Neutrophil Caspase-11 Is Required for Cleavage of Caspase-1 and Secretion of IL-1? in Aspergillus fumigatus Infection.

ABSTRACT: Neutrophils are an important source of IL-1? secretion in bacterial infections, where they infiltrate affected tissues in log-fold higher numbers than macrophages. Neutrophils also have functional NLRP3 and NLRC4 inflammasomes that can process pro-IL-1? to the bioactive 17-kDa form. In the current study, we examined the role of IL-1? in response to corneal infection with the filamentous fungus Aspergillus fumigatus and found that neutrophils were the predominant source of bioactive IL-1? in the cornea. We also observed that caspase-11-/- mice exhibit the same susceptibility phenotype as IL-1?-/-, ASC-/-, NLRP3-/-, and caspase-1-/- mice, with impaired neutrophil recruitment to infected corneas and increased hyphal growth. We further demonstrate that caspase-11 is required for caspase-1 activation and IL-1? processing during infection. In vitro, we show that caspase-11 is regulated by the common type I IFN receptor (IFNAR) through JAK-STAT signaling and that caspase-11 is required for speck formation and caspase-1 activity. Aspergillus spores (conidia) stimulate IL-1? processing and secretion in neutrophils activation of Dectin-1 and signaling through the Raf1 kinase/MEKK rather than the spleen tyrosine kinase pathway. Collectively, these findings reveal unexpected regulation of IL-1? production by neutrophils in response to pathogenic fungi.

SUBMITTER: Sun Y 

PROVIDER: S-EPMC6200591 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature