Lactoferrin-induced myeloid-derived suppressor cell therapy attenuates pathologic inflammatory conditions in newborn mice
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
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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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 5

The effect of LF on myeloid cells is mediated by the LRP2 receptor.

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The effect of LF on myeloid cells is mediated by the LRP2 receptor. (A) ...
(A) Expression of indicated LF receptors in MDSCs from 2-week-old mice measured by qRT-PCR (n = 6). (B) Expression of Lrp2 in myeloid cells from mice of different ages measured by qRT-PCR (n = 6). (C) Surface expression of Lrp2 on mouse myeloid cells measured by flow cytometry (n = 6). (D) Expression of LF receptors in myeloid cells from PB (PBMC) or CB in full-term infants measured by qRT-PCR (n = 5). (E) Expression of ITLN1 and LRP2 in myeloid cells from PB of adults (AD) and full-term, preterm, and NEC infants or CB measured by qRT-PCR (n = 5–6). (F–K) Silencing of Itln1 and Lrp2 in newborn mouse BM cells with shRNA or scramble shRNA (control) lentiviruses, followed by treatment with PBS or LF for 2 days. (F) The absolute numbers of PMN-MDSCs and M-MDSCs measured by flow cytometry (n = 4–6). (G) Suppressive activity of PMN-MDSCs. Effectors were OT-I CD8+ T cells stimulated with SIINFEKL. T cell proliferation was measured in triplicate by CFSE staining (n = 3). Upper panel shows typical example. Lower panel shows cumulative results. (H) Suppressive activity of M-MDSCs. Effectors were CD4+ or CD8+ T cells stimulated with CD3/CD28 antibodies (n = 3). Left panel shows typical example. Right panel shows cumulative results. (I) The amount of S100A9 in PMN-MDSCs measured by ELISA. (J) The amount of PGE2 in PMN-MDSCs measured by ELISA. (K) The amounts of nitrites in M-MDSCs measured by the Nitrite Assay Kit. (I–K, n = 6) Data represent individual results and mean ± SD. P values were calculated using 2-sided Student’ s t tests (F–K) or 1-way ANOVA followed by Tukey-Kramer multiple-comparisons test (A–E). *P < 0.05; **P < 0.01; ***P < 0.001.