Mesenchymal Stromal Cells and Their Extracellular Vesicles Enhance the Anti-Inflammatory Phenotype of Regulatory Macrophages by Downregulating the Production of Interleukin (IL)-23 and IL-22.

Kati Hyvärinen,Matti Korhonen,Hanna Ruhanen,Vita Skirdenko,Reijo Käkelä,Petri Lehenkari,Saara Laitinen,Erja Kerkelä,Minna Holopainen

doi:10.3389/fimmu.2018.00771

Abstract

Resolution-phase macrophage population orchestrates active dampening of the inflammation by secreting anti-inflammatory and proresolving products including interleukin (IL)-10 and lipid mediators (LMs). We investigated the effects of both human bone marrow-derived mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) on mature human regulatory macrophages (Mregs). The cytokines and LMs were determined from cell culture media of Mregs cultivated with MSCs and MSC-EVs. In addition, the alterations in the expression of cell surface markers and the phagocytic ability of Mregs were investigated. Our novel findings indicate that both MSC coculture and MSC-EVs downregulated the production of IL-23 and IL-22 enhancing the anti-inflammatory phenotype of Mregs and amplifying proresolving properties. The levels of prostaglandin E2 (PGE2) were substantially upregulated in MSC coculture media, which may endorse proresolving LM class switching. In addition, our results manifest, for the first time, that MSC-EVs mediate the Mreg phenotype change via PGE2. These data suggest that both human MSC and MSC-EVs may potentiate tolerance-promoting proresolving phenotype of human Mregs.

Highlights

Inflammation is a crucial component of host tissue response, and controlling its initiation, progress, resolution, and post-resolution phases is essential for recovering tissue homeostasis
We focused on interplay in resolution and investigated the effects of human mesenchymal stromal cells (MSCs) coculture and MSC-derived extracellular vesicles (MSC-extracellular vesicles (EVs)) on the human Mreg population
We observed that both MSC coculture and MSC-EVs enhanced the anti-inflammatory phenotype of Mreg by downregulating the production of IL-23 and IL-22

Summary

Introduction

Inflammation is a crucial component of host tissue response, and controlling its initiation, progress, resolution, and post-resolution phases is essential for recovering tissue homeostasis. The overlapping stages of the cascade are moderated by macrophages, which are highly versatile and dynamic cells responding to various microenvironmental stimuli [1, 2]. Macrophages exist as a heterogeneous population and display a spectrum of phenotypes both in vivo and in vitro depending on the provided signals. Conventional terms for two paradigmatic populations include classically activated “host defense” M1 and alternatively activated “wound-healing” M2. Additional concepts of “regulatory macrophages” or “Mregs” have emerged within the last decade [3,4,5,6].

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Conclusion