Mesenchymal stem cells enhance NOX2-dependent reactive oxygen species production and bacterial killing in macrophages during sepsis

Razieh Rabani, Allen Volchuk, Mirjana Jerkic, Lindsay Ormesher, Linda Garces-Ramirez, Johnathan Canton, Claire Masterson, Stephane Gagnon, Kate C. Tatham, John Marshall, Sergio Grinstein, John G. Laffey, Katalin Szaszi, Gerard F. Curley

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Human mesenchymal stem/stromal cells (MSCs) have been reported to produce an M2-like, alternatively activated phenotype in macrophages. In addition, MSCs mediate effective bacterial clearance in pre-clinical sepsis models. Thus, MSCs have a paradoxical antimicrobial and anti-inflammatory response that is not understood. Here, we studied the phenotypic and functional response of monocyte-derived human macrophages to MSC exposure in vitro. MSCs induced two distinct, coexistent phenotypes: M2-like macrophages (generally elongated morphology, CD163+, acute phagosomal acidification, low NOX2 expression and limited phagosomal superoxide production) and M1-like macrophages characterised by high levels of phagosomal superoxide production. Enhanced phagosomal reactive oxygen species production was also observed in alveolar macrophages from a rodent model of pneumonia-induced sepsis. The production of M1-like macrophages was dependent on prostaglandin E2 and phosphatidylinositol 3-kinase. MSCs enhanced human macrophage phagocytosis of unopsonised bacteria and enhanced bacterial killing compared with untreated macrophages. Bacterial killing was significantly reduced by blockade of NOX2 using diphenyleneiodonium, suggesting that M1-like cells are primarily responsible for this effect. MSCs also enhanced phagocytosis and polarisation of M1-like macrophages derived from patients with severe sepsis. The enhanced antimicrobial capacity (M1-like) and inflammation resolving phenotype (M2-like) may account for the paradoxical effect of these cells in sepsis in vivo.

Original languageEnglish
Article number1702021
JournalEuropean Respiratory Journal
Volume51
Issue number4
DOIs
StatePublished - 2018

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