Rapamycin unbalances the polarization of human macrophages to M1.

Abstract

Plasticity is a hallmark of macrophages, and in response to environmental signals these cells undergo different forms of polarized activation, the extremes of which are called classic (M1) and alternative (M2). Rapamycin (RAPA) is crucial for survival and functions of myeloid phagocytes, but its effects on macrophage polarization are not yet studied. To address this issue, human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon-γ or interleukin-4 (IL-4), respectively. The presence of RAPA (10 ng/ml) induced macrophage apoptosis in M2 but not in M1. Beyond the impact on survival in M2, RAPA reduced CXCR4, CD206 and CD209 expression and stem cell growth factor-β, CCL18 and CCL13 release. In contrast, in M1 RAPA increased CD86 and CCR7 expression and IL-6, tumour necrosis factor-α and IL-1β release but reduced CD206 and CD209 expression and IL-10, vascular endothelial growth factor and CCL18 release. In view of the in vitro data, we examined the in vivo effect of RAPA monotherapy (0·1 mg/kg/day) in 12 patients who were treated for at least 1 month before islet transplant. Cytokine release by Toll-like receptor 4-stimulated peripheral blood mononuclear cells showed a clear shift to an M1-like profile. Moreover, macrophage polarization 21 days after treatment showed a significant quantitative shift to M1. These results suggest a role of mammalian target of rapamycin (mTOR) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2-related diseases through mTOR inhibitor treatment.

• Authors: Alessia Mercalli, Ines Calavita, Erica Dugnani, Antonio Citro, Elisa Cantarelli, Rita Nano, Raffaella Melzi, Paola Maffi, Antonio Secchi, Valeria Sordi, Lorenzo Piemonti
• Journal: Immunology (Immunology) Vol. 140 Issue 2 Pg. 179-90 (Oct 2013) ISSN: 1365-2567 [Electronic] England
• PMID: 23710834 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 John Wiley & Sons Ltd.

Chemical References

• Cytokines
• Immunosuppressive Agents
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Adult
• Apoptosis (drug effects)
• Cytokines (immunology)
• Diabetes Mellitus, Type 1 (surgery)
• Female
• Flow Cytometry
• Graft Rejection (prevention & control)
• Humans
• Immunosuppressive Agents (pharmacology)
• Islets of Langerhans Transplantation (immunology)
• Macrophage Activation (drug effects)
• Macrophages (drug effects, immunology)
• Male
• Middle Aged
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases (immunology, metabolism)