2. Academic Validation
  3. Early or late IL-10 blockade enhances Th1 and Th17 effector responses and promotes fungal clearance in mice with cryptococcal lung infection

Early or late IL-10 blockade enhances Th1 and Th17 effector responses and promotes fungal clearance in mice with cryptococcal lung infection

  • J Immunol. 2014 Oct 15;193(8):4107-16. doi: 10.4049/jimmunol.1400650.
Benjamin J Murdock 1,  Seagal Teitz-Tennenbaum 1,  Gwo-Hsiao Chen 1,  Anthony J Dils 1,  Antoni N Malachowski 1,  Jeffrey L Curtis 2,  Michal A Olszewski 3,  John J Osterholzer 4
Affiliations

Affiliations

  • 1 Research Service, Veterans Affairs Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;
  • 2 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; Pulmonary Section, Medical Service, Veterans Affairs Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, MI 48109.
  • 3 Research Service, Veterans Affairs Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, MI 48109.
  • 4 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; Pulmonary Section, Medical Service, Veterans Affairs Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, MI 48109 oster@umich.edu.
PMID: 25225664 DOI: 10.4049/jimmunol.1400650
Abstract

The potent immunoregulatory properties of IL-10 can counteract protective immune responses and, thereby, promote persistent infections, as evidenced by studies of cryptococcal lung Infection in IL-10-deficient mice. To further investigate how IL-10 impairs Fungal clearance, the current study used an established murine model of C57BL/6J mice infected with Cryptococcus neoformans strain 52D. Our results demonstrate that Fungal persistence is associated with an early and sustained expression of IL-10 by lung leukocytes. To examine whether IL-10-mediated immune modulation occurs during the early or late phase of Infection, assessments of Fungal burden and immunophenotyping were performed on mice treated with anti-IL-10R-blocking Ab at 3, 6, and 9 d postinfection (dpi) (early phase) or at 15, 18, and 21 dpi (late phase). We found that both early and late IL-10 blockade significantly improved Fungal clearance within the lung compared with isotype control treatment when assessed 35 dpi. Immunophenotyping identified that IL-10 blockade enhanced several critical effector mechanisms, including increased accumulation of CD4(+) T cells and B cells, but not CD8(+) T cells; specific increases in the total numbers of Th1 and Th17 cells; and increased accumulation and activation of CD11b(+) dendritic cells and exudate macrophages. Importantly, IL-10 blockade effectively abrogated dissemination of C. neoformans to the brain. Collectively, this study identifies early and late cellular and molecular mechanisms through which IL-10 impairs Fungal clearance and highlights the therapeutic potential of IL-10 blockade in the treatment of Fungal lung infections.

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