Type I Interferons Promote Fatal Immunopathology by Regulating Inflammatory Monocytes and Neutrophils during Candida Infections

PLoS Pathogens

Olivia Majer¹  Florian Zwolanek¹  Karl Kuchler¹  Christelle Bourgeois¹  Dontscho Kerjaschki²  Matthias Mack³  Caroline Lassnig⁴  Mathias Müller⁴ 

[1] Medical University Vienna - Max F. Perutz Laboratories, Christian Doppler Laboratory for Infection Biology, Campus Vienna Biocenter, Vienna, Austria;Medical University of Vienna – Clinical Institute of Pathology, AKH - General Hospital of Vienna, Vienna, Austria;University Hospital of Regensburg, Internal Medicine II – Nephrology, Regensburg, Germany;University of Veterinary Medicine Vienna, Institute of Animal Breeding and Genetics & Biomodels Austria, Vienna, Austria

关键词: Kidneys;    Inflammation;    Monocytes;    Neutrophils;    Mouse models;    Inflammatory diseases;    Fungal diseases;    White blood cells;   

DOI  :  10.1371/journal.ppat.1002811

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Invasive fungal infections by Candida albicans (Ca) are a frequent cause of lethal sepsis in intensive care unit patients. While a contribution of type I interferons (IFNs-I) in fungal sepsis remains unknown, these immunostimulatory cytokines mediate the lethal effects of endotoxemia and bacterial sepsis. Using a mouse model lacking a functional IFN-I receptor (Ifnar1−/−), we demonstrate a remarkable protection against invasive Ca infections. We discover a mechanism whereby IFN-I signaling controls the recruitment of inflammatory myeloid cells, including Ly6Chi monocytes and neutrophils, to infected kidneys by driving expression of the chemokines CCL2 and KC. Within kidneys, monocytes differentiate into inflammatory DCs but fail to functionally mature in Ifnar1−/− mice, as demonstrated by the impaired upregulation of the key activation markers PDCA1 and iNOS. The increased activity of inflammatory monocytes and neutrophils results in hyper-inflammation and lethal kidney pathology. Pharmacological diminution of monocytes and neutrophils by treating mice with pioglitazone, a synthetic agonist of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ), strongly reduces renal immunopathology during Ca infection and improves mouse survival. Taken together, our data connect for the first time the sepsis-promoting functions of IFNs-I to the CCL2-mediated recruitment and the activation of inflammatory monocytes/DCs with high host-destructing potency. Moreover, our data demonstrate a therapeutic relevance of PPAR-γ agonists for microbial infectious diseases where inflammatory myeloid cells may contribute to fatal tissue damage.

【 授权许可】

CC BY