The Inflammasome NLRC4 Protects against Cryptococcus gattii by Inducing the Classic Caspase-1 to Activate the Pyroptosis Signal

Abstract

Cryptococcus is one of the most pathogenic invasive fungi, and its interaction with the host’s natural immunity, especially the role of the inflammasome family, has not been fully elucidated. As an important member of the inflammasome family, NOD-like receptor (NLR) family caspase recruitment domain (CARD) containing 4 (NLRC4) has been proven to protect lungs from damage from a variety of pathogens. In this study, we investigated the protective effect and mechanism of NLRC4 on cryptococcal pulmonary infection using NLRC4-/-mice in vivo and NLRC4-/-macrophages in vitro models stimulated by cryptococcal cells. We apply small animal fluorescence imaging to detect the fungal burden in the lungs and living body micro-CT scans of mice and in vitro tissue micro-CT scans to compare differences in infection foci nodules and histopathological lesions, and the activation of caspase-1 and downstream cytokines were detected by Western bolt and ELISA, etc. The results demonstrated that cryptococcal infection can activate the Nod-like receptors of caspase-1 activation and NLRC4 inflammasomes in macrophages and dendritic cells and affect downstream IL-1β and IL-18 release. After cryptococcal infection, the survival rate, lung fungal burden, and histopathological damage of NLRC4-/- mice were significantly impaired. NLRC4-/- macrophages showed a lower release of inflammatory factors, reactive oxygen species (ROS), and lactate dehydrogenase (LDH). Collectively, our results demonstrated that the activation of caspase-1 and downstream cytokines mediated by NLRC4 inflammasome in immune cells during Cryptococcus infection can enhance pyroptosis of macrophages, affect the phagocytic ability of macrophages, and inhibit the intracellular parasitism of cryptococcus, eventually reducing the burden of fungi.

Cryptococcus: History, Epidemiology and Immune Evasion

“…In this sense, some analyses were carried out with regard to autophagy markers during an infection caused by C. neoformans and it was noted that unlike in other pathogenic yeast species, cryptococcosis caused by the selective intracellular pathogen C. neoformans is less severe in the absence of autophagy [239]. Furthermore, NLRC4 inflammasome-mediated activation of caspase-1 during C. gattii cryptococcosis increases pyroptosis in phagocytes and affects their phagocytic capacity by inhibiting the yeast intracellular parasitism [240]. Ueno and colleagues even describe that C. gattii has a greater resistance to oxidative stress generated by the antifungal activity of neutrophils than C. neoformans [241].…”

Retracted: The Inflammasome NLRC4 Protects against Cryptococcus gattii by Inducing the Classic Caspase-1 to Activate the Pyroptosis Signal

“…This article has been retracted by Hindawi following an investigation undertaken by the publisher [ 1 ]. This investigation has uncovered evidence of one or more of the following indicators of systematic manipulation of the publication process: Discrepancies in scope Discrepancies in the description of the research reported Discrepancies between the availability of data and the research described Inappropriate citations Incoherent, meaningless and/or irrelevant content included in the article Peer-review manipulation …”

“…Tis article has been retracted by Hindawi following an investigation undertaken by the publisher [1]. Tis investigation has uncovered evidence of one or more of the following indicators of systematic manipulation of the publication process:…”