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
Pathogens, tissue damage, and cellular stress are detected by innate immune sensor molecules to drive inflammatory signaling and cell death. Mutations in the sensor NLRP1 are associated with inflammatory disease, but the regulation of this sensor is not well understood. Here, we find that LPS, a TLR4 ligand and canonical activator of innate immunity, inhibits NLRP1-mediated caspase activation, IL-18 release, and inflammatory cell death, PANoptosis. This inhibition requires TRIF but not MyD88, implicating TRIF-dependent TLR signaling. IRF3 is also required, suggesting an essential role for type I IFN signaling. Indeed, IFN-β production or treatment with exogenous IFN-α or IFN-β inhibits NLRP1-dependent PANoptosis in mouse bone marrow-derived macrophages and human macrophages and monocytes. Mechanistically, Nlrp1b/NLRP1 expression is significantly reduced in LPS- or type I IFN-treated cells. Overall, our study identifies a TLR4-TRIF-IRF3 signaling axis that induces type I IFNs to negatively regulate NLRP1 transcription, thereby blocking NLRP1-driven, caspase-1/caspase-8/RIPK3-dependent PANoptosis. These findings suggest type I IFNs as a potential therapeutic strategy for NLRP1-driven inflammatory diseases.
B. Sharma, Harisankeerth Mummareddy, S. Chadchan et al.· EMBO Reports· 1 citation
Severe infections often cause life-threatening inflammation, multi-organ failure, and death. During infection, pathogens carry multiple pathogen-associated molecular patterns (PAMPs) such as LPS, flagellin, nucleic acids, and lipoproteins which activate more than one pattern-recognition receptor (PRR). These PRRs trigger cytokine secretion and inflammatory cell death to control pathogen load; however, a dysregulated immune response can lead to excessive inflammation and lethality. While earlier studies have primarily focused on single PAMP responses, cells in vivo are exposed to multiple microbial ligands simultaneously.
Primary bone marrow-derived macrophages (BMDMs) were stimulated with PAMPs, and real-time imaging of cell death was performed using the IncuCyte system. Microarray analysis was conducted to examine differential gene expression.
We found that specific PAMP combinations induce lytic cell death, while other combinations do not. Toll-like receptors (TLRs) and their adaptor molecules, MyD88 and TRIF, functioned as upstream regulators that activated inflammatory cell death. In addition, signaling through the interferon-α/β receptor (IFNAR) and interferon regulatory factor 1 (IRF1) was essential for the induction of inflammatory cell death. We also performed microarray analysis to understand the upregulated and downregulated genes in PAMP combinations compared with the untreated control. Through this analysis, we identified significant differences in specific molecules, and we performed genetic, functional validation to show that these molecules directly modulated the induction of inflammatory cell death.
These findings identify key mediators of lytic cell death and suggest that targeting these pathways can be used to mitigate inflammation and lethality during infections.
This research was supported by NIH grants AI101935, AI124346, AI160179, AR056296, and CA253095 and the American Lebanese Syrian Associated Charities to Dr. Kanneganti.
Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)
Balamurugan Sundaram, T. Kanneganti· Journal of Immunology· 0 citations
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