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.

Eosinophilic granulocytes are innate effector cells that are important in immune responses against helminth parasitic infections and contribute towards the pathology associated with allergic inflammatory conditions, including allergic rhinitis and asthma. Their recruitment to inflammatory sites occurs in response to chemotactic and activation signals, such as eotaxin and interleukin-5, and is a tightly controlled process. However, the mechanisms that counterbalance these positive chemoattractive processes, thereby preventing excessive eosinophil infiltration, have received little attention. Here, we show that, lactoferrin (LTF), a pleiotropic 80-kDa glycoprotein with iron-binding properties, acts as a powerful inhibitor of eosinophil migration. Irrespective of its source (milk or neutrophil derived), LTF inhibits eotaxin-stimulated eosinophil migration with no effects on eosinophil viability. Transferrin, a closely related cationic glycoprotein, failed to produce an analogous effect. Furthermore, the iron-saturation status of LTF did not influence the observed inhibitory effect on migration, proving that LTF exerts its effect on eosinophil chemotaxis independent of its iron-chelating activity. These results highlight LTF as one of the few molecules reported to negatively regulate eosinophil migration. Thus, through its ability to inhibit eosinophil migration, LTF has potential as an effective therapeutic in the control of eosinophil infiltration in atopic inflammatory conditions.

Background: Several genes exhibit copy number variation (CNV), including FCGR3B which encodes the IgG receptor FcγRIIIb. Engagement of Fcγ receptors by IgG complexes may contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Objectives: To investigate whether FCGR3B CNV is associated with susceptibility to IPF. Methods: In a case-control study we compared FCGR3B copy number in 142 patients with IPF and in 221 controls by real-time quantitative PCR using CD36 as gene copy control. Results: Significantly increased FCGR3B:CD36 ratio was evident in the IPF cohort compared to controls (p = 0.009). Association of FCGR3B copy number with IPF susceptibility was further confirmed by a likelihood ratio statistical approach (p = 0.003). FCGR3B copy number assignment based on FCGR3B:CD36 ratios revealed significant skewing in the distribution of FCGR3B copy number between IPF patients and controls. In the IPF cohort, there was increased frequency of >2 FCGR3B copies compared to controls (0.30 vs. 0.19; χ² = 9.27; d.f. 2; p = 0.0097). The presence of >2 FCGR3B copies was associated with higher risk of IPF (p = 0.01, OR: 1.914, 95% CI: 1.17–3.12). Conclusions: These findings support an association of FCGR3B copy number with susceptibility to IPF and propose a novel role for Fcγ receptors in IPF disease pathogenesis.