TY - JOUR
T1 - Mesenchymal stem cells enhance NOX2-dependent reactive oxygen species production and bacterial killing in macrophages during sepsis
AU - Rabani, Razieh
AU - Volchuk, Allen
AU - Jerkic, Mirjana
AU - Ormesher, Lindsay
AU - Garces-Ramirez, Linda
AU - Canton, Johnathan
AU - Masterson, Claire
AU - Gagnon, Stephane
AU - Tatham, Kate C.
AU - Marshall, John
AU - Grinstein, Sergio
AU - Laffey, John G.
AU - Szaszi, Katalin
AU - Curley, Gerard F.
N1 - Publisher Copyright:
© ERS 2018.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85055060627&partnerID=8YFLogxK
U2 - 10.1183/13993003.02021-2017
DO - 10.1183/13993003.02021-2017
M3 - Artículo
C2 - 29519920
SN - 0903-1936
VL - 51
JO - European Respiratory Journal
JF - European Respiratory Journal
IS - 4
M1 - 1702021
ER -