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

Abstract

Candida albicans is the most common, opportunistic human fungal pathogen whose complex interplay with the host innate immune system remains incompletely understood. In this study, we revealed that infection macrophages with C. albicans triggers prominent cell death, which is largely attributed to the RIPK3/MLKL-mediated necroptosis. Our results further demonstrated that the TSC1-mTOR pathway plays a pivotal role in the control of macrophage necroptosis upon engaging the Dectin-1/2 and TLR-2/4 pathways through fungal components b-glucan/a-mannan or Sel1, respectively. Notably, the rapamycin-sensitive mTORC1 pathway, rather than the rapamycin-insensitive mTORC2 pathway, was responsible for elevated activation of RIPK1, RIPK3, and MLKL in TSC1deficient macrophages. Following systemic infection with C. albicans, mice with macrophage/neutrophil-specific deletion of Tsc1 (Tsc1 M/N2/2) showed heightened fungal burden in multiple organs, such as the kidney, liver, and spleen, severe morbidity, and mortality. Notably, Tsc1 M/N2/2 kidneys exhibited prominent cell death and concomitant loss of tissue-resident macrophages, which likely contributing to a dampened phagocytosis of fungal pathogens. Together, our data demonstrate a crucial role for the TSC1-mTOR pathway in the regulation of macrophage necroptosis and suggest that both Dectin-and TLRs-induced necroptosis may undermine the immune defense effector functions of these innate receptors during C. albicans infection. ImmunoHorizons, 2021, 5: 90-101.

Necroptosis Underlies Neutrophilic Inflammation Associated with the Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)

“…It is possible that both the inflammatory cytokines and the nasal commensals work together to induce macrophage necroptosis in CRSwNP. Our recent studies revealed mTOR hyperactivation sensitized cells to necroptosis by promoting RIPK3 and MLKL expression in both intestinal epithelial cells and murine macrophages, 18 , 33 here we uncovered a positive role of mTOR in facilitating TNF-α and IFN-γ-induced cell death without affecting RIPK3 and MLKL protein abundance. However, the detailed mechanisms of how mTOR regulates this process need to be further elucidated.…”

“…Our previous studies reported mTOR signaling can promote necroptosis in intestinal epithelial cells and murine macrophages upon induction by PAMPs or fungal pathogen. 18 , 33 We wondered whether mTOR also played a role in TNF-α and IFN-γ mediated necroptosis. Intriguingly, mTOR was greatly activated upon TNF-α plus IFN-γ treatment as evidenced by increased phosphorylation of the mTOR substrate S6 ( Figure 5D ).…”

“…Besides, pathogen-associated molecular patterns (PAMPs) and live pathogens such as influenza virus, Candida albicans and Staphylococcus aureus can also cause necroptosis through different mechanisms. [16][17][18][19] Not surprisingly, necroptosis is implicated in the pathogenesis of multiple inflammatory diseases, such as inflammatory bowel diseases, dermatitis and hepatitis. 15,20,21 In these settings, necroptosis can promote inflammation through at least two distinct mechanisms.…”

IL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis

“…Inflammatory RCD depends on the release of damage-associated molecular pattern (DAMPs) and inflammatory mediators 28 . RCD is increasingly understood to benefit the host 29 , and C. albicans is known to induce inflammatory RCDs, such as necroptosis, and pyroptosis to promote inflammation 30,31 . Indeed, deficiencies in these pathways accelerate disease progression during fungal infection 31,32 .…”

“…RCD is increasingly understood to benefit the host 29 , and C. albicans is known to induce inflammatory RCDs, such as necroptosis, and pyroptosis to promote inflammation 30,31 . Indeed, deficiencies in these pathways accelerate disease progression during fungal infection 31,32 . However, excessive inflammation results in renal immunopathology during candidiasis suggesting that other mechanisms or RCDs fine-tune immunopathology and fungal control.…”