title: An immunomodulatory activity of micafungin in preclinical aspergillosis.
abstract: OBJECTIVE
  Micafungin inhibits 1,3-β-D-glucan synthase and interferes with fungal cell wall synthesis. Clinically, micafungin has been shown to be efficacious for the treatment of invasive fungal infections. However, little is known about the immunomodulatory activity of micafungin in these infections.
  
  
  METHODS
  We evaluated the immunomodulatory activity of escalating doses of micafungin in murine and human polymorphonuclear neutrophils (PMNs) in vitro and in vivo in different preclinical models of invasive aspergillosis, including mice deficient for selected innate immune receptors.
  
  
  RESULTS
  Micafungin was able to regulate PMN cytokine response to Aspergillus fumigatus conidia by decreasing the expression of tumour necrosis factor-α and increasing that of interleukin-10 (IL-10). In vivo, the therapeutic efficacy of micafungin was strictly dose-dependent, with the maximum activity observed at the highest dose, concomitant with reduced inflammatory pathology. The anti-inflammatory activity of micafungin required IL-10 and occurred through signalling via the TLR2/dectin-1 and TLR3/TRIF pathways.
  
  
  CONCLUSIONS
  Together, these findings suggest that the therapeutic efficacy of micafungin in aspergillosis is orchestrated by the activation of innate immune receptors affecting the inflammatory/anti-inflammatory balance during infection.
authors.affiliation: Department of Experimental Medicine and Biochemical Science, University of Perugia, Polo Unico Sant'Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Moretti
authors.forename: Silvia
authors.initials: S
authors.lastname: Bozza
authors.forename: Cristina
authors.initials: C
authors.lastname: Massi-Benedetti
authors.forename: Lucia
authors.initials: L
authors.lastname: Prezioso
authors.forename: Elena
authors.initials: E
authors.lastname: Rossetti
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
authors.forename: Franco
authors.initials: F
authors.lastname: Aversa
authors.forename: Lucia
authors.initials: L
authors.lastname: Pitzurra
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects*; D058491:Bacterial Load; D002478:Cells, Cultured; D054714:Echinocandins / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D055666:Lipopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D000077551:Micafungin; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000382:microbiology; D016896:Treatment Outcome
chemical_list: D054714:Echinocandins; D007155:Immunologic Factors; D055666:Lipopeptides; D000077551:Micafungin
keywords: IL-10; fungi; innate receptors