Majer, Olivia and Bourgeois, Christelle and Zwolanek, Florian and Lassnig, Caroline and Kerjaschki, Dontscho and Mack, Matthias and Mueller, Mathias and Kuchler, Karl (2012) Type I Interferons Promote Fatal Immunopathology by Regulating Inflammatory Monocytes and Neutrophils during Candida Infections. PLOS PATHOGENS, 8 (7): e1002811. ISSN 1553-7374,
Full text not available from this repository. (Request a copy)Abstract
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 Ly6C(hi) 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-gamma (PPAR-gamma), 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-gamma agonists for microbial infectious diseases where inflammatory myeloid cells may contribute to fatal tissue damage.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACTIVATED RECEPTOR-GAMMA; INTRAVENOUS CHALLENGE MODEL; INNATE IMMUNE-RESPONSE; BONE-MARROW; DENDRITIC CELLS; BACTERIAL-INFECTION; HOST-DEFENSE; CRYPTOCOCCUS-NEOFORMANS; ALBICANS INFECTIONS; PROGENITOR CELLS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II Medicine > Abteilung für Nephrologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 11 May 2020 07:11 |
| Last Modified: | 11 May 2020 07:11 |
| URI: | https://pred.uni-regensburg.de/id/eprint/18490 |
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