6533b7d7fe1ef96bd1267c24
RESEARCH PRODUCT
Janus -faced liposomes enhance antimicrobial innate immune response in Mycobacterium tuberculosis infection
Marco De SpiritoM. SantucciMaurizio FrazianoRoberto NisiniGiuseppe MaulucciMassimo AndreoniAnna Rita CiccaglioneFrancesco DieliTom H. M. OttenhoffNadia CaccamoCinzia MarcantonioLoredana SarmatiMario Giuseppe AlmaDelia GolettiDiana Di LibertoMassimiliano PapiGiovanni DeloguAlfonso AltieriAnnalucia SerafinoEmanuela GrecoGianluca QuintilianiAngelo MartinoNigel D. L. Savagesubject
MaleAntitubercular AgentsApoptosisSettore MED/07Mice0302 clinical medicineInnateInbred BALB CMycobacterium tuberculosis liposomes0303 health sciencesMice Inbred BALB CMultidisciplinaryLeukemiaTumorbiologyMacrophages; Leukemia Monocytic Acute; Animals; Apoptosis; Calcium; Humans; Disease Models Animal; Mice; Cell Line Tumor; Immunity Innate; Reactive Oxygen Species; Mice Inbred BALB C; Liposomes; Phosphatidylserines; Tuberculosis Pulmonary; Adult; Bronchoalveolar Lavage Fluid; Middle Aged; Antitubercular Agents; Phagocytosis; Male; Mycobacterium tuberculosis; IsoniazidInterleukinPulmonaryMiddle AgedSettore BIO/193. Good healthPNAS PlusLeukemia Monocytic AcuteTumor necrosis factor alphaBronchoalveolar Lavage FluidIntracellularAdultPhagocytosisPhosphatidylserinesAcutePhagolysosomeSettore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICAMicrobiologyCell LineMycobacterium tuberculosis03 medical and health sciencesPhagocytosisCell Line TumorIsoniazidTuberculosisAnimalsHumansTuberculosis Pulmonary030304 developmental biologySettore MED/04 - Patologia GeneraletherapyInnate immune systemMonocyticAnimalMacrophagesImmunityMycobacterium tuberculosisbiology.organism_classificationImmunity InnateDisease Models AnimalApoptosisImmunologyDisease ModelsLiposomesCalciumReactive Oxygen Species030215 immunologydescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2012-05-22 |