In recent decades, chemotherapies targeting apoptosis have emerged and demonstrated remarkable achievements. However, emerging evidence has shown that chemoresistance is mediated by impairing or bypassing apoptotic cell death. Several novel types of programmed cell death, such as ferroptosis, necroptosis, and pyroptosis, have recently been reported to play significant roles in the modulation of cancer progression and are considered a promising strategy for cancer treatment. Thus, the switch between apoptosis and pyroptosis is also discussed. Cancer immunotherapy has gained increasing attention due to breakthroughs in immune checkpoint inhibitors; moreover, ferroptosis, necroptosis, and pyroptosis are highly correlated with the modulation of immunity in the tumor microenvironment. Compared with necroptosis and ferroptosis, pyroptosis is the primary mechanism for host defense and is crucial for bridging innate and adaptive immunity. Furthermore, recent evidence has demonstrated that pyroptosis exerts benefits on cancer immunotherapies, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell therapy (CAR-T). Hence, in this review, we elucidate the role of pyroptosis in cancer progression and the modulation of immunity. We also summarize the potential small molecules and nanomaterials that target pyroptotic cell death mechanisms and their therapeutic effects on cancer.

Inflammation-related pyroptosis, a novel programmed cell death pathway, and its crosstalk with immune therapy in cancer treatment.

AIM2 is a cytosolic innate immune receptor which recognizes double-stranded DNA (dsDNA) released during cellular perturbation and pathogenic assault. AIM2 recognition of dsDNA leads to the assembly of a large multiprotein oligomeric complex termed the inflammasome. This inflammasome assembly leads to the secretion of bioactive interleukin-1β (IL-1β) and IL-18 and induction of an inflammatory form of cell death called pyroptosis. Sensing of dsDNA by AIM2 in the cytosol is crucial to mediate protection against the invading pathogens including bacteria, virus, fungi and parasites. AIM2 also responds to dsDNA released from damaged host cells, resulting in the secretion of the effector cytokines thereby driving the progression of sterile inflammatory diseases such as skin disease, neuronal disease, chronic kidney disease, cardiovascular disease and diabetes. Additionally, the protection mediated by AIM2 in the development of colorectal cancer depends on its ability to regulate epithelial cell proliferation and gut microbiota in maintaining intestinal homeostasis independently of the effector cytokines. In this review, we will highlight the recent progress on the role of the AIM2 inflammasome as a guardian of cellular integrity in modulating chronic inflammatory diseases, cancer and infection.

https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.201848070

Role of AIM2 inflammasome in inflammatory diseases, cancer and infection

NLRP3 inflammasome is a vital player in macrophages pyroptosis, which is a type of proinflammatory cell-death and takes part in the pathogenesis of atherosclerosis. In this study, we used apoE−/− mice and ox-LDL induced THP-1 derived macrophages to explore the mechanisms of MCC950, a selective NLRP3 inhibitor in treating atherosclerosis. For the in vivo study, MCC950 was intraperitoneal injected to 8-week-old apoE−/− mice fed with high-fat diet for 12 weeks. For the in vitro study, THP-1 derived macrophages were treated with ox-LDL and MCC950 for 48 h. MCC950 administration reduced plaque areas and macrophages contents, but did not improve the serum lipid profiles in aortic root of apoE−/− mice. MCC950 inhibited the activation of NLRP3/ASC/Caspase-1/GSDMD-N axis, and alleviated macrophages pyroptosis and the production of IL-1β and IL-18 both in aorta and in cell lysates. However, MCC950 did not affect the expression of TLR4 or the mRNA levels of NLRP3 inflammasome and its downstream proteins, suggesting that MCC950 had no effects on the priming of NLRP3 inflammasome activation in macrophages. The anti-atherosclerotic mechanisms of MCC950 on attenuating macrophages inflammation and pyroptosis involved in inhibiting the assembly and activation of NLRP3 inflammasome, rather than interrupting its priming.

/pdf/the-selective-nlrp3-inhibitor-mcc950-hinders-atherosclerosis-2268w9t4a5.pdf

The selective NLRP3 inhibitor MCC950 hinders atherosclerosis development by attenuating inflammation and pyroptosis in macrophages.

Pyroptosis, a lytic pro-inflammatory type of programmed cell death, has been widely studied in diverse inflammatory disease models. Membrane perforation and cell swelling induced by cleaved gasdermin family members is the main characteristic of pyroptosis. Emerging evidence has revealed a complicated relationship between pyroptosis and cancer. On the one hand, as inflammatory cell death, pyroptosis provides a comfortable environment for tumor proliferation. On the other hand, excessive activation of pyroptosis can inhibit the development of tumor cells. In this review, we first summarized the latest progress about the molecular mechanism of pyroptosis. Then, members from gasdermin family, the central molecules of pyroptosis which formed pores on the cell membrane, were highlighted. In the second part of this review, we summarized drugs that induced pyroptosis in different tumors and their concrete mechanisms based on recent literature reports. In the final section, we discussed several hotspots in pyroptosis and cancer therapy, which will point out the direction of sequent research. In brief, inducing pyroptosis in cancer cells is a promising strategy for cancer therapy.

/pdf/induction-of-pyroptosis-a-promising-strategy-for-cancer-34j1f0jmvl.pdf

Induction of Pyroptosis: A Promising Strategy for Cancer Treatment.

Exploration of the mechanism of Zisheng Shenqi decoction against gout arthritis using network pharmacology

MCC950 has been proposed as a specific small molecule inhibitor that can selectively block NLRP3 inflammasome activation. However, the exact mechanism of its action is still ambiguous. Accumulating investigations imply that chloride efflux-dependent ASC speck oligomerization and potassium efflux-dependent activation of caspase-1 are the two relatively independent, but indispensable events for NLRP3 inflammasome activation. Previous studies suggested that influence of MCC950 on potassium efflux and its consequent events such as interaction between NEK7 and NLRP3 are limited. However, inhibiting chloride intracellular channel-dependent chloride efflux leads to a modification of inflammatory response, which is similar to the function of MCC950. Based on these findings, we shed new insights on the understanding of MCC950 that its function might correlate with chloride efflux, chloride intracellular channels, or other targets that act upstream of chloride efflux.

Target of MCC950 in Inhibition of NLRP3 Inflammasome Activation: a Literature Review.

Purpose Macrophages play vital roles in the development of atherosclerosis in responding to lipid accumulation and inflammation. Macrophages were classified as inflammatory (M1) and alternatively activated (M2) macrophage types based on results of in vitro experiments. On the other hand, the composition of macrophages in vivo is more complex and remains unresolved. This review summarizes the transcriptional variations of macrophages in atherosclerosis plaques that were discovered by single-cell RNA sequencing (scRNA-seq) to better understand their contribution to atherosclerosis. Recent findings ScRNA-seq provides a more detailed transcriptional landscape of macrophages in atherosclerosis, which challenges the traditional view. By mining the data of GSE97310, we discovered the transcriptional variations of macrophages in LDLR-/- mice that were fed with high-fat diet (HFD) for 11 and 20 weeks. Cells were represented in a two-dimensional tSNE plane and clusters were identified and annotated via Seurat and SingleR respectively, which were R toolkits for single-cell genomics. The results showed that in healthy conditions, Trem2hi (high expression of triggering receptors expressed on myeloid cells 2)-positive, inflammatory, and resident-like macrophages make up 68%, 18%, and 6% of total macrophages respectively. When mice were fed with HFD for 11 weeks, Trem2hi, monocytes, and monocyte-derived dendritic cells take possession of 40%, 18%, and 17% of total macrophages respectively. After 20 weeks of HFD feeding, Trem2hi, inflammatory, and resident-like macrophages occupied 12%, 37%, and 35% of total macrophages respectively. The phenotypes of macrophages are very different from the previous studies. In general, Trem2hi macrophages are the most abundant population in healthy mice, while the proportion of monocytes increases after 11 weeks of HFD. Most importantly, inflammatory and resident-like macrophages make up 70% of the macrophage populations after 20 weeks of HFD. These strongly indicate that inflammatory and resident-like macrophages promote the progression of atherosclerosis plaques.

New Classification of Macrophages in Plaques: a Revolution

This review focuses on current advances in researches of gasdermin family. The distinctive expression patterns and biological roles of members in this family were discussed. Most of them exhibit pore-forming activity on cell membranes and are executors for programmed cell death with cytokines release, and play roles in cancers and inflammation-driven diseases. Therefore, they can be used as potential therapeutic targets to treat related diseases.

Gasdermin family: a promising therapeutic target for cancers and inflammation-driven diseases

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Target of MCC950 in Inhibition of NLRP3 Inflammasome Activation: a Literature Review.

New Classification of Macrophages in Plaques: a Revolution

Gasdermin family: a promising therapeutic target for cancers and inflammation-driven diseases