Abstract
Fas-associated death domain (FADD) and receptor interacting protein kinase 3 (RIPK3) are multifunctional regulators of cell death and immune response. Using a mouse model of cryptococcal infection, the roles of FADD and RIPK3 in anti-cryptococcal defense were investigated. Deletion of RIPK3 alone led to increased inflammatory cytokine production in the Cryptococcus neoformans-infected lungs, but in combination with FADD deletion, it led to a robust Th1-biased response with M1-biased macrophage activation. Rather than being protective, these responses led to paradoxical C. neoformans expansion and rapid clinical deterioration in Ripk3−/− and Ripk3−/−Fadd−/− mice. The increased mortality of Ripk3−/− and even more accelerated mortality in Ripk3−/−Fadd−/− mice was attributed to profound pulmonary damage due to neutrophil-dominant infiltration with prominent upregulation of pro-inflammatory cytokines. This phenomenon was partially associated with selective alterations in the apoptotic frequency of some leukocyte subsets, such as eosinophils and neutrophils, in infected Ripk3−/−Fadd−/− mice. In conclusion, our study shows that RIPK3 in concert with FADD serve as physiological “brakes,” preventing the development of excessive inflammation and Th1 bias, which in turn contributes to pulmonary damage and defective fungal clearance. This novel link between the protective effect of FADD and RIPK3 in antifungal defense and sustenance of immune homeostasis may be important for the development of novel immunomodulatory therapies against invasive fungal infections.
Highlights
Invasive fungal infections have become an increasingly significant challenge to public health due to the ever-increasing population of immunosuppressed patients, associated with aging of the global population, immunosuppressive infections such as HIV, and the growing use of immunosuppressive therapies
These results demonstrate that Fas-associated death domain (FADD) and receptor interacting protein kinase 3 (RIPK3) signaling critically contribute to host defense against cryptococcal infection, most likely in a synergistic fashion
RIPK3 deletion had no effect on Lung-Associated Lymph Node (LALN) DC cytokine expression. These results suggested that RIPK3/FADD deletions synergistically promoted LALN DC maturation and DC1 activation during C. neoformans infection, which was consistent with strongly enhanced Th1 responses in these mice, while changes in Ripk3−/− DC activation profile was subtle, consistent with subtle were stained with CD80 (A–D), IFNγ (E), and IL-4 (F) antibodies and analyzed by flow cytometry
Summary
Invasive fungal infections have become an increasingly significant challenge to public health due to the ever-increasing population of immunosuppressed patients, associated with aging of the global population, immunosuppressive infections such as HIV, and the growing use of immunosuppressive therapies. Emerging evidence supports the view that the excessive inflammation and pathology is frequently derived by a Th1 response, which is often initiated during highly active antiretroviral therapy (HAART) in HIV+ patients with cryptococcosis. This paradoxical response, known as immune reconstitution inflammatory syndrome (IRIS), contributes to worsening symptoms and patient mortality despite ongoing antifungal and HAART treatments [3]. This unique clinical problem underscores the importance of immunoregulatory processes during opportunistic fungal infections of which many aspects remain to be elucidated
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