Mesenchymal stem cells alleviate idiopathic pneumonia syndrome by facilitating M2 polarization via CCL2/CCR2 axis and further inducing formation of regulatory CCR2 + CD4 + T cells

Abstract

Abstract Background Our previous study revealed that mesenchymal stem cells (MSCs) can secrete large amounts of the chemokine CCL2 under inflammatory conditions and alleviate idiopathic pneumonia syndrome (IPS) by promoting regulatory CCR2 + CD4 + T-cell formation through the CCL2‒CCR2 axis. Given the abundance of macrophages in lung tissue, how these macrophages are regulated by MSC-based prophylaxis via IPS and their interactions with T cells in lung tissue during allo-HSCT are still not fully understood. Methods An IPS mouse model was established, and MSC-based prophylaxis was administered. In vitro coculture systems and an IPS model were used to study the interactions among MSCs, macrophages and T cells. Results Prophylactic administration of MSCs induced M2 polarization and alleviated acute graft-versus-host disease (aGVHD) and lung injury in an IPS mouse model. In vitro coculture studies revealed that M2 polarization was induced by MSC-released CCL2 and that these M2 macrophages promoted the formation of regulatory CCR2 + CD4 + T cells. Blocking the CCL2-CCR2 interaction in vitro reversed MSC-induced M2 polarization and abolished the induction of CCR2 + CD4 + T-cell formation. Additionally, in vivo administration of a CCL2 or CCR2 antagonist in the IPS mouse model exacerbated aGVHD and lung injury, accompanied by a reduction in M2 macrophages and reduced formation of regulatory CCR2 + CD4 + T cells in lung tissue. Conclusions MSCs alleviate IPS by facilitating M2 polarization via the CCL2‒CCR2 axis and further inducing the formation of regulatory CCR2 + CD4 + T cells.

Keywords

• Allogeneic haematopoietic stem cell transplantation
• Idiopathic pneumonia syndrome
• Mesenchymal stem cells
• CCL2-CCR2
• Macrophage
• Polarization