Amnion Epithelial Cells Promote Lung Repair via Lipoxin A4.

Jean L Tan,Rebecca Lim,Siow T Chan,Ruth Muljadi,Euan M Wallace,Joanne C Mockler,Yan Z Tan,Sin N Lau

doi:10.5966/sctm.2016-0077

Jean L Tan, Rebecca Lim + Show 6 more

Open Access

https://doi.org/10.5966/sctm.2016-0077

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Abstract

Human amnion epithelial cells (hAECs) have been shown to possess potent immunomodulatory properties across a number of disease models. Recently, we reported that hAECs influence macrophage polarization and activity, and that this step was dependent on regulatory T cells. In this study, we aimed to assess the effects of hAEC‐derived proresolution lipoxin‐A4 (LXA4) on T‐cell, macrophage, and neutrophil phenotype and function during the acute phase of bleomycin‐induced lung injury. Using C57Bl6 mice, we administered 4 million hAECs intraperitoneally 24 hours after bleomycin challenge. Outcomes were measured at days 3, 5, and 7. hAEC administration resulted in significant changes to T‐cell, macrophage, dendritic cell, and monocyte/macrophage infiltration and phenotypes. Endogenous levels of lipoxygenases, LXA4, and the lipoxin receptor FPR2 were elevated in hAEC‐treated animals. Furthermore, we showed that the effects of hAECs on macrophage phagocytic activity and T‐cell suppression are LXA4 dependent, whereas the inhibition of neutrophil‐derived myleoperoxidase by hAECs is independent of LXA4. This study provides the first evidence that lipid‐based mediators contribute to the immunomodulatory effects of hAECs and further supports the growing body of evidence that LXA4 is proresolutionary in lung injury. This discovery of LXA4‐dependent communication between hAECs, macrophages, T cells, and neutrophils is important to the understanding of hAEC biodynamics and would be expected to inform future clinical applications. Stem Cells Translational Medicine 2017;6:1085–1095

Highlights

Idiopathic pulmonary fibrosis (IPF) is a debilitating chronic inflammatory disease that affects more than 300 million people worldwide
These findings demonstrate that human amnion epithelial cells (hAECs) treatment 24 hours after bleomycin exposure suppressed the macrophage and dendritic cell milieu during onset of inflammation
Given earlier reports that lipoxin A4 is highly expressed in placental tissues [20, 22] and plays a valuable role in resolving inflammation and fibrosis, we evaluated the role of lipoxin A4 in hAEC-mediated lung repair

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a debilitating chronic inflammatory disease that affects more than 300 million people worldwide. The disease is characterized by progressive chronic inflammation; patients usually have limited numbers of CD4+/ CD28+/CD25+/Foxp3+ regulatory T-regulatory cells and higher numbers of Th1 effector CD4+ T cells in the lung [1]. Patients with severe forms of IPF have significantly higher numbers of neutrophils, macrophages, and dendritic cells present in their bronchoalveolar lavage fluid (BALF) [2]. There is no effective treatment; lung transplantation is the only therapeutic option for end-stage disease. Studies with early administration of mesenchymal stromal cells (MSCs) after bleomycin challenge reported significant anti-inflammatory effects [10]

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