The relevance of the migration inhibitory factor (MIF) for peripheral tissue response in murine sublethal systemic Aspergillus fumigatus infection

Abstract

We recently demonstrated that macrophage migration inhibitory factor deficient (MIF ^{− / −}) mice exhibited a higher susceptibility to lethal systemic Aspergillus fumigatus infections than genetically matched, wild-type (WT) C57BL/6 mice, and displayed altered cytokine profiles in the spleen when challenged by sublethal infections. In this report we focused on the potential involvement of MIF in the response of mice to sublethal systemic A. fumigatus infections in tissues other than spleen. Impaired fungal clearance from lungs, kidneys, liver and brain in MIF ^{− / −} mice was noted and was associated with histologically-evident differences in signs of inflammation in these organs. Higher values of some indicators of pathologic changes in urine parameters (increases in bilirubin, glucose and ketones), as well as a greater degree of brain tissue damage, pointed to multiple organs being affected in MIF ^{− / −} mice. Analysis of the lung response revealed differences in the composition of infiltrated cells between MIF-sufficient and MIF-deficient mice. MPO activity and reactive oxygen species production were impaired, as well as production of IL-17 and IFN-γ in MIF ^{− / −} mice as compared to WT counterparts. Lower systemic IL-1β and IL-6 levels in infected MIF ^{− / −} mice coincided with reduced blood neutrophil counts and organ infiltration. Collectively, this study identifies MIF as a resistance factor that orchestrates events in several non-lymphoid areas which provide a milieu that accomplishes anti-fungal A. fumigatus defense.

Keywords:

• Sublethal systemic aspergillosis
• MIF-deficient mice
• visceral organ histology
• lung inflammation

Acknowledgements

The authors are grateful to Dr Ferdinando Nicoletti (Department of Biomedical Sciences, University of Catania, Catania, Italy) and Dr Yousef Al-Abed (The Feinstein Institute for Medical Research, North Shore LIJ Health System, New York, USA) for generously providing breeding stock of MIF ^−/− mice. This work was supported by the Ministry of Education and Science of the Republic of Serbia, grants no. 173013 (S. S-G) and 173039 (M. K).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This paper was first published online on Early Online on 3 January 2012.