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Pathogenic fungi regulate immunity by inducing neutrophilic myeloid-derived suppressor cells.

ABSTRACT: Despite continuous contact with fungi, immunocompetent individuals rarely develop pro-inflammatory antifungal immune responses. The underlying tolerogenic mechanisms are incompletely understood. Using both mouse models and human patients, we show that infection with the human pathogenic fungi Aspergillus fumigatus and Candida albicans induces a distinct subset of neutrophilic myeloid-derived suppressor cells (MDSCs), which functionally suppress T and NK cell responses. Mechanistically, pathogenic fungi induce neutrophilic MDSCs through the pattern recognition receptor Dectin-1 and its downstream adaptor protein CARD9. Fungal MDSC induction is further dependent on pathways downstream of Dectin-1 signaling, notably reactive oxygen species (ROS) generation as well as caspase-8 activity and interleukin-1 (IL-1) production. Additionally, exogenous IL-1? induces MDSCs to comparable levels observed during C. albicans infection. Adoptive transfer and survival experiments show that MDSCs are protective during invasive C. albicans infection, but not A. fumigatus infection. These studies define an innate immune mechanism by which pathogenic fungi regulate host defense.

SUBMITTER: Rieber N

PROVIDER: S-EPMC4400268 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Pathogenic fungi regulate immunity by inducing neutrophilic myeloid-derived suppressor cells.

Rieber Nikolaus N Singh Anurag A Öz Hasan H Carevic Melanie M Bouzani Maria M Amich Jorge J Ost Michael M Ye Zhiyong Z Ballbach Marlene M Schäfer Iris I Mezger Markus M Klimosch Sascha N SN Weber Alexander N R AN Handgretinger Rupert R Krappmann Sven S Liese Johannes J Engeholm Maik M Schüle Rebecca R Salih Helmut Rainer HR Marodi Laszlo L Speckmann Carsten C Grimbacher Bodo B Ruland Jürgen J Brown Gordon D GD Beilhack Andreas A Loeffler Juergen J Hartl Dominik D

Cell host & microbe 20150312 4

Despite continuous contact with fungi, immunocompetent individuals rarely develop pro-inflammatory antifungal immune responses. The underlying tolerogenic mechanisms are incompletely understood. Using both mouse models and human patients, we show that infection with the human pathogenic fungi Aspergillus fumigatus and Candida albicans induces a distinct subset of neutrophilic myeloid-derived suppressor cells (MDSCs), which functionally suppress T and NK cell responses. Mechanistically, pathogeni ...[more]

PMID: 25771792

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Project description:BackgroundGranulocyte colony-stimulating factor (G-CSF) can increase populations of myeloid-derived suppressor cells, innate immune suppressors that play an immunoregulatory role in antitumor immunity. However, the roles of myeloid-derived suppressor cells and G-CSF in renal ischemia-reperfusion injury remain unclear.MethodsWe used mouse models of ischemia-reperfusion injury to investigate whether G-CSF can attenuate renal injury by increasing infiltration of myeloid-derived suppressor cells into kidney tissue.ResultsG-CSF treatment before ischemia-reperfusion injury subsequently attenuated acute renal dysfunction, tissue injury, and tubular apoptosis. Additionally, G-CSF treatment suppressed renal infiltration of macrophages and T cells as well as renal levels of IL-6, MCP-1, IL-12, TNF-α, and IFN-γ, but it increased levels of IL-10, arginase-1, and reactive oxygen species. Moreover, administering G-CSF after ischemia-reperfusion injury improved the recovery of renal function and attenuated renal fibrosis on day 28. G-CSF treatment increased renal infiltration of myeloid-derived suppressor cells (F4/80-CD11b+Gr-1int), especially the granulocytic myeloid-derived suppressor cell population (CD11b+Ly6GintLy6Clow); splenic F4/80-CD11b+Gr-1+ cells sorted from G-CSF-treated mice displayed higher levels of arginase-1, IL-10, and reactive oxygen species relative to those from control mice. Furthermore, these splenic cells effectively suppressed in vitro T cell activation mainly through arginase-1 and reactive oxygen species, and their adoptive transfer attenuated renal injury. Combined treatment with anti-Gr-1 and G-CSF showed better renoprotective effects than G-CSF alone, whereas preferential depletion of myeloid-derived suppressor cells by pep-G3 or gemcitabine abrogated the beneficial effects of G-CSF against renal injury.ConclusionsG-CSF induced renal myeloid-derived suppressor cells, thereby attenuating acute renal injury and chronic renal fibrosis after ischemia-reperfusion injury. These results suggest therapeutic potential of myeloid-derived suppressor cells and G-CSF in renal ischemia-reperfusion injury.

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Pathogenic fungi regulate immunity by inducing neutrophilic myeloid-derived suppressor cells.

Publications

Pathogenic fungi regulate immunity by inducing neutrophilic myeloid-derived suppressor cells.

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