hMSCs treatment attenuates murine herpesvirus-68 (MHV-68) pneumonia through altering innate immune response via ROS/NLRP3 signaling pathway

Abstract

Abstract Immunocompromised individuals are particularly vulnerable to viral infections and reactivation, especially endogenous herpes viruses such as Epstein-Barr virus (EBV), a member of oncogenic gamma-herpesviruses, which are commonly linked to pneumonia and consequently significant morbidity and mortality. In the study of human and animal oncogenic gammaherpesviruses, the murine gamma-herpesviruses-68 (MHV-68) model has been applied, as it can induce pneumonia in immunocompromised mice. Mesenchymal stem cell (MSC) treatment has demonstrated therapeutic potential for pneumonia, as well as other forms of acute lung injury, in preclinical models. In this study, we aim to investigate the therapeutic efficacy and underlying mechanisms of human bone marrow-derived MSC (hMSC) on MHV-68-induced pneumonia. We found that intravenous administration of hMSCs significantly reduced lung damages, diminished inflammatory mediators and somehow inhibited MHV-68 replication. Furthermore, hMSCs treatment can regulate innate immune response and induce macrophage polarization from M1 to M2 phenotype, could significantly alter leukocyte infiltration and reduce pulmonary fibrosis. Our findings with co-culture system indicated that hMSCs effectively reduced the secretion of of inflammation-related factors and induced a shift in macrophage polarization, consistent with in vivo results. Further investigations revealed that hMSCs treatment suppressed the activation of macrophage ROS/NLRP3 signaling pathway in vivo and in vitro. Moreover, administration of MCC950, a selective NLRP3 inhibitor has been shown to effectively reduce ROS production and subsequently alleviate inflammation induced by MHV-68. Taken together, our work has shown that hMSCs can effectively protect mice from lethal MHV-68 pneumonia, which may throw new light on strategy for combating human EBV-associated pneumonia.

Keywords

• Mesenchymal stem cell
• Murine gammaherpesviruses 68
• Pneumonia
• Innate immune
• NLRP3 inflammasome