SPION-MSCs enhance therapeutic efficacy in sepsis by regulating MSC-expressed TRAF1-dependent macrophage polarization.

BACKGROUND: Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The liver has a crucial role in sepsis and is also a target for sepsis-related injury. Macrophage polarization between the M1 and M2 types is involved in the progression and resolution of both inflammation and liver injury. Iron oxide-based synthetic nanoparticles (SPIONs) can be used as antibacterial agents to regulate the inflammatory response. Mesenchymal stromal/stem cells (MSCs) have been widely used in the treatment of autoimmune diseases, sepsis, and other diseases. However, to date, both the effects of SPIONs on MSCs and the fate of SPION-labelled MSCs in sepsis and other diseases are still unclear. METHODS: Mice were subjected to caecal ligation and puncture (CLP) or lipopolysaccharide (LPS) induction to develop sepsis models. The CLP or LPS models were treated with MSCs or SPION-labelled/pretreated MSCs (SPION-MSCs). Bone marrow (BM)-derived macrophages and RAW 264.7 cells were cocultured with MSCs or SPION-MSCs under different conditions. Flow cytometry, transmission electron microscopy, western blotting, quantitative real-time PCR, and immunohistochemical analysis were performed. RESULTS: We found that SPIONs did not affect the basic characteristics of MSCs. SPIONs promoted the survival of MSCs by upregulating HO-1 expression under inflammatory conditions. SPION-MSCs enhanced the therapeutic efficacy of liver injury in both the CLP- and LPS-induced mouse models of sepsis. Moreover, the protective effect of SPION-MSCs against sepsis-induced liver injury was related to macrophages. Systemic depletion of macrophages reduced the efficacy of SPION-MSC therapy. Furthermore, SPION-MSCs promoted macrophages to polarize towards the M2 phenotype under sepsis-induced liver injury in mice. The enhanced polarization towards M2 macrophages was attributed to their phagocytosis of SPION-MSCs. SPION-MSC-expressed TRAF1 was critical for promotion of macrophage polarization and alleviation of sepsis in mice. CONCLUSION: MSCs labelled/pretreated with SPIONs may be a novel therapeutic strategy to prevent or treat sepsis and sepsis-induced liver injury. HIGHLIGHTS: 1. SPIONs enhance the viability of MSCs by promoting HO-1 expression. 2. SPION-labelled/pretreated MSCs effectively improve sepsis by regulating macrophage polarization to M2 macrophages. 3. SPION-labelled/pretreated MSCs regulate macrophage polarization in a manner dependent on MSC-expressed TRAF1 protein.