Pyroptosis, metabolism, and tumor immune microenvironment

Abstract

In response to a wide range of stimulations, host cells activate pyroptosis, a kind of inflammatory cell death which is provoked by the cytosolic sensing of danger signals and pathogen infection. In manipulating the cleavage of gasdermins (GSDMs), researchers have found that GSDM proteins serve as the real executors and the deterministic players in fate decisions of pyroptotic cells. Whether inflammatory characteristics induced by pyroptosis could cause damage the host or improve immune activity is largely dependent on the context, timing, and response degree. Here, we systematically review current points involved in regulatory mechanisms and the multidimensional roles of pyroptosis in several metabolic diseases and the tumor microenvironment. Targeting pyroptosis may reveal potential therapeutic avenues.

Ferroptosis as a Major Factor and Therapeutic Target for Neuroinflammation in Parkinson’s Disease

“…Of note, necrostatin-1 has been reported to suppress necroptosis via inhibition of RIP1 activity [ 16 ]. With regards to pyroptosis, the predominant hallmarks are the activation of the inflammasome, a cytosolic multiprotein complex accounting for the release of interleukin-1 beta (IL1B) and IL18, the formation of apoptosis-associated speck-like protein containing a CARD (ASC), and the activation of proinflammatory cascades [ 17 ]. In general, when pattern recognition receptors (PRRs, e.g., nod-like receptor 3 (NLRP3) and absent in melanoma like receptor 2 (AIM2)) first identify various danger signals, they proceed to activate pro-caspase-1 cleavage and ASC recruitment in order to assemble inflammasomes.…”

“…Meanwhile, caspase-1 cleaves and activates the precursors of IL1B and IL18 to generate mature IL-1β and IL-18. The intracellular contents are subsequently released via GSDMD-MT-caused pores, leading to pyroptosis [ 17 ]. Additionally, an inflammasome-independent, noncanonical pathway mediated by a caspase-1/4/5/11-cleaved GSDMD-MT has been identified [ 18 , 19 , 20 ].…”

In Silico Drug Repurposing for Anti-Inflammatory Therapy: Virtual Search for Dual Inhibitors of Caspase-1 and TNF-Alpha

“…At the biomolecular level, caspase-1 and tumor necrosis factor-alpha (TNF-alpha) are two key proteins involved in the development and progression of dysregulated inflammation. From one side, caspase-1 acts as an inflammatory response initiator, inducing a proinflammatory response by cleaving (and thus activating) two inflammatory cytokines [ 6 , 7 , 8 ] known as interleukin 1β (IL-1β) and interleukin 18 (IL-18) while inducing pyroptosis (a programmed lytic cell-death pathway) [ 9 , 10 ] through the cleavage of the protein gasdermin D. On the other hand, TNF-alpha is a cytokine that has been identified as a central player in the pathogenesis of inflammation and autoimmune diseases [ 11 ] and can trigger several inflammation-related proteins such as caspase-1 [ 12 ], as well as other cytokines and chemokines [ 13 ]. An important aspect to highlight here is that both caspase-1 and TNF-alpha are essential in the development of the hyperinflammatory physiological reaction known as cytokine storm, which is present in viral infections caused by coronaviruses [ 14 , 15 ], including the causal agent of the current COVID-19 pandemic (SARS-CoV-2) [ 14 , 15 , 16 ].…”

The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future

“…As a necroptotic effector, the activated MLKL translocates to the plasma membrane, causing permeabilization and subsequent cell death. The predominant hallmarks of pyroptosis are the activation of an inflammasome, a cytosolic multiprotein complex accounting for the release of interleukin-1β (IL-1β) and IL-18, the formation of an apoptosis-associated speck-like protein containing a CARD (ASC), and the activation of proinflammatory cascades [16]. Generally, pattern recognition receptors (PRRs, e.g., nod-like receptor 3 (NLRP3) and absent in melanoma-like receptor 2 (AIM2)) first recognize a variety of dangerous signals, then activate procaspase-1 cleavage and ASC recruitment to assemble inflammasomes.…”

“…Meanwhile, caspase-1 cleaves and activates the precursors of IL-1β and IL-18 to produce mature IL-1β and IL-18. The intracellular contents are then released through pores caused by GSDMD-NT, leading to pyroptosis [16]. In addition, an inflammasome-independent, non-canonical pathway mediated by a caspase-1/4/5/11cleaved GSDMD-NT was recognized [17][18][19].…”