Toll-Like Receptor-3-Activated Human Mesenchymal Stromal Cells Significantly Prolong the Survival and Function of Neutrophils

Abstract

Bone marrow-derived mesenchymal stromal cells (BMMSCs) are stromal precursors endowed with extensive immunomodulative properties. In this study, we aimed to assess whether Toll-like receptor-3 (TLR3)-and TLR4-activated BM-MSC influence human neutrophil (PMN) responses under coculture conditions. We show that TLR3 triggering by polyinosinic:polycytidylic acid dramatically amplifies, in a more significant manner than TLR4 triggering by lipopolysaccharide, the antiapoptotic effects that resting BM-MSC constitutively exert on PMN under coculture conditions, preserving a significant fraction of viable and functional PMN up to 72 hours. In addition, TLR3-and TLR4-activated BM-MSC enhance respiratory burst ability and CD11b expression by PMN. The coculture in the absence of cell contact and the incubation of PMN in supernatants harvested from TLR3-and TLR4-activated BM-MSC yield comparable results in terms of increased survival and immunophenotypic changes, thus suggesting the involvement of endogenous soluble factors. Neutralizing experiments reveal that the biological effects exerted on PMN by TLR3-activated BM-MSC are mediated by the combined action of interleukin 6, interferon-b (IFN-b), and granulocyte macrophage colony-stimulating factor (GM-CSF), while those exerted by TLR4-activated BM-MSC mostly depend on GM-CSF. MSC isolated from thymus, spleen, and subcutaneous adipose tissue behaves similarly. Finally, the effects exerted by TLR3-or TLR4-stimulated BM-MSC on PMN are conserved even after the previous priming of BM-MSC with IFN-c and tumor necrosis factor-a. Our data highlight a novel mechanism by which MSC sustain and amplify the functions of PMN in response to TLR3-and TLR4-triggering and may consequently contribute to inflammatory disorders. STEM CELLS

Therapeutic Effects of Human Mesenchymal Stem Cell–derived Microvesicles in Severe Pneumonia in Mice

“…Recent studies indicated that TLR3 activation with Poly (I:C) can boost the immunomodulatory potential of MSCs, while TLR4 activation could reduce it (24,(43)(44)(45). Watterman and colleagues showed that pretreated MSCs secreted higher levels of PGE2 (24).…”

Emerging roles for multipotent, bone marrow–derived stromal cells in host defense

“…Maintenance of quiescent HSC pool 56,57 BM emigration of activated HSCs 57 BMSC effects on immune effector cells Mobilization and emigration from BM 58 Thymic development to augment immune effector cell response [79][80][81][82] Phase 3: Pathogen elimination BMSC effects on pathogen Production of microbiocidal soluble factors 3,60,61 Containment of infectious pathogen within microenvironment (eg, pathogen phagocytosis) 62 Enhance microbiocidal function of immune effector cells 62,83 Phase 4 Augment wound healing, minimize tissue cytotoxicity, or enhance revascularization [62][63][64]71,72 Modulation of inflammation and organ dysfunction after in vivo infectious challenge [61][62][63][64] Figure 4. Proposed plasticity in BMSC response and function during infectious challenge.…”

“…To this end, TLR3-primed human BMSCs have recently been shown to prolong in vitro neutrophil survival and function. 83 MSCs seem resistant to immune effector cell lysis, particularly by NK cells and cytotoxic T lymphocytes. 84 Therefore, BMSCs should then remain functionally viable cells during host immune response to infection.…”

Dual Role of TLR3 in Inflammation and Cancer Cell Apoptosis

“…Lastly, Toll-Like Receptor 3, which is strongly expressed by human mesenchymal stem cells (MSC), inhibits their Notch-dependent immunosuppressive effect on T cells [14]. In addition, in response to TLR3-triggering, MSC sustain and amplify the functions of neutrophils and may consequently contribute to local inflammation [123].…”