Rapamycin unbalances the polarization of human macrophages to M1

Alessia Mercalli, Ines Calavita, Erica Dugnani, Antonio Citro, Elisa Cantarelli, Rita Nano, Raffaella Melzi, Paola Maffi, Antonio Secchi, Valeria Sordi, Lorenzo Piemonti

Research output: Contribution to journalArticle

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Abstract

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 (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.

Original languageEnglish
Pages (from-to)179-190
Number of pages12
JournalImmunology
Volume140
Issue number2
DOIs
Publication statusPublished - Oct 2013

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Sirolimus
Macrophages
Toll-Like Receptor 4
Stem Cell Factor
Survival
Phagocytes
Blood Donors
Interleukin-1
Interleukin-4
Interleukin-10
Interferons
Vascular Endothelial Growth Factor A
Lipopolysaccharides
Interleukin-6
Blood Cells
Intercellular Signaling Peptides and Proteins
Therapeutics
Tumor Necrosis Factor-alpha
Apoptosis
Cytokines

Keywords

  • Cytokines
  • Immunotherapeutics
  • Macrophage polarization
  • Macrophages/monocytes
  • Rapamycin
  • Transplantation

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Rapamycin unbalances the polarization of human macrophages to M1. / Mercalli, Alessia; Calavita, Ines; Dugnani, Erica; Citro, Antonio; Cantarelli, Elisa; Nano, Rita; Melzi, Raffaella; Maffi, Paola; Secchi, Antonio; Sordi, Valeria; Piemonti, Lorenzo.

In: Immunology, Vol. 140, No. 2, 10.2013, p. 179-190.

Research output: Contribution to journalArticle

Mercalli, A, Calavita, I, Dugnani, E, Citro, A, Cantarelli, E, Nano, R, Melzi, R, Maffi, P, Secchi, A, Sordi, V & Piemonti, L 2013, 'Rapamycin unbalances the polarization of human macrophages to M1', Immunology, vol. 140, no. 2, pp. 179-190. https://doi.org/10.1111/imm.12126
Mercalli, Alessia ; Calavita, Ines ; Dugnani, Erica ; Citro, Antonio ; Cantarelli, Elisa ; Nano, Rita ; Melzi, Raffaella ; Maffi, Paola ; Secchi, Antonio ; Sordi, Valeria ; Piemonti, Lorenzo. / Rapamycin unbalances the polarization of human macrophages to M1. In: Immunology. 2013 ; Vol. 140, No. 2. pp. 179-190.
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