Type I interferons promote fatal immunopathology by regulating inflammatory monocytes and neutrophils during Candida infections.
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-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.
Medical University Vienna-Max F. Perutz Laboratories, Christian Doppler Laboratory for Infection Biology, Campus Vienna Biocenter, Vienna, Austria.
Olivia
O
Majer
Christelle
C
Bourgeois
Florian
F
Zwolanek
Caroline
C
Lassnig
Dontscho
D
Kerjaschki
Matthias
M
Mack
Mathias
M
Müller
Karl
K
Kuchler
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000950:Antigens, Ly / Q000096:biosynthesis; D002176:Candida albicans / Q000276:immunology*; D058387:Candidemia / Q000401:mortality; D002177:Candidiasis / Q000276:immunology* / Q000473:pathology; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D007370:Interferon Type I / Q000378:metabolism*; D007668:Kidney / Q000276:immunology / Q000382:microbiology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D047495:PPAR gamma / Q000819:agonists; D000077205:Pioglitazone; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use; D000074010:Bone Marrow Stromal Antigen 2
D015703:Antigens, CD; D000950:Antigens, Ly; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D007370:Interferon Type I; D008562:Membrane Glycoproteins; D052247:Nitric Oxide Synthase Type II; D047495:PPAR gamma; D000077205:Pioglitazone; D017471:Receptors, Interferon; D045162:Thiazolidinediones; C513868:BST2 protein, mouse; D000074010:Bone Marrow Stromal Antigen 2; C491768:Ccl2 protein, mouse; C475895:Cxcl1 protein, mouse; C494192:Ly-6C antigen, mouse