has not been determined. Here, we show that apoptotic human cell lines of diverse lineages synthesize and secrete lactoferrin, a pleiotropic glycoprotein with known antiinflammatory properties. We further demonstrated that lactoferrin selectively inhibited migration of granulocytes but not mononuclear phagocytes, both in vitro and in vivo. Finally, we were able to attribute this antiinflammatory function of lactoferrin to its effects on granulocyte signaling pathways that regulate cell adhesion and motility. Together, our results identify lactoferrin as an antiinflammatory component of the apoptosis milieu and define what we believe to be a novel antiinflammatory property of lactoferrin: the ability to function as a negative regulator of granulocyte migration.

Authors

Irini Bournazou, John D. Pound, Rodger Duffin, Stylianos Bournazos, Lynsey A. Melville, Simon B. Brown, Adriano G. Rossi, Christopher D. Gregory

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Figure 7

Effect of lactoferrin on neutrophil activation status.

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Induction of apoptosis upregulates lactoferrin expression and release. (...
The expression of CD62L (A and B) and CD11b (C and D) was assessed in fMLP- (100 nM), TNF-α– (1 ng ml), or PMA-stimulated (100 nM) neutrophils (30 minutes at 37°C) that were preincubated (40 minutes at 37°C) in the presence or absence of lactoferrin (10 μg/ml). Representative flow cytometry overlays of CD62L (A) and CD11b (C) expression in control (gray) and stimulated neutrophils (lactoferrin-treated: red; untreated: blue). n = 3; *P < 0.05, **P < 0.01. Error bars indicate SEM. (E) Western blot analysis to determine levels of ERK1/2 phosphorylation. Neutrophils were incubated with lactoferrin (10 μg/ml; 40 minutes at 37°C), followed by stimulation with fMLP (100 nM) for the indicated times. Membrane was stripped and reprobed for total ERK2. Results are representative of 3 independent experiments.