Lactoferrin-induced myeloid-derived suppressor cell therapy attenuates pathologic inflammatory conditions in newborn mice
Yufeng Liu, … , Dmitry I. Gabrilovich, Jie Zhou
Yufeng Liu, … , Dmitry I. Gabrilovich, Jie Zhou
Published September 4, 2019
Citation Information: J Clin Invest. 2019;129(10):4261-4275. https://doi.org/10.1172/JCI128164.
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Research Article Immunology Inflammation

Lactoferrin-induced myeloid-derived suppressor cell therapy attenuates pathologic inflammatory conditions in newborn mice

Abstract

Inflammation plays a critical role in the development of severe neonatal morbidities. Myeloid-derived suppressor cells (MDSCs) were recently implicated in the regulation of immune responses in newborns. Here, we report that the presence of MDSCs and their functional activity in infants are closely associated with the maturity of newborns and the presence of lactoferrin (LF) in serum. Low amounts of MDSCs at birth predicted the development of severe pathology in preterm infants — necrotizing enterocolitis (NEC). In vitro treatment of newborn neutrophils and monocytes with LF converted these cells to MDSCs via the LRP2 receptor and activation of the NF-κB transcription factor. Decrease in the expression of LRP2 was responsible for the loss of sensitivity of adult myeloid cells to LF. LF-induced MDSCs (LF-MDSCs) were effective in the treatment of newborn mice with NEC, acting by blocking inflammation, resulting in increased survival. LF-MDSCs were more effective than treatment with LF protein alone. In addition to affecting NEC, LF-MDSCs demonstrated potent ability to control ovalbumin-induced (OVA-induced) lung inflammation, dextran sulfate sodium–induced (DSS-induced) colitis, and concanavalin A–induced (ConA-induced) hepatitis. These results suggest that cell therapy with LF-MDSCs may provide potent therapeutic benefits in infants with various pathological conditions associated with dysregulated inflammation.

Authors

Yufeng Liu, Michela Perego, Qiang Xiao, Yumei He, Shuyu Fu, Juan He, Wangkai Liu, Xing Li, Yanlai Tang, Xiaoyu Li, Weiming Yuan, Wei Zhou, Fan Wu, Chunhong Jia, Qiliang Cui, George S. Worthen, Erik A. Jensen, Dmitry I. Gabrilovich, Jie Zhou

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Figure 2

LF converts PMN and MON to MDSCs.

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LF converts PMN and MON to MDSCs. (A) BM cells from 2-week-old mice were...
(A) BM cells from 2-week-old mice were treated with LF or vehicle (PBS) in the presence of GM-CSF for 2 days. Typical example of flow cytometry (left), absolute numbers, and proportion of PMN and MON (right) (n = 6). (B) Suppressive activity of LF-induced PMN-MDSCs against proliferation of OT-I–derived CD8+ T cells stimulated with cognate peptide (n = 6). Nonstimulated T cells (No-stim) and stimulated T cells without PMN (No-PMN) were used as controls. (C) Absolute numbers of CD11b+HLA-DR–/lo cells in PBS- or LF-treated CB mononuclear cells for 2 days (n = 6). (D) Suppression of LF-induced CD11b+HLA-DR–/lo cells from CB mononuclear cells against T cells stimulated with CD3/CD28 antibodies. T cell proliferation was measured in triplicate by CFSE dilution (n = 6). (E) PGE2 and NO in myeloid cells from PBS- or LF-treated CB mononuclear cells (n = 6). (F) Absolute numbers of myeloid cells in PBS- or LF-treated preterm infant–derived CB mononuclear cells for 2 days (n = 6). (G) CD11b+HLA-DR–/lo were sorted from PBS- or LF-treated preterm infant CB mononuclear cells, followed by incubation with T cells stimulated with CD3/CD28 antibodies. T cell proliferation was measured in triplicate by CFSE labeling (n = 6). In all plots, the results of individual experiments and mean ± SD are shown. P values were calculated using 2-sided Student’s t tests (A and C–G) or 1-way ANOVA followed by Tukey-Kramer multiple-comparisons test (B). *P < 0.05; **P < 0.01; ***P < 0.001.