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Rapamycin unbalances the polarization of human macrophages to M 1
Author(s) -
Mercalli Alessia,
Calavita Ines,
Dugnani Erica,
Citro Antonio,
Cantarelli Elisa,
Nano Rita,
Melzi Raffaella,
Maffi Paola,
Secchi Antonio,
Sordi Valeria,
Piemonti Lorenzo
Publication year - 2013
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12126
Subject(s) - macrophage polarization , cytokine , m2 macrophage , in vitro , tumor necrosis factor alpha , peripheral blood mononuclear cell , in vivo , lipopolysaccharide , macrophage , immunology , chemistry , growth factor , interleukin 10 , apoptosis , receptor , cancer research , biology , biochemistry , microbiology and biotechnology
Summary 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 ( M 1) and alternative ( M 2). 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 M 1 or M 2 in vitro by lipopolysaccharide plus interferon‐γ or interleukin‐4 ( IL ‐4), respectively. The presence of RAPA (10 ng/ml) induced macrophage apoptosis in M 2 but not in M 1. Beyond the impact on survival in M 2, RAPA reduced CXCR 4, CD 206 and CD 209 expression and stem cell growth factor‐β, CCL 18 and CCL 13 release. In contrast, in M 1 RAPA increased CD 86 and CCR 7 expression and IL ‐6, tumour necrosis factor‐α and IL ‐1β release but reduced CD 206 and CD 209 expression and IL ‐10, vascular endothelial growth factor and CCL 18 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 T oll‐like receptor 4‐stimulated peripheral blood mononuclear cells showed a clear shift to an M 1‐like profile. Moreover, macrophage polarization 21 days after treatment showed a significant quantitative shift to M 1. 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 M 2‐related diseases through m TOR inhibitor treatment.