Investigation of the Mechanism of Interaction between Mesenchymal Stromal Cells and Macrophages and the Potential for Mesenchymal Stromal Cells and their Secreted Mediators to Enhance Bacterial Phagocytosis and Killing in Sepsis

Background: Sepsis is the leading cause of death among the critically ill. The development of immune suppression in these patients leads to the inability to clear infection and ultimately results in a poor outcome. It is thought that immunomodulatory therapies directed at enhancing the host response to infection may represent a novel means for treating sepsis. Mesenchymal stromal cells (MSCs) represent one such option as they have been shown to improve organ function and clear infection in preclinical models of sepsis. The interaction between MSCs and macrophages has been demonstrated as essential to their therapeutic effects, however their specific mechanism of action to improve bacterial clearance remains unclear.

Methods: The impact of MSC therapy on macrophage functions of phagocytosis, reactive oxygen species production and bacterial killing was assessed using co-culture assays. The specific molecular mechanism of phagocytosis activated was investigated by interrogating phagocytic receptor expression and activity. Lipid mediator profiling of MSC and macrophage co-cultures was performed to identify important mediators of MSCmacrophage crosstalk. Finally, the therapeutic effects of MSCs and Lipoxin A4 (LXA4) were examined in an in vivo model of rodent pneumonia.

Results: MSCs improved macrophage functions of phagocytosis and bacterial killing in a paracrine manner. Specifically, MSCs improved phagocytosis by modulating Fcgreceptors. MSCs shifted the lipid mediator profile of macrophages towards resolution, with a significant increase in LXA4 production. Furthermore, LXA4 itself enhanced phagocytosis to a similar level as MSCs, also in an Fcg-receptor dependent manner. Both MSCs and LXA4 demonstrated safety and efficacy as therapeutics in rodent pneumonia by enhancing measures of pulmonary mechanics, reducing indices of inflammation, and improving bacterial clearance.

Conclusion: MSCs, and their secreted mediator LXA4, improve macrophage phagocytosis in an Fcg-receptor dependent manner. Both MSCs and LXA4 represent novel immunomodulatory therapeutics that enhance host defence and thus may improve outcome in sepsis.