Inflammatory Cell Death Pathways Research Articles

RIPK3 and Caspase-1/11 Are Necessary for Optimal Antigen-Specific CD8 T Cell Response Elicited by Genetically Modified Listeria monocytogenes.

Efficient induction of effector and long-term protective antigen-specific CD8+ T memory response by vaccination is essential to eliminate malignant and pathogen-infected cells. Intracellular infectious bacteria, including Listeria monocytogenes, have been considered potent vectors to carry multiple therapeutic proteins and generate antigen-specific CD8+ T cell responses. Although the role of molecules involved in inflammatory cell death pathways, such as necroptosis (RIPK3-mediated) and pyroptosis (Caspase-1/11-mediated), as effectors of immune response against intracellular bacteria are relatively well understood, their contribution to the adjuvant effect of recombinant bacterial vectors in the context of antigen-specific CD8+ T cell response remained obscure. Therefore, we evaluated the impact of RIPK3 and Caspase-1/11 (Casp-1/11) individual and combined deficiencies on the modulation of antigen-specific CD8+ T cell response during vaccination of mice with ovalbumin-expressing L. monocytogenes (LM-OVA). We observed that Casp-1/11 but not RIPK3 deficiency negatively impacts the capacity of mice to clear LM-OVA. Importantly, both RIPK3 and Casp-1/11 are necessary for optimal LM-OVA-mediated antigen-specific CD8+ T cell response, as measured by in vivo antigen-specific CD8+ T cell proliferation, target cell elimination, and cytokine production. Furthermore, Casp-1/11 and Casp-1/11/RIPK3 combined deficiencies restrict the early initiation of antigen-specific CD8+ T cell memory response. Taken together, our findings demonstrate that RIPK3 and Casp-1/11 influence the quality of CD8+ T cell responses induced by recombinant L. monocytogenes vectors.

Programmed Cell Death Pathways in the Pathogenesis of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by excessive inflammatory and immune responses and tissue damage. Increasing evidence has demonstrated the important role of programmed cell death in SLE pathogenesis. When apoptosis encounters with defective clearance, accumulated apoptotic cells lead to secondary necrosis. Different forms of lytic cell death, including secondary necrosis after apoptosis, NETosis, necroptosis, and pyroptosis, contribute to the release of damage-associated molecular patterns (DAMPs) and autoantigens, resulting in triggering immunity and tissue damage in SLE. However, the role of autophagy in SLE pathogenesis is in dispute. This review briefly discusses different forms of programmed cell death pathways and lay particular emphasis on inflammatory cell death pathways such as NETosis, pyroptosis, and necroptosis and their roles in the inflammatory and immune responses in SLE.

Pyroptosis is a critical inflammatory pathway in the placenta from early onset preeclampsia and in human trophoblasts exposed to hypoxia and endoplasmic reticulum stressors

Systemic manifestation of preeclampsia (PE) is associated with circulating factors, including inflammatory cytokines and damage-associated molecular patterns (DAMPs), or alarmins. However, it is unclear whether the placenta directly contributes to the increased levels of these inflammatory triggers. Here, we demonstrate that pyroptosis, a unique inflammatory cell death pathway, occurs in the placenta predominantly from early onset PE, as evidenced by elevated levels of active caspase-1 and its substrate or cleaved products, gasdermin D (GSDMD), IL-1β, and IL-18. Using cellular models mimicking pathophysiological conditions (e.g., autophagy deficiency, hypoxia, and endoplasmic reticulum (ER) stress), we observed that pyroptosis could be induced in autophagy-deficient human trophoblasts treated with sera from PE patients as well as in primary human trophoblasts exposed to hypoxia. Exposure to hypoxia elicits excessive unfolded protein response (UPR) and ER stress and activation of the NOD-like receptor pyrin-containing 3 (NLRP3) inflammasome in primary human trophoblasts. Thioredoxin-interacting protein (TXNIP), a marker for hyperactivated UPR and a crucial signaling molecule linked to NLRP3 inflammasome activation, is significantly increased in hypoxia-treated trophoblasts. No evidence was observed for necroptosis-associated events. Importantly, these molecular events in hypoxia-treated human trophoblasts are significantly observed in placental tissue from women with early onset PE. Taken together, we propose that placental pyroptosis is a key event that induces the release of factors into maternal circulation that possibly contribute to severe sterile inflammation and early onset PE pathology.

ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis).

Cell death is central to development, organismal homeostasis, and immune responses. The cell death field has experienced tremendous progress by delineating the molecular programs specific to each of the apoptotic and inflammatory cell death pathways. Moreover, the discovery of the inflammasomes and pyroptosis and necroptosis pathway regulators have provided the genetic basis for the programmed inflammatory cell death pathways. Earlier research highlighted the unique regulation of each of these pathways, but emerging studies discovered co-regulation and crosstalk between these seemingly different cell death complexes. The progress in this area has led to an idea that master regulators play central roles in orchestrating multiple cell death pathways. Here, we provide a brief review of the master regulators, the innate immune sensor ZBP1 and the essential cell survival kinase TAK1, that play vital roles in the regulation of RIPK1/RIPK3–FADD–caspase-8 cell death complex assembly and its versatility in executing Pyroptosis, Apoptosis, and Necroptosis, which we dubbed here as PAN-optosis. Furthermore, we discuss the implications and therapeutic potential of targeting these master regulators in health and disease.One Sentence SummaryZBP1 and TAK1 regulate PAN-optosis.

Culling of APCs by inflammatory cell death pathways restricts TIM3 and PD-1 expression and promotes the survival of primed CD8 T cells.

We evaluated the impact of premature cell death of antigen-presenting cells (APCs) by Caspase-1- and RipK3-signaling pathways on CD8+ T-cell priming during infection of mice with Salmonella typhimurium (ST). Our results indicate that Caspase1 and RipK3 synergize to rapidly eliminate infected APCs, which does not influence the initial activation of CD8+ T cells. However, the maintenance of primed CD8+ T cells was greatly compromised when both these pathways were disabled. Caspase-1- and RipK3-signaling did not influence NF-κB signaling in APCs, but synergized to promote processing of IL-1 and IL-18. Combined deficiency of Caspase1 and RipK3 resulted in compromised innate immunity and accelerated host fatality due to poor processing of IL-18. In contrast, synergism in cell death by Caspase-1- and RipK3 resulted in restriction of PD-1 and TIM3 expression on primed CD8+ T cells, which promoted the survival of activated CD8+ T cells.

Necrotic liver induces pyroptosis through caspase-1 in eosinophils.

Abstract During sterile inflammatory reactions, damage associated molecular patterns (DAMPS) are released from necrotic cells and recruit immune cells to the sites of tissue injury. We found that necrotic liver homogenates, when injected intraperitoneally, can recruit large numbers of immune cells. Among these immune cells were activated eosinophils. While eosinophils are well known to accumulate in the lungs of asthmatics or in response to helminths and parasites, several studies have shown the presence of eosinophils in liver biopsies of drug-induced liver injury, primary biliary cirrhosis, chronic hepatitis C, hepatic allograft rejection, and liver fibrosis. The prevalence of eosinophilic infiltrates in the liver points to a correlation between infiltration and disease outcome. Our results demonstrated eosinophil activation upon exposure to necrotic liver components. Exposure to necrotic liver cells induced eosinophil degranulation as measured by expression of CD107a and eosinophil peroxidase release into the supernatant as measured by ELISA. Further study of eosinophil activation during necrotic liver exposure showed IL-1β and IL-18 release as well as cell death. All of these responses were dependent upon caspase-1 activation. Caspase-1 mediated cell death accompanied by IL-1β and IL-18 release are hallmarks of pyroptosis, an inflammatory cell death pathway. We verified eosinophil pyroptosis in vivo using a liver fibrosis model involving Schistosoma mansoni infected mice. Eosinophils extracted from S. mansoni infected livers showed caspase-1 activation and cytokine release indicating that these cells undergo pyroptosis in vivo in response to hepatocyte injury.

Necrotic liver induces pyroptosis through Caspase-1 in eosinophils

Abstract During sterile inflammatory reactions damage associated molecular patterns (DAMPS) are released from necrotic cells and recruit immune cells to the sites of tissue injury. We found that necrotic liver homogenates, when injected intraperitoneally, can recruit large numbers of immune cells. Among these immune cells were activated eosinophils. Eosinophils are polymorphonuclear leukocytes typically found within tissues of the gastrointestinal and respiratory tracts. While eosinophils are well known to accumulate in the lungs of asthmatics or in response to helminths and parasites, several studies have shown the presence of eosinophils in liver biopsies of drug-induced liver injury, chronic hepatitis C and liver fibrosis. The prevalence of eosinophilic infiltrates in the liver points to a correlation between infiltration and disease outcome. Our results demonstrated eosinophil activation upon exposure to necrotic liver components. Exposure to necrotic liver cells induced eosinophil degranulation as measured by expression of CD107a and eosinophil peroxidase release as measured by ELISA. Further study of eosinophil activation during necrotic liver exposure showed IL-1β and IL-18 release as well as cell death. All of these responses were dependent upon caspase-1 activation. Caspase-1 mediated cell death accompanied by IL-1β and IL-18 release are hallmarks of pyroptosis, an inflammatory cell death pathway. We verified eosinophil pyroptosis in vivo using a liver fibrosis model involving Schistosoma mansoni infected mice. Eosinophils extracted from S. mansoni infected livers showed caspase-1 activation and cytokine release indicating that these cells undergo pyroptosis in vivo in response to hepatocyte injury.

Evasion of inflammasome activation by microbial pathogens.

Activation of the inflammasome occurs in response to infection with a wide array of pathogenic microbes. The inflammasome serves as a platform to activate caspase-1, which results in the subsequent processing and secretion of the proinflammatory cytokines IL-1β and IL-18 and the initiation of an inflammatory cell death pathway termed pyroptosis. Effective inflammasome activation is essential in controlling pathogen replication as well as initiating adaptive immune responses against the offending pathogens. However, a number of pathogens have developed strategies to evade inflammasome activation. In this Review, we discuss these pathogen evasion strategies as well as the potential infectious complications of therapeutic blockade of IL-1 pathways.

Cytosolic flagellin-induced lysosomal pathway regulates inflammasome-dependent and independent macrophage responses (P4141)

Abstract NAIP5/NLRC4 inflammasome activation by cytosolic flagellin results in caspase-1-mediated processing and secretion of IL-1β/IL-18 and pyroptosis, an inflammatory cell death pathway. Here, we found that although NLRC4, ASC and caspase-1 are required for IL-1β secretion in response to cytosolic flagellin, cell death nevertheless occurs in the absence of these molecules. Cytosolic flagellin-induced inflammasome-independent cell death was accompanied by IL-1α secretion and was temporally correlated with the restriction of S. Typhimurium infection. Despite displaying some apoptotic features, this peculiar form of cell death did not require caspase activation but was regulated by a lysosomal pathway, in which cathepsin B and cathepsin D play redundant roles. Moreover, cathepsin B contributed to NAIP5/NLRC4-inflammasome-induced pyroptosis, and IL-1α and IL-1β production in response to cytosolic flagellin. Together, our data describe a novel pathway induced by cytosolic flagellin that induces a peculiar form of cell death and regulates inflammasome-mediated effector mechanisms of macrophages.