The noncanonical inflammasome-induced pyroptosis and septic shock.

Sepsis remains one of the most common and lethal conditions globally. Currently, no proposed target specific to sepsis improves survival in clinical trials. Thus, an in-depth understanding of the pathogenesis of sepsis is needed to propel the discovery of effective treatment. Recently attention to sepsis has intensified because of a growing recognition of a non-canonical inflammasome-triggered lytic mode of cell death termed pyroptosis upon sensing cytosolic lipopolysaccharide (LPS). Although the consequences of activation of the canonical and non-canonical inflammasome are similar, the non-canonical inflammasome formation requires caspase-4/5/11, which enzymatically cleave the pore-forming protein gasdermin D (GSDMD) and thereby cause pyroptosis. The non-canonical inflammasome assembly triggers such inflammatory cell death by itself; or leverages a secondary activation of the canonical NLRP3 inflammasome pathway. Excessive cell death induced by oligomerization of GSDMD and NINJ1 leads to cytokine release and massive tissue damage, facilitating devastating consequences and death. This review summarized the updated mechanisms that initiate and regulate non-canonical inflammasome activation and pyroptosis and highlighted various endogenous or synthetic molecules as potential therapeutic targets for treating sepsis.

Spotlight on pyroptosis: role in pathogenesis and therapeutic potential of ocular diseases.

Pyroptosis is a programmed cell death characterized by swift plasma membrane disruption and subsequent release of cellular contents and pro-inflammatory mediators (cytokines), including IL-1ß and IL-18. It differs from other types of programmed cell death such as apoptosis, autophagy, necroptosis, ferroptosis, and NETosis in terms of its morphology and mechanism. As a recently discovered form of cell death, pyroptosis has been demonstrated to be involved in the progression of multiple diseases. Recent studies have also suggested that pyroptosis is linked to various ocular diseases. In this review, we systematically summarized and discussed recent scientific discoveries of the involvement of pyroptosis in common ocular diseases, including diabetic retinopathy, age-related macular degeneration, AIDS-related human cytomegalovirus retinitis, glaucoma, dry eye disease, keratitis, uveitis, and cataract. We also organized new and emerging evidence suggesting that pyroptosis signaling pathways may be potential therapeutic targets in ocular diseases, hoping to provide a summary of overall intervention strategies and relevant multi-dimensional evaluations for various ocular diseases, as well as offer valuable ideas for further research and development from the perspective of pyroptosis.

Wedelolactone ameliorates Pseudomonas aeruginosa-induced inflammation and corneal injury by suppressing caspase-4/5/11/GSDMD-mediated non-canonical pyroptosis.

Pseudomonas aeruginosa (P. aeruginosa) keratitis, a worldwide leading cause of corneal perforation and blindness, which is associated with contact lens usage. Increasing evidence has indicated that pyroptosis, a novel proinflammatory programmed cell death, is linked with ocular diseases, little is known about the role of noncanonical pyroptosis in microbial keratitis. Here, we first indicated the involvement of noncanonical pyroptosis in P. aeruginosa keratitis and investigated whether wedelolactone (WDL), a major active component of Eclipta prostrate known to target caspase-11, could alleviate P. aeruginosa keratitis development. We found the expression of caspase-4/5/11 and cleaved GSDMD in corneas of P. aeruginosa keratitis patients, animal models and lipopolysaccharide (LPS)-induced primary cultured human corneal keratocytes (piHCKs) were increased. Combining ciprofloxacin with WDL significantly ameliorated the severity of P. aeruginosa keratitis, as manifested by decreased inflammatory responses and reduced corneal epithelial defects. Consistent with these findings, WDL also dose-dependently alleviated LPS-induced noncanonical pyroptosis by reversing the increased expression of caspase-4/5 and GSDMD in piHCKs. In summary, our results demonstrated that by targeting the activation of caspase-4/5/11, wedelolactone inhibited the development of P. aeruginosa keratitis and suppressed the release of proinflammatory cytokines. Wedelolactone may be a promising anti-inflammatory candidate to combat P. aeruginosa keratitis.

Role of Pyroptosis in Respiratory Diseases and its Therapeutic Potential.

Pyroptosis is an inflammatory type of regulated cell death that is dependent on inflammasome activation and downstream proteases such as caspase-1 or caspase 4/5/11. The main executors are gasdermins, which have an inherent pore-forming function on the membrane and release inflammatory cytokines, such as interleukin (IL)-1ß, IL-18 and high mobility group box 1. Emerging evidence demonstrates that pyroptosis is involved in the pathogenesis of various pulmonary diseases. In this review, we mainly discuss the biological mechanisms of pyroptosis, explore the relationship between pyroptosis and respiratory diseases, and discuss emerging therapeutic strategies for respiratory diseases.

Switch Off "Parallel Circuit": Insight of New Strategy of Simultaneously Suppressing Canonical and Noncanonical Inflammation Activation in Endotoxemic Mice.

Sepsis is a life-threatening inflammatory disease with a high mortality rate and huge implicative costs. Lipopolysaccharide (LPS) from gram-negative bacteria activates toll-like receptor 4 (TLR4) and may trigger septic shock. However, potent TLR4 inhibitors TAK-242 and Eritoran have been terminated in phase III clinical trials because of inadequate efficacy. Inspired by the recently discovered intracellular, noncanonical LPS receptors, it is considered that TLR4-mediated canonical and caspase-mediated noncanonical inflammation can be seen as a "parallel circuit" to induce sepsis and endotoxemia. Logically, it is proposed that the dual inhibition of caspase-4/5/11 and TLR4 can be a potential novel strategy to develop new therapeutics for sepsis. To verify the strategy, two potential compounds are found: Luteolin and Diacerein with substantial antiinflammatory activity in vitro and in vivo. The results show that the survival rate of endotoxemic mice treated by these compounds is increased remarkably. LPS-induced organ damage is also prevented. Moreover, these compounds result in physical and mental recovery for endotoxemic mice. Notably, Luteolin exhibits better antiinflammatory activity than TAK-242 at comparable TLR4-inhibitory levels. These findings indicate that simultaneous inhibition of TLR4 and caspase-4/5/11 can be an anticipative strategy defeating sepsis and endotoxemia, which can be translated into significant medical and economic benefits.

Role of pyroptosis in cardiovascular diseases.

Pyroptosis is a form of programmed necrosis, and is morphologically and mechanistically unique form of programmed cell death compared to others, such as apoptosis and autophagic cell death. More specifically, pyroptosis features gasdermin family-mediated membrane pore formation and subsequent cell lysis, as well as release of pro-inflammatory intracellular contents including IL-1ß, IL-18 and HMGB1. Mechanistically, pyroptosis is driven by two main signaling pathways - one mediated by caspase-1 and the other by caspase-4/5/11. Recent studies show that pyroptosis is implicated in several cardiovascular diseases. In this review, we summarize recent scientific discoveries of pyroptosis's involvement in atherosclerosis, myocardial infarction, diabetic cardiomyopathy, reperfusion injury and myocarditis. We also organized new and emerging evidence suggesting that pyroptosis signaling pathways may be potential therapeutic targets in cardiovascular diseases.

Mass Spectrometry-based Structural Analysis and Systems Immunoproteomics Strategies for Deciphering the Host Response to Endotoxin.

One cause of sepsis is systemic maladaptive immune response of the host to bacteria and specifically, to Gram-negative bacterial outer-membrane glycolipid lipopolysaccharide (LPS). On the host myeloid cell surface, proinflammatory LPS activates the innate immune system via Toll-like receptor-4/myeloid differentiation factor-2 complex. Intracellularly, LPS is also sensed by the noncanonical inflammasome through caspase-11 in mice and 4/5 in humans. The minimal functional determinant for innate immune activation is the membrane anchor of LPS called lipid A. Even subtle modifications to the lipid A scaffold can enable, diminish, or abolish immune activation. Bacteria are known to modify their LPS structure during environmental stress and infection of hosts to alter cellular immune phenotypes. In this review, we describe how mass spectrometry-based structural analysis of endotoxin helped uncover major determinations of molecular pathogenesis. Through characterization of LPS modifications, we now better understand resistance to antibiotics and cationic antimicrobial peptides, as well as how the environment impacts overall endotoxin structure. In addition, mass spectrometry-based systems immunoproteomics approaches can assist in elucidating the immune response against LPS. Many regulatory proteins have been characterized through proteomics and global/targeted analysis of protein modifications, enabling the discovery and characterization of novel endotoxin-mediated protein translational modifications.