Therapeutic potential of lipids obtained from γ-irradiated PBMCs in dendritic cell-mediated skin inflammation

Abstract

Background: Since numerous pathological conditions are evoked by unwanted dendritic cell (DC) activity, therapeutic agents modulating DC functions are of great medical interest. In regenerative medicine, cellular secretomes have gained increasing attention and valuable immunomodulatory properties have been attributed to the secretome of g-irradiated peripheral blood mononuclear cells (PBMCs). Potential effects of the PBMC secretome (PBMCsec) on key DC functions have not been elucidated so far. Methods: We used a hapten-mediated murine model of contact hypersensitivity (CH) to study the effects of PBMCsec on DCs in vivo. Effects of PBMCsec on human DCs were investigated in monocyte-derived DCs (MoDC) and ex vivo skin cultures. DCs were phenotypically characterised by transcriptomics analyses and flow cytometry. DC function was evaluated by cytokine secretion, antigen uptake, PBMC proliferation and Tcell priming. Findings: PBMCsec significantly alleviated tissue inflammation and cellular infiltration in hapten-sensitized mice. We found that PBMCsec abrogated differentiation of MoDCs, indicated by lower expression of classical DC markers CD1a, CD11c and MHC class II molecules. Furthermore, PBMCsec reduced DC maturation, antigen uptake, lipopolysaccharides-induced cytokine secretion, and DC-mediated immune cell proliferation. Moreover, MoDCs differentiated with PBMCsec displayed diminished ability to prime naïve CD4 + T-cells into T H 1 and T H 2 cells. Furthermore, PBMCsec modulated the phenotype of DCs present in the skin in situ. Mechanistically, we identified lipids as the main biomolecule accountable for the observed immunomodulatory effects. Interpretation: Together, our data describe DC-modulatory actions of lipids secreted by stressed PBMCs and suggest PBMCsec as a therapeutic option for treatment of DC-mediated inflammatory skin conditions.

The secretome of stressed peripheral blood mononuclear cells increases tissue survival in a rodent epigastric flap model

“…10,49 The immunomodulatory and cytoprotective effects of PBMCsec were previously described in animal models of myocarditis, contact hypersensitivity, and cerebral ischemia. 37,50,51 The reduction of postischemic inflamma-…”

Role for Lipids Secreted by Irradiated Peripheral Blood Mononuclear Cells in Inflammatory Resolution in Vitro

“…It is known that lipids exert potent immunomodulatory actions [34]. Therefore, we determine whether the lipid fraction of the secretome from γ-irradiated PBMCs is involved in mediating the reduced expression of inflammatory cytokines.…”

“…The secretome of irradiated PBMCs has already been shown to promote angiogenesis [26], however, its role in modulating an inflammatory response and resolution of inflammation has not been investigated so far. Lipids are known, potent modulators of the immune system, and presence of (non-)oxidized lipids and resolvins in the secretome of irradiated PBMCs has been reported previously [33,34]. Though immunomodulatory actions of lipids have been demonstrated in dendritic cell-mediated inflammation [34], the effects of lipids secreted by irradiated PBMCs on macrophages have not been elucidated so far.…”

Quantitative Hybrid Cardiac [18F]FDG-PET-MRI Images for Assessment of Cardiac Repair by Preconditioned Cardiosphere-Derived Cells

“…APOSEC has anti-inflammatory and cell-protective effects and has been extensively characterized in vitro and in vivo . 13 , 17 , 21 , 22 Clinical development for a topical application for wound healing in diabetic foot ulcers has been initiated. Direct induction of cardiac repair by APOSEC after AMI in pigs was evaluated earlier.…”