Gasdermins were recently identified as the mediators of pyroptosis — inflammatory cell death triggered by cytosolic sensing of invasive infection and danger signals. Upon activation, gasdermins form cell membrane pores, which release pro-inflammatory cytokines and alarmins and damage the integrity of the cell membrane. Roles for gasdermins in autoimmune and inflammatory diseases, infectious diseases, deafness and cancer are emerging, revealing potential novel therapeutic avenues. Here, we review current knowledge of the family of gasdermins, focusing on their mechanisms of action and roles in normal physiology and disease. Efforts to develop drugs to modulate gasdermin activity to reduce inflammation or activate more potent immune responses are highlighted. Gasdermins (GSDMs) are a recently characterized protein family that mediate a programmed inflammatory cell death termed pyroptosis. Here, Lieberman and colleagues review current understanding of the expression, activation and regulation of GSDMs, highlighting their roles in cell death, cytokine secretion and inflammation. Emerging opportunities to develop GSDM-targeted drugs and the associated challenges are highlighted.

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Channelling inflammation: gasdermins in physiology and disease.

Airway epithelial barrier dysfunction is frequently observed in asthma and may have important implications. The physical barrier function of the airway epithelium is tightly interwoven with its immunomodulatory actions, while abnormal epithelial repair responses may contribute to remodelling of the airway wall. We propose that abnormalities in the airway epithelial barrier play a crucial role in the sensitization to allergens and pathogenesis of asthma. Many of the identified susceptibility genes for asthma are expressed in the airway epithelium, supporting the notion that events at the airway epithelial surface are critical for the development of the disease. However, the exact mechanisms by which the expression of epithelial susceptibility genes translates into a functionally altered response to environmental risk factors of asthma are still unknown. Interactions between genetic factors and epigenetic regulatory mechanisms may be crucial for asthma susceptibility. Understanding these mechanisms may lead to identification of novel targets for asthma intervention by targeting the airway epithelium. Moreover, exciting new insights have come from recent studies using single-cell RNA sequencing (scRNA-Seq) to study the airway epithelium in asthma. This review focuses on the role of airway epithelial barrier function in the susceptibility to develop asthma and novel insights in the modulation of epithelial cell dysfunction in asthma.

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Epithelial cell dysfunction, a major driver of asthma development

Pyroptosis, apoptosis and necroptosis are the most genetically well-defined programmed cell death (PCD) pathways, and they are intricately involved in both homeostasis and disease. Although the identification of key initiators, effectors and executioners in each of these three PCD pathways has historically delineated them as distinct, growing evidence has highlighted extensive crosstalk among them. These observations have led to the establishment of the concept of PANoptosis, defined as an inflammatory PCD pathway regulated by the PANoptosome complex with key features of pyroptosis, apoptosis and/or necroptosis that cannot be accounted for by any of these PCD pathways alone. In this review, we provide a brief overview of the research history of pyroptosis, apoptosis and necroptosis. We then examine the intricate crosstalk among these PCD pathways to discuss the current evidence for PANoptosis. We also detail the molecular evidence for the assembly of the PANoptosome complex, a molecular scaffold for contemporaneous engagement of key molecules from pyroptosis, apoptosis, and/or necroptosis. PANoptosis is now known to be critically involved in many diseases, including infection, sterile inflammation and cancer, and future discovery of novel PANoptotic components will continue to broaden our understanding of the fundamental processes of cell death and inform the development of new therapeutics.

From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways

A new research hot spot: The role of NLRP3 inflammasome activation, a key step in pyroptosis, in diabetes and diabetic complications.

Hyperglycemia-induced oxidative stress and fibrosis play a crucial role in the development of diabetic cardiomyopathy (DCM). Tetrahydrocurcumin (THC), a major bioactive metabolite of natural antioxidant curcumin, is reported to exert even more effective antioxidative and superior antifibrotic properties as well as anti-inflammatory and antidiabetic abilities. This study was designed to investigate the potential protective effects of THC on experimental DCM and its underlying mechanisms, pointing to the role of high glucose-induced oxidative stress and interrelated fibrosis. In STZ-induced diabetic mice, oral administration of THC (120 mg/kg/d) for 12 weeks significantly improved the cardiac function and ameliorated myocardial fibrosis and cardiac hypertrophy, accompanied by reduced reactive oxygen species (ROS) generation. Mechanically, THC administration remarkably increased the expression of the SIRT1 signaling pathway both in vitro and in vivo, further evidenced by decreased downstream molecule Ac-SOD2 and enhanced deacetylated production SOD2, which finally strengthened antioxidative stress capacity proven by repaired activities of SOD and GSH-Px and reduced MDA production. Additionally, THC treatment accomplished its antifibrotic effect by depressing the ROS-induced TGFβ1/Smad3 signaling pathway followed by reduced expression of cardiac fibrotic markers α-SMA, collagen I, and collagen III. Collectively, these finds demonstrated the therapeutic potential of THC treatment to alleviate DCM mainly by attenuating hyperglycemia-induced oxidative stress and fibrosis via activating the SIRT1 pathway.

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Tetrahydrocurcumin Ameliorates Diabetic Cardiomyopathy by Attenuating High Glucose-Induced Oxidative Stress and Fibrosis via Activating the SIRT1 Pathway.

Background The airway epithelium maintains mucosal homeostasis and effectively responds to pathogens. The roles of the epithelial NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in human rhinovirus (hRV) infection and its effects mediating epithelial functional changes remain poorly understood. Objective We investigated the mechanisms and cellular functions mediated by the epithelial NLRP3 inflammasome on hRV infection. Methods Using models of primary human nasal epithelial progenitor cells and differentiated human nasal epithelial cells (hNECs) infected by hRV, we functionally examined key factors for NLRP3 inflammasome activation, cell death, and mucus production. Furthermore, NLRP3 and IL-1β in human epithelium from nasal mucosal inflammation induced by hRV were evaluated. Results The inflammasome-mediated IL-1β secretion and pyroptosis in human nasal epithelial progenitor cells and hNECs on hRV infection were dependent on the DDX33/DDX58–NLRP3–caspase-1–GSDMD axis. In differentiated hNECs hRV could also promote major airway epithelial mucin (MUC5AC) production through this axis. Our results further confirmed that the NLRP3 inflammasome signaling pathway was responsible for suppressing hRV replication in airway epithelium. Finally, hRV infection in chronically inflamed nasal mucosa was associated with epithelial mucus hyperproduction, whereas NLRP3 and IL-1β expression levels were significantly increased in hRV-infected epithelium with goblet cell hyperplasia compared with normal epithelium without viral infection. Conclusion The current study showed that the NLRP3 inflammasome signaling axis could functionally mediate hRV-induced inflammation, pyroptosis, and mucus production in airway epithelium, which might be an essential mechanism associated with hRV-induced airway remodeling.

NOD-like receptor family, pyrin domain containing 3 (NLRP3) contributes to inflammation, pyroptosis, and mucin production in human airway epithelium on rhinovirus infection

Background Curcumin (Cur), derived from Curcuma species, exhibits anti‐inflammatory, antioxidant, and anticancer effects. Although Cur has some beneficial effects on asthma, its clinical application is limited by its low bioavailability. Tetrahydrocurcumin (THC), the major active metabolite of Cur, has multiple biological functions, similarly to Cur, and importantly, it showed enhanced bioavailability in tissues and plasma. However, the effect of THC on asthma has not been reported. Objective The current study sought to investigate the efficacy of dietary THC on allergic asthma compared to that of Cur in an animal model. Methods The anti‐inflammatory effects of Cur and THC were evaluated in an ovalbumin‐induced asthmatic mouse model. The nasal symptoms, pathological alterations of the lung tissues, oxidants and antioxidants, cytokine production, T cell subsets, and Th2‐related signalling pathway activity were assessed. Results Both THC and Cur had beneficial effects on asthmatic mice with regard to nasal symptoms, pathological changes (eosinophils and mucus hyper‐production), oxidative stress (malondialdehyde), cytokine production (IL‐13), Th17 and cytotoxic T cell subsets, and Th2 signalling pathway (IL‐4Rα‐Jak1‐STAT6 and Jagged1/Jagged2‐Notch1/Notch2 axis) activity. THC was more effective than Cur in suppressing tissue eosinophilia, mucus production, and IL‐4Rα/Jak1/STAT6 pathway activity. Furthermore, only THC inhibited peripheral eosinophil levels, Th2 cytokines (IL‐4 and IL‐5), and Th2 cell subsets and enhanced an antioxidant enzyme (glutathione). Conclusion and Clinical Relevance The above results demonstrated for the first time that THC was superior to Cur in modulating allergic asthmatic phenotypes, especially attenuating the Th2 response. THC might be a potentially effective agent for asthma treatment.

Tetrahydrocurcumin, a major metabolite of curcumin, ameliorates allergic airway inflammation by attenuating Th2 response and suppressing the IL-4Rα-Jak1-STAT6 and Jagged1/Jagged2 -Notch1/Notch2 pathways in asthmatic mice

Objective Neutrophil infiltration in patients with sinonasal inverted papilloma (SNIP) is significantly high. Whether IL-17, which is a potent factor mediating neutrophilic inflammation, is involved in the neutrophilic phenotype of SNIP is investigated in the current study. Study design Laboratorial study. Participants Nasal papilloma and inferior turbinate were collected from patients with SNIP (n = 50) and control subjects with septal deviation (n = 15). Methods IL-17 + cells were evaluated in tissues obtained from patients with SNIP and control subjects with septal deviation, by immunohistochemistry and flow cytometry. Main outcome measures The IL-17 + cells were mainly localised in mononuclear cells and neutrophils, and were up-regulated in the SNIP samples compared with those in the controls. The IL-17 + T-cell subsets mainly included CD4+ (Th17, 60.0%) and CD8+ (Tc17, 30.0%), and both subsets were enhanced in the SNIP samples than controls. The total level of IL-17 + cells was significantly correlated with neutrophil infiltration in the SNIP tissues. Furthermore, the SNIP homogenates could significantly promote IL-17 production in peripheral blood mononuclear cells. Conclusions An increase in IL-17 + cells is evident in SNIP and may be involved in neutrophil infiltration in local tissues. IL-17 could be a potential therapeutic target to relieve the neutrophilic pathological change in SNIP.

Increase in IL-17-positive cells in sinonasal inverted papilloma

Background Recent studies have shown that human nasal epithelial progenitor cells (hNEPCs) are characterized by poor proliferation capacities during chronic nasal inflammation. Objective We sought to investigate the key molecular functions and candidates that contribute to the reduced growth potential of hNEPCs in chronically inflamed nasal mucosa. Methods Nasal biopsy specimens were obtained from 28 patients with nasal polyps (NPs) and 13 healthy controls. hNEPCs from nasal samples were cultured for 3 consecutive passages, and their molecular and functional profiles were analyzed by RNA sequencing. The minichromosome maintenance protein (MCM) family gene MCM2 was validated in hNEPCs and tissue samples from patients with NPs and control subjects by cell cycle, quantitative PCR, and Western blot analyses; small interfering RNA–mediated knockdown assay; and immunofluorescent staining. Results Compared with control hNEPCs, NP-derived hNEPCs showed (1) reduced growth kinetics, as evidenced by the colony-forming efficiency and doubling time; (2) inhibited cell cycle progression, as evidenced by gene ontology and/or pathway and cell cycle analyses; and (3) downregulated expression of MCM2, the key protein of the MCM complex, which is critical for DNA replication at the G1/S checkpoint. Moreover, hNEPCs with MCM2 knockdown showed a decreased proliferation rate, and the MCM2 protein level in basal cells was significantly lower in abnormally remodeled nasal epithelium than in normal epithelium. Conclusion These results demonstrate inhibited cell cycle progression and MCM2 downregulation in basal or progenitor nasal epithelial cells from NP tissue, which may contribute to the decreased growth potential of hNEPCs in chronically inflamed upper airways.

Yu Tao Zhou

Papers

NOD-like receptor family, pyrin domain containing 3 (NLRP3) contributes to inflammation, pyroptosis, and mucin production in human airway epithelium on rhinovirus infection

Tetrahydrocurcumin, a major metabolite of curcumin, ameliorates allergic airway inflammation by attenuating Th2 response and suppressing the IL-4Rα-Jak1-STAT6 and Jagged1/Jagged2 -Notch1/Notch2 pathways in asthmatic mice

Increase in IL-17-positive cells in sinonasal inverted papilloma

Downregulation of MCM2 contributes to the reduced growth potential of epithelial progenitor cells in chronic nasal inflammation