Dataset Information

Peripheral Blood Monocytes With an Antiinflammatory Phenotype Display Limited Phagocytosis and Oxidative Burst in Patients With Visceral Leishmaniasis.

ABSTRACT:

Background

Monocytes are important effector cells during Leishmania infection, and changes in their functions may impact development of immunity. However, functional characteristics of monocytes in patients with visceral leishmaniasis (VL) remains poorly understood.

Methods

Peripheral blood monocytes from patients with VL and healthy endemic controls from Muzaffarpur, India, were isolated and compared in an ex vivo setting, using cell-culture techniques, flow cytometry, and reverse transcription quantitative polymerase chain reaction analysis.

Results

A blood monocyte population with a gene signature comprising upregulated expression of TGM2, CTLRs, VDR, PKM, SOCS1, and CAMP1 and downregulated expression of NOS2 and HIF1A was observed in patients with VL but not in controls. Monocytes from patients with VL also had impaired expression of chemokine receptors and adhesion molecules and decreased frequencies of interleukin 1?- and interleukin 6-producing cells. Importantly, monocytes from patients with VL had a markedly reduced capacity for phagocytosis of amastigotes, p47phox and p67phox expression, and reactive oxygen species production.

Conclusions

Monocytes from patients with VL express antiinflammatory molecules and lack a classically activated phenotype. They have reduced expression of molecules related to activation and antiparasitic effector functions, indicating that monocytes are skewed toward an antiinflammatory phenotype. These findings provide insights into the functional status of monocytes during VL and advise that therapeutic manipulation of this important cell population may result in favorable patient outcomes.

SUBMITTER: Singh N

PROVIDER: S-EPMC6107747 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

Peripheral Blood Monocytes With an Antiinflammatory Phenotype Display Limited Phagocytosis and Oxidative Burst in Patients With Visceral Leishmaniasis.

Singh Neetu N Kumar Rajiv R Chauhan Shashi Bhushan SB Engwerda Christian C Sundar Shyam S

The Journal of infectious diseases 20180801 7

<h4>Background</h4>Monocytes are important effector cells during Leishmania infection, and changes in their functions may impact development of immunity. However, functional characteristics of monocytes in patients with visceral leishmaniasis (VL) remains poorly understood.<h4>Methods</h4>Peripheral blood monocytes from patients with VL and healthy endemic controls from Muzaffarpur, India, were isolated and compared in an ex vivo setting, using cell-culture techniques, flow cytometry, and revers ...[more]

PMID: 30053070

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Project description:Monocyte-derived macrophages orchestrate tissue regeneration by homing to sites of injury, phagocytosing pathological debris, and stimulating other cell types to repair the tissue. Accordingly, monocytes have been investigated as a translational and potent source for cell therapy, but their utility has been hampered by their rapid acquisition of a pro-inflammatory phenotype in response to the inflammatory injury microenvironment. To overcome this problem, we designed a cell therapy strategy where monocytes are exogenously reprogrammed by intracellularly loading the cells with biodegradable microparticles containing an anti-inflammatory drug in order to modulate and maintain an anti-inflammatory phenotype over time. To test this concept, poly(lactic-co-glycolic) acid microparticles were loaded with the anti-inflammatory drug dexamethasone (Dex) and administered to primary human monocytes for four hours to facilitate phagocytic uptake. After removal of non-phagocytosed microparticles, microparticle-loaded monocytes differentiated into macrophages and stored the microparticles intracellularly for several weeks in vitro, releasing drug into the extracellular environment over time. Cells loaded with intracellular Dex microparticles showed decreased expression and secretion of inflammatory factors even in the presence of pro-inflammatory stimuli up to 7 days after microparticle uptake compared to untreated cells or cells loaded with blank microparticles, without interfering with phagocytosis of tissue debris. This study represents a new strategy for long-term maintenance of anti-inflammatory macrophage phenotype using a translational monocyte-based cell therapy strategy without the use of genetic modification. Because of the ubiquitous nature of monocyte-derived macrophage involvement in pathology and regeneration, this strategy holds potential as a treatment for a vast number of diseases and disorders. STATEMENT OF SIGNIFICANCE: We report a unique and translational strategy to overcome the challenges associated with monocyte- and macrophage-based cell therapies, in which the cells rapidly take on inflammatory phenotypes when administered to sites of injury. By intracellularly loading monocytes with drug-loaded microparticles prior to administration via phagocytosis, we were able to inhibit inflammation while preserving functional behaviors of human primary macrophages derived from those monocytes up to seven days later. To our knowledge, this study represents the first report of reprogramming macrophages to an anti-inflammatory phenotype without the use of genetic modification.

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Dataset Information

Peripheral Blood Monocytes With an Antiinflammatory Phenotype Display Limited Phagocytosis and Oxidative Burst in Patients With Visceral Leishmaniasis.

Background

Methods

Results

Conclusions

Publications

Peripheral Blood Monocytes With an Antiinflammatory Phenotype Display Limited Phagocytosis and Oxidative Burst in Patients With Visceral Leishmaniasis.

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