Janus-faced liposomes enhance antimicrobial innate immune response in Mycobacterium tuberculosis infection

Emanuela Greco, Gianluca Quintiliani, Marilina B. Santucci, Annalucia Serafino, Anna Rita Ciccaglione, Cinzia Marcantonio, Massimiliano Papi, Giuseppe Maulucci, Giovanni Delogu, Angelo Martino, Delia Goletti, Loredana Sarmati, Massimo Andreoni, Alfonso Altieri, Mario Alma, Nadia Caccamo, Diana Di Liberto, Marco De Spirito, Nigel D. Savage, Roberto NisiniFrancesco Dieli, Tom H. Ottenhoff, Maurizio Fraziano

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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 Ca2+ influx, (iii) promote Ca2+-dependent maturation of phagolysosomes containing Mycobacterium tuberculosis (MTB), (iv) induce Ca2+-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)-βwithout 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.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number21
DOIs
Publication statusPublished - May 22 2012

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    Greco, E., Quintiliani, G., Santucci, M. B., Serafino, A., Ciccaglione, A. R., Marcantonio, C., Papi, M., Maulucci, G., Delogu, G., Martino, A., Goletti, D., Sarmati, L., Andreoni, M., Altieri, A., Alma, M., Caccamo, N., Di Liberto, D., De Spirito, M., Savage, N. D., ... Fraziano, M. (2012). Janus-faced liposomes enhance antimicrobial innate immune response in Mycobacterium tuberculosis infection. Proceedings of the National Academy of Sciences of the United States of America, 109(21). https://doi.org/10.1073/pnas.1200484109