This work aims to understand the molecular mechanisms governing fungal intracellular sensing and inflammasome activation, to provide critical insights into host—fungi interactions and inform the development of therapies for the increasing emergence of invasive and inflammatory fungal diseases.
Abstract
Fungal pathogens are increasingly recognized as important activators of the innate immune system, particularly through engagement of inflammasomes. These are large protein complexes that trigger pyroptosis, an inflammatory cell death resulting in the release of IL-1 family cytokines. Although a large body of evidence demonstrates that diverse fungal species activate inflammasomes, they employ various evasion mechanisms that can limit the level of cell death and IL-1 release.
Among the inflammasomes, NLRP3 has emerged as a central mediator of antifungal immunity. However, NLRP3 is not regarded as a direct pathogen sensor, but rather integrates signals related to potassium efflux, reactive oxygen species, and lysosomal damage. Given that many cytosolic sensors have defined ligands, a question that remains largely unexplored in the field of fungal innate immunity is whether specific cytosolic detection pathways exist for fungal cell wall components.
Our work aims to understand the molecular mechanisms governing fungal intracellular sensing and inflammasome activation, to provide critical insights into host—fungi interactions and inform the development of therapies for the increasing emergence of invasive and inflammatory fungal diseases.
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Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)
Innate immunity provides a critical first line of defense against pathogens and homeostatic perturbations. Pattern recognition receptors detect these disruptions and initiate immune responses through multi-protein complex formation to drive inflammatory signaling and cell death pathways. Key cytosolic complexes formed by these sensors include inflammasomes and PANoptosomes. Inflammasomes induce caspase-1 activation and the subsequent maturation of interleukin (IL)-1β and IL-18, and they can act as integral components of larger PANoptosomes, whose formation and functions have been defined by genetic, biochemical, and single-cell imaging evidence. PANoptosomes induce lytic, inflammatory cell death (PANoptosis) and promote the release of damage-associated molecular patterns (DAMPs) and cytokines beyond IL-1β and IL-18, including TNF, IFNs, IL-6, and others. Given their critical functions in driving cell death and the release of cytokines and DAMPs, dysregulation of innate immune sensors is associated with a wide range of diseases, including infections, autoinflammatory syndromes, cardiovascular disorders, neurodegeneration, metabolic conditions, and cancer. Therefore, understanding innate immune sensors and how they assemble inflammasomes and PANoptosomes to drive cell death is critical for identifying therapeutic strategies. In this review, we discuss innate immune sensors that form inflammasomes and PANoptosomes, such as NLRP1, NLRP3, NLRC4, AIM2, Pyrin, and others. We highlight recent structural and mechanistic insights into these sensors, along with emerging structural studies of inflammasome assemblies and the biochemical and functional evidence supporting the formation of PANoptosomes. Given the physiological relevance of innate immune sensors and the complexes they form across the disease spectrum, an improved understanding of their structure-function relationships will be critical for informing therapeutic strategies that target these molecules, their associated complexes, and their physiological functions.
Saurabh Upadhyay, R. Nagampalli, S. Resende et al.· Cell Research· 0 citations
Deletion of MEX3B inhibited caspase-4 and gasdermin D activation, pyroptosis, and secretion of inflammasome-dependent inflammatory cytokines in human cell lines and murine primary macrophages and suggested that MEX3B is a pan-inflammasome regulator targeting inflammatory caspases.
Peng-Hua Wang, Jason G. Cahoon, Duo-Meng Yang et al.· Journal of Immunology· 0 citations
The NLRP3 inflammasome is a central signaling pathway of innate immunity that orchestrates host defense and inflammatory responses through the activation of proinflammatory cytokines and the induction of pyroptotic cell death. Accumulating evidence indicates that NLRP3 functions within an extensive network of innate immune and cell death pathways. Reciprocal interactions between NLRP3 and other pattern-recognition receptor pathways, including Toll-like receptors, DNA-sensing cGAS-STING signaling, and RNA-sensing RIG-I/MDA5-MAVS signaling, shape the magnitude and duration of inflammatory responses during pathogen infection. Moreover, substantial crosstalk exists between NLRP3 and other inflammasomes and programmed cell death pathways, reflecting the integrated nature of cellular stress and inflammatory signaling. In this review, we summarize recent advances in our understanding of the molecular mechanisms that mediate these interactions, focusing on shared signaling components, organelle dynamics, posttranslational modifications, and feedback regulatory circuits. We further discuss how these signaling networks contribute to infectious and inflammatory diseases and highlight key unanswered questions and emerging areas of investigation that may guide the development of therapies targeting inflammasome-associated pathologies.
Nan-Yang Xiao, Ze-Xuan Lu, Destiny K. Cooper et al.· Cellular & Molecular Immunol...· 0 citations
Pyroptosis is an emerging form of inflammatory programmed cell death primarily mediated by the gasdermin protein family, characterized by cell swelling, membrane pore formation, and the release of pro-inflammatory cytokines such as IL-1β and IL-18. This mode of cell death has garnered significant attention due to its critical involvement in a variety of diseases, including cancer, cardiovascular disorders, autoimmune diseases, and metabolic syndromes, positioning it as a promising therapeutic target. Despite advances, the complexity of pyroptosis regulation and its dual roles in disease pathogenesis present challenges that necessitate comprehensive understanding. This review systematically summarizes the molecular regulatory mechanisms of pyroptosis, encompassing classical and non-classical inflammasome pathways, activation and modulation of gasdermin proteins, and the intricate signaling networks involved. We further highlight the dualistic roles of pyroptosis in tumor development, immune modulation, and chronic inflammatory conditions. Incorporating the latest research progress, we explore emerging therapeutic strategies targeting pyroptosis, including small molecule inhibitors, nanomaterials, stem cell-derived exosomes, and gene regulation technologies, critically evaluating their clinical applicability and limitations. By providing an integrative overview of pyroptosis-related mechanisms and innovative treatment approaches, this article aims to offer a theoretical foundation and future research direction for precision medicine and novel drug development.
Yi Shen, Qiang-Qiang Zheng, Yang Yuan et al.· Frontiers in Cell and Develo...· 0 citations
The mechanism by which MARCO facilitates LPS clearance to limit activation of the non-canonical inflammasome is defined, which shows that activation of the non-canonical inflammasome is preceded by a priming step by which type I interferon (IFN) suppresses MARCO expression on TRMs to allow for optimal recognition of LPS and activation of caspase-11.
Shriram Ramani, Sara E Cahill, M. Finnegan et al.· Journal of Immunology· 0 citations
Inflammasomes are central mediators of innate immune defense but can also drive pathological inflammation and pyroptotic cell death in numerous diseases. While several small-molecule inhibitors have been described, many selectively target individual inflammasomes or act through the adaptor protein ASC, leaving ASC-independent pathways unaffected. We previously identified thiomuscimol as a broad-spectrum inflammasome inhibitor that blocks both ASC-dependent and ASC-independent activation, although the structural basis for this activity remains unclear. Here, we examined the structure–activity relationship of thiomuscimol using related compounds and synthetic analogs. In primary macrophages, inflammasome activation and pyroptosis were assessed by live cell imaging of ASC speck formation, gasdermin D-mediated dye uptake, and cellular ATP levels. Structurally related sulfur-containing molecules, including taurine and isothiazole, failed to inhibit inflammasome activation, indicating that neither the sulfur in an electron-rich environment nor the heterocyclic scaffold confer activity. Replacement of the primary amine with a carbonyl group abolished activity, whereas substitution with a secondary amine preserved inhibitory potency comparable to thiomuscimol. Incorporation of the amine into an annulated piperidine ring reduced potency and revealed sensitivity to the precise positioning of the amine within the ring. Together, these findings identify key structural features required for thiomuscimol-mediated inflammasome inhibition and provide a framework for future studies to define its mechanism of action and guide the development of improved inhibitors.
Marisa J. Anderson, W. P. Loomis, Andreas B. den Hartigh et al.· International Journal of Mol...· 0 citations
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