title: 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.affiliation: Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Mercalli
authors.forename: Ines
authors.initials: I
authors.lastname: Calavita
authors.forename: Erica
authors.initials: E
authors.lastname: Dugnani
authors.forename: Antonio
authors.initials: A
authors.lastname: Citro
authors.forename: Elisa
authors.initials: E
authors.lastname: Cantarelli
authors.forename: Rita
authors.initials: R
authors.lastname: Nano
authors.forename: Raffaella
authors.initials: R
authors.lastname: Melzi
authors.forename: Paola
authors.initials: P
authors.lastname: Maffi
authors.forename: Antonio
authors.initials: A
authors.lastname: Secchi
authors.forename: Valeria
authors.initials: V
authors.lastname: Sordi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Immunotherapeutics; cytokines; macrophage polarization; macrophages/monocytes; rapamycin; transplantation