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

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 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.

Immunity against fungi

“…Despite the obligate requirement for IL-17 signaling during systemic candidiasis (61), FOXP3 + Treg-mediated potentiation of Th17 responses appears detrimental (130), consistent with the notion that high IL-17 levels lead to immunopathology, as described for type I IFN (38) and CCR1 signaling (131).…”

“…In addition, dectin-1/SYK signaling in DCs induces IFN-β production via IRF5 (37). The role of type I IFN signaling in defense against candidiasis remains controversial, with both protective (37) and detrimental (38) phenotypes reported.…”

IL-33 Enhances Host Tolerance to Candida albicans Kidney Infections through Induction of IL-13 Production by CD4+ T Cells

“…In our experimental system, disease severity in IL-33-injected mice seemed not to be totally dissociated from fungal burden, because IL-33 kept fungal burden in check in kidneys. However, IL-33 conferred persistent immunosuppression that involved the production of lower levels of inflammatory mediators, relatively little granulocytic infiltrate, and M2 macrophage polarization throughout the course of infection, indicating that IL-33 decreased Candida-induced immunopathology, leading to renal damage (16). Therefore, IL-33 provides a unique example of a factor that helps to reduce host vulnerability to damage by promoting pathogen clearance and disabling immunopathology.…”

The role of pattern recognition receptors in the innate recognition ofCandida albicans

“…They are rapidly recruited at the infection locations. [102][103][104][105] Monocytes mainly recognize invading fungi in circulation, expressing high levels of TLRs and moderate levels of CLRs. 21 When monocytes reside at infected tissues and differentiate into macrophages, they keep on expressing TLRs and upregulate the expression of CLRs.…”