title: Janus-faced liposomes enhance antimicrobial innate immune response in Mycobacterium tuberculosis infection.
abstract: We have generated unique asymmetric liposomes with phosphatidylserine (PS) distributed at the outer membrane surface to resemble apoptotic bodies and phosphatidic acid (PA) at the inner layer as a strategy to enhance innate antimycobacterial activity in phagocytes while limiting the inflammatory response. Results show that these apoptotic body-like liposomes carrying PA (ABL/PA) (i) are more efficiently internalized by human macrophages than by nonprofessional phagocytes, (ii) induce cytosolic Ca(2+) influx, (iii) promote Ca(2+)-dependent maturation of phagolysosomes containing Mycobacterium tuberculosis (MTB), (iv) induce Ca(2+)-dependent reactive oxygen species (ROS) production, (v) inhibit intracellular mycobacterial growth in differentiated THP-1 cells as well as in type-1 and -2 human macrophages, and (vi) down-regulate tumor necrosis factor (TNF)-α, interleukin (IL)-12, IL-1β, IL-18, and IL-23 and up-regulate transforming growth factor (TGF)-β without altering IL-10, IL-27, and IL-6 mRNA expression. Also, ABL/PA promoted intracellular killing of M. tuberculosis in bronchoalveolar lavage cells from patients with active pulmonary tuberculosis. Furthermore, the treatment of MTB-infected mice with ABL/PA, in combination or not with isoniazid (INH), dramatically reduced lung and, to a lesser extent, liver and spleen mycobacterial loads, with a concomitant 10-fold reduction of serum TNF-α, IL-1β, and IFN-γ compared with that in untreated mice. Altogether, these results suggest that apoptotic body-like liposomes may be used as a Janus-faced immunotherapeutic platform to deliver polar secondary lipid messengers, such as PA, into phagocytes to improve and recover phagolysosome biogenesis and pathogen killing while limiting the inflammatory response.
authors.affiliation: Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Greco
authors.forename: Gianluca
authors.initials: G
authors.lastname: Quintiliani
authors.forename: Marilina B
authors.initials: MB
authors.lastname: Santucci
authors.forename: Annalucia
authors.initials: A
authors.lastname: Serafino
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Ciccaglione
authors.forename: Cinzia
authors.initials: C
authors.lastname: Marcantonio
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Papi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Maulucci
authors.forename: Giovanni
authors.initials: G
authors.lastname: Delogu
authors.forename: Angelo
authors.initials: A
authors.lastname: Martino
authors.forename: Delia
authors.initials: D
authors.lastname: Goletti
authors.forename: Loredana
authors.initials: L
authors.lastname: Sarmati
authors.forename: Massimo
authors.initials: M
authors.lastname: Andreoni
authors.forename: Alfonso
authors.initials: A
authors.lastname: Altieri
authors.forename: Mario
authors.initials: M
authors.lastname: Alma
authors.forename: Nadia
authors.initials: N
authors.lastname: Caccamo
authors.forename: Diana
authors.initials: D
authors.lastname: Di Liberto
authors.forename: Marco
authors.initials: M
authors.lastname: De Spirito
authors.forename: Nigel D
authors.initials: ND
authors.lastname: Savage
authors.forename: Roberto
authors.initials: R
authors.lastname: Nisini
authors.forename: Francesco
authors.initials: F
authors.lastname: Dieli
authors.forename: Tom H
authors.initials: TH
authors.lastname: Ottenhoff
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fraziano
mesh_terms: D000328:Adult; D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007538:Isoniazid / Q000494:pharmacology; D007948:Leukemia, Monocytic, Acute; D008081:Liposomes / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000382:microbiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology; D010718:Phosphatidylserines / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000276:immunology*
chemical_list: D000995:Antitubercular Agents; D008081:Liposomes; D010718:Phosphatidylserines; D017382:Reactive Oxygen Species; D002118:Calcium; D007538:Isoniazid