Dectin-1-induced RIPK1 and RIPK3 activation protects host against Candida albicans infection

Abstract

Necroptosis is a recently defined type of programmed cell death with the specific signaling cascade of receptor-interacting protein 1 (RIPK1) and RIPK3 complex to activate the executor MLKL. However, the pathophysiological roles of necroptosis are largely unexplored. Here, we report that fungus triggers myeloid cell necroptosis and this type of cell death contributes to host defense against the pathogen infection. Candida albicans as well as its sensor Dectin-1 activation strongly induced necroptosis in myeloid cells through the RIPK1-RIPK3-MLKL cascade. CARD9, a key adaptor in Dectin-1 signaling, was identified to bridge the RIPK1 and RIPK3 complex-mediated necroptosis pathway. RIPK1 and RIPK3 also potentiated Dectin-1-induced MLKL-independent inflammatory response. Both the MLKL-dependent and MLKL-independent pathways were required for host defense against C. albicans infection. Thus, our study demonstrates a new type of host defense system against fungal infection.

TSC1 Suppresses Macrophage Necroptosis for the Control of Infection by Fungal Pathogen Candida albicans

“…Recently, Cao et al (21) found that C. albicans was able to trigger necroptosis in peritoneal macrophages in the presence of pan-caspase inhibitor z-VAD. They also suggested that fungusinduced necroptosis and inflammation is important for host defense against fungal infection (21).…”

“…Recently, Cao et al (21) found that C. albicans was able to trigger necroptosis in peritoneal macrophages in the presence of pan-caspase inhibitor z-VAD. They also suggested that fungusinduced necroptosis and inflammation is important for host defense against fungal infection (21). Nevertheless, we demonstrated that C. albicans alone can induce necroptosis in macrophages, and Tsc1 M/N2/2 mice exhibited comparable inflammation but more necroptotic macrophages in the kidney.…”

“…Upon phosphorylated by RIPK1, RIPK3 then phosphorylates and activates MLKL, the executioner of necroptosis, whereby triggering cell membrane disruption (14)(15)(16)(17)(18). Although TNF is the widely studied trigger of necroptosis, other stimuli such as poly(I:C), LPS, dsDNA, glucan, and IFNs are also known to elicit necroptosis in a variety of cell types, especially when caspase-8 is inhibited (19)(20)(21). Like cytokines and pathogen-associated molecular patterns (PAMPs), live viruses and bacteria, such as HSV, murine CMV, influenza virus, vaccinia virus, Staphylococcus aureus, and Listeria monocytogenes can also trigger necroptosis, which can contribute to host defense or immunopathology (22)(23)(24)(25)(26)(27)(28)(29).…”

Fungal-Induced Programmed Cell Death

“…Once MLKL has been phosphorylated, it will translocate to the cell membrane forming pores, causing a loss of cell membrane integrity and the release of many inflammatory DAMPs [ 50 ]. Necroptosis has also been shown to be mediated via a number of other receptors, including the death receptors Fas and TRAIL, TLRs, and most recently dectin-1 ( Figure 3 ) [ 52 , 53 ].…”

Multitasking Kinase RIPK1 Regulates Cell Death and Inflammation

“…Cite this article as Cold Spring Harb Perspect Biol 2020;12:a036368 less able to clear the Gram-negative bacteria Salmonella typhimurium (Shutinoski et al 2016) and Yersinia pseudotuberculosis (Peterson et al 2017). Inhibition of RIPK1 with Nec-1 has also been shown to increase the susceptibility of mice to the fungus Candida albicans (Cao et al 2019). In other infections, however, activation of RIPK1 appears deleterious to the host.…”