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 4

LF regulates MDSC function via NF-κB transcription factor.

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LF regulates MDSC function via NF-κB transcription factor. (A) Western b...
(A) Western blot of p65 in cytoplasm (Cyt) and nuclei (Nuc) in MDSCs from newborn mouse BM cells treated with LF and/or NF-κB inhibitor (JSH23, 2.5 μM). Control cells were treated with PBS. Typical example of 3 performed experiments is shown. (B) Typical example of staining (on the left) and absolute numbers of PMN-MDSCs and M-MDSCs (right) from mouse BM cells treated with LF and/or JSH23 (n = 6). (C) Suppressive activity of PMN-MDSCs (n = 6). T cell proliferation of OT-I CD8+ T cells stimulated with SIINFEKL was measured in triplicate by CFSE staining. Mean ± SD are shown. (D) The amount of S100A9 in PMN-MDSCs measured by ELISA. (E) The amount of PGE2 in PMN-MDSCs measured by ELISA (n = 6). (F) Absolute numbers of myeloid cells from LF-treated CB mononuclear cells in the presence or absence of JSH23 (n = 6). (G) Suppressive activity of myeloid cells from LF-treated CB cells in the presence or absence of JSH23. Effectors were CD4+ or CD8+ T cells stimulated with CD3/CD28 antibodies. Proliferation was measured in triplicate by CFSE staining. Results of individual experiments are shown (n = 4). In all plots, data represent mean ± SD. P values were calculated using 1-way ANOVA followed by Tukey-Kramer multiple-comparisons test. *P < 0.05; **P < 0.01; ***P < 0.001.